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nyse:abbv
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AbbVie
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Apr 26th, 2022 12:00AM
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Oct 1st, 2020 12:00AM
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https://www.uspto.gov?id=US11312668-20220426
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Organic reactions carried out in aqueous solution in the presence of a hydroxyalkyl(alkyl)cellulose or an alkylcellulose
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The present invention relates to a method of carrying out an organic reaction in aqueous solution in the presence of a hydroxyalkyl(alkyl)cellulose or an alkylcellulose.
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11312668
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1. A method of carrying out an organic reaction in a solvent containing at least 90% by weight, based on the total weight of the solvent, of water, which method comprises reacting the reagents in said solvent in the presence of a cellulose derivative as a surfactant which is selected from the group consisting of cellulose modified with one or more alkylene oxides or other hydroxyalkyl precursors, and alkylcellulose; where the organic reaction is not a polymerization or oligomerization reaction of olefinically unsaturated compounds; and
where the organic reaction is
a transition metal catalyzed reaction in which a transition metal catalyst is used; where the transition metal catalyzed reaction is
a transition metal catalyzed C—C coupling reaction;
a transition metal catalyzed reaction involving C—N bond formation which is an Au-catalyzed cyclodehydratization of α,β-amino alcohols containing a C—C triple bond;
a transition metal catalyzed reaction involving C—O bond formation;
a transition metal catalyzed reaction involving C—S bond formation;
a transition metal catalyzed reaction involving C—B bond formation; or
a transition metal catalyzed reaction involving C-halogen bond formation; or
a C—C coupling reaction not requiring transition metal catalysis which is selected from the group consisting of reactions of carbonyl or nitrile compounds and pericyclic reactions;
a nucleophilic substitution reaction;
a reduction or an oxidation reaction; or
an ester formation reaction or an ester hydrolysis reaction.
2. The method as claimed in claim 1, where the cellulose derivative has a viscosity of from 1 to 150000 mPa·s, determined as a 2% by weight aqueous solution, relative to the weight of water.
3. The method as claimed in claim 1, where in the cellulose derivative 5 to 70% of the hydrogen atoms in the hydroxyl groups of the cellulose on which the cellulose derivative is based are replaced by a hydroxyalkyl and/or alkyl group.
4. The method as claimed in claim 1, where the cellulose modified with one or more alkylene oxides or other hydroxyalkyl precursors is selected from the group consisting of hydroxyalkylcelluloses which are celluloses in which a part of the hydrogen atoms of the OH groups is replaced by a C2-C4-hydroxyalkyl group; hydroxyalkylalkylcelluloses which are celluloses in which a part of the hydrogen atoms of the OH groups is replaced by a C2-C4-hydroxyalkyl group and a part of the hydrogen atoms of the OH groups is replaced by a C1-C3-alkyl group; and alkylcelluloses which are celluloses in which a part of the hydrogen atoms of the OH groups is replaced by a C1-C3-alkyl group.
5. The method as claimed in any claim 4, where the cellulose derivative is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose, methylcellulose and ethylcellulose.
6. The method as claimed in claim 5, where the cellulose derivative is hydroxypropylmethylcellulose.
7. The method as claimed in claim 1, where the cellulose derivative is used in an amount of from 0.01 to 15% by weight, based on the weight of the solvent, or, alternatively, based on the weight of water.
8. The method as claimed in claim 1, where the weight ratio of the cellulose derivative and all reagents is from 1:1 to 1:200.
9. The method as claimed in claim 1, where at least one of the reagents has a water solubility of at most 100 g per 1 l of water at 20° C.+/−20% and 101325 Pascal+/−20%.
10. The method as claimed in claim 1, where the organic reaction is a transition metal catalyzed reaction in which a transition metal catalyst is used.
11. The method as claimed in claim 10, where the transition metal catalyst is not a catalyst supported on the cellulose derivative.
12. The method as claimed in claim 10, where the transition metal is selected from the group consisting of Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, and Zn.
13. The method as claimed in claim 1, where the transition metal catalyzed C—C-coupling reaction is selected from the group consisting of the Suzuki-Miyaura reaction, Negishi coupling, Heck reaction, C—C coupling reactions involving C—H activation different from Heck reaction, Sonogashira coupling, Stille coupling, Grubbs olefin metathesis, 1,4 additions of organoborane compounds to α,β-olefinically unsaturated carbonyl compounds, Kumada coupling, Hiyama coupling, Ullmann reactions, Glaser coupling inclusive the Eglinton and the Hay coupling, Cadiot-Chodkiewicz coupling, the Fukuyama coupling, hydroformylation and cyclopropanation.
14. The method as claimed in claim 13, where the transition metal catalyzed C—C-coupling reaction is a Suzuki-Miyaura reaction in which an organoboron compound is reacted with an organic halogenide or sulfonate in the presence of a transition metal catalyst and optionally a base;
where the organoboron compound is a compound of formula R1—BY2, where R1 is an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl group and Y is an alkyl, O-alkyl or hydroxyl group, or the two substituents Y form together with the boron atom they are bound to a mono-, bi- or polycyclic ring; or the organoboron compound is a compound of formula R1—BF3M, where M is a metal equivalent; and
the organic halogenide or sulfonate is a compound of formula R2—(Z)n, where R2 is an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl group, Z is a halogenide or sulfonate group, and n is 1, 2, 3 or 4;
where the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl groups R1 and R2 can carry one or more substituents.
15. The method as claimed in claim 13, where the transition metal catalyzed C—C-coupling reaction is a Sonogashira reaction, where an aryl, heteroaryl or vinyl halogenide or sulfonate is reacted with a terminal alkyne in the presence of a transition metal catalyst, optionally of a copper(I) salt, and optionally of a base;
where the aryl, heteroaryl or vinyl halogenide or sulfonate is a compound of formula R2—(Z)n, where R2 is a terminal alkenyl, aryl or heteroaryl group, Z is a halogenide or sulfonate group and n is 1, 2, 3 or 4;
the terminal alkyne is a compound of formula H—C≡C—R1, where R1 is hydrogen or an alkyl, alkenyl, alkapolyenyl, alkynyl (provided that the alkyne group is not terminal), alkapolyynyl (provided there is no terminal alkyne group in this radical), mixed alkenyl/alkynyl (provided there is no terminal alkyne group in this radical), cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl or silyl group Si(R14′)3,
where the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl and heteroaryl groups R1 and R2 can carry one or more substituents; and
where each R14′ is independently selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, and phenyl, optionally substituted with 1, 2, 3, 4, or 5 radicals selected from the group consisting of halogen, cyano, nitro, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy and C1-C6-haloalkoxy.
16. The method as claimed in claim 13, where the transition metal catalyzed C—C coupling reaction is a Heck reaction, where an aryl, heteroaryl, benzyl, vinyl or alkyl halogenide or sulfonate (the alkyl group must not contain any β-hydrogen atoms) is reacted with an olefinically unsaturated compound in the presence of a transition metal catalyst and optionally in the presence of a base;
where the aryl, heteroaryl, benzyl, vinyl or alkyl halogenide or sulfonate is a compound of the formula R2—(Z)n, where R2 is an aryl, heteroaryl, benzyl, vinyl or alkyl group, where the alkyl group must not contain any β-hydrogen atoms, Z is a halogen atom or a sulfonate group, and n is 1, 2, 3 or 4, and
the olefinically unsaturated compound is a compound of the formula R1(H)C═C(R3)(R4) where R1, R3, and R4, independently of each other, are selected from the group consisting of hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13, —Si(R14)3, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, where the five last-mentioned substituents may carry one or more substituents R15; aryl which may be substituted by one or more radicals R15; heterocyclyl which may be substituted by one or more radicals R15; and heteroaryl which may be substituted by one or more radicals R15; where
each R11 is independently selected from the group consisting of hydrogen, cyano, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, where the aliphatic and cycloaliphatic moieties in the 11 last-mentioned radicals may be partially or fully halogenated and/or may be substituted by one or more radicals R17,
-alkyl-C(═O)OR18, -alkyl-C(═O)N(R12a)R12b,
-alkyl-C(═S)N(R12a)R12b, -alkyl-C(═NR12)N(R12a)R12b,
—Si(R14)3, —S(O)mR18, —S(O)mN(R12a)R12b, —N(R12a)R12b, —N═C(R16)2,
—C(═O)R13, —C(═O)N(R12a)R12b, —C(═S)N(R12a)R12b, —C(═O)OR18,
aryl, optionally substituted with one or more substituents R15;
heterocyclyl, optionally substituted with one or more substituents R15; and
heteroaryl, optionally substituted with one or more substituents R15; and
R11 in the group —S(O)mR11 is additionally selected from the group consisting of alkoxy and haloalkoxy;
R12, R12a and R12b, independently of each other and independently of each occurrence, are selected from the group consisting of hydrogen, cyano, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, wherein the 11 last-mentioned aliphatic and cycloaliphatic radicals may be partially or fully halogenated and/or may be substituted by one or more substituents R19,
—OR20, —NR21aR21b, —S(O)mR20, —C(═O)N(R21aR21b), —C(═O)NR21N(R21aR21b), —Si(R14)3, —C(═O)R13,
aryl which may be substituted with 1, 2, 3, 4, or 5 substituents R15,
heterocyclyl which may be substituted with one or more substituents R15; and
heteroaryl which may be substituted with one or more substituents R15;
or R12a and R12b, together with the nitrogen atom to which they are bound, form a saturated, partially unsaturated or maximally unsaturated heterocyclic or heteroaromatic ring, where the ring may further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from the group consisting of O, S, N, SO, SO2, C═O and C═S as ring members, wherein the heterocyclic or heteroaromatic ring may be substituted with 1, 2, 3, 4 or 5 independent R15 substituents;
or R12a and R12b together form a group ═C(R22)2, ═S(O)m(R20)2, ═NR21a or ═NOR20;
each R13 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, where the aliphatic and cycloaliphatic moieties in the 11 last-mentioned radicals may be partially or fully halogenated and/or may be substituted by one or more radicals R17; aryl, optionally substituted with one or more radicals R15; heterocyclyl, optionally substituted with one or more radicals R15; heteroaryl, optionally substituted with one or more radicals R15; OR20, —S(O)mR20, —N(R21a)R21b, —C(═O)N(R21a)R21b,
—C(═S)N(R21a)R21b and —C(═O)OR20;
each R14 is independently selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, and phenyl, optionally substituted with 1, 2, 3, 4, or 5 radicals R15;
each R15 is independently selected from the group consisting of halogen, azido, nitro, cyano, —OH, —SH, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, —Si(R23)3;
C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkapolyenyl, C2-C20-alkynyl, C2-C20-alkapolyynyl, mixed C2-C20-alkenyl/alkynyl, wherein the six last-mentioned aliphatic radicals may be partially or fully halogenated and/or may carry one or more radicals selected from the group consisting of OH, C1-C20-alkoxy, C1-C20-haloalkoxy, SH, C1-C20-alkylthio, C1-C20-haloalkylthio, C1-C20-alkylsulfinyl, C1-C20-haloalkylsulfinyl, C1-C20-alkylsulfonyl, C1-C20-haloalkylsulfonyl, —Si(R23)3, oxo, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, C8-C20-cycloalkynyl, mixed C3-C20-cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl and heteroaryl, wherein the 8 last-mentioned cyclic radicals may in turn be partially or fully halogenated and/or may carry one or more radicals selected from the group consisting of OH, C1-C20-alkoxy, C1-C20-haloalkoxy, SH, C1-C20-alkylthio, C1-C20-haloalkylthio, C1-C20-alkylsulfinyl, C1-C20-haloalkylsulfinyl, C1-C20-alkylsulfonyl, C1-C20-haloalkylsulfonyl, —Si(R23)3, oxo, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, C8-C20-cycloalkynyl, mixed C3-C20-cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl and heteroaryl, wherein the 8 last mentioned radicals may in turn be unsubstituted, partially or fully halogenated and/or carry 1, 2 or 3 substituents selected from the group consisting of cyano, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl;
C3-C8-cycloalkyl, C3-C8-cycloalkenyl, C8-C20-cycloalkynyl, mixed C3-C20-cycloalkenyl/cycloalkynyl, polycarbocyclyl, wherein the 5 last-mentioned cycloaliphatic radicals may be partially or fully halogenated and/or may carry one or more radicals selected from the group consisting of cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and oxo;
aryl, O-aryl, heterocyclyl, O-heterocyclyl, heteroaryl and O-heteroaryl, wherein the cyclic moieties in the 6 last mentioned radicals may be unsubstituted, partially or fully halogenated and/or carry 1, 2 or 3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl;
or
two R15 present together on the same atom of an unsaturated or partially unsaturated ring may be ═O, ═S, ═N(C1-C6-alkyl), ═NO(C1-C6-alkyl), ═CH(C1-C4-alkyl) or ═C(C1-C4-alkyl)C1-C4-alkyl;
or
two R15 on two adjacent carbon or nitrogen atoms form together with the carbon or nitrogen atoms they are bonded to a 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated, including heteroaromatic, ring, wherein the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members, and wherein the ring optionally carries one or more substituents selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;
each R16 is independently selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl and C2-C6-haloalkynyl, wherein the six last-mentioned aliphatic radicals may carry 1 or 2 radicals selected from the group consisting of CN, C3-C4-cycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and oxo;
each R17 is independently selected from the group consisting of cyano, nitro,
—OH, —SH, —SCN, —SF5, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, —Si(R14)3,
C3-C8-cycloalkyl which may be unsubstituted, partially or fully halogenated and/or may carry 1 or 2 radicals selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and oxo;
aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy, where the cyclic moiety in the 6 last-mentioned radicals may be unsubstituted, partially or fully halogenated and/or carry 1, 2, 3, 4 or 5 substituents R15; or
two R17 present on the same carbon atom (of an alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl or mixed alkenyl/alkynyl group) may together be ═O, ═CH(C1-C4-alkyl), ═C(C1-C4-alkyl)C1-C4-alkyl, ═N(C1-C6-alkyl) or ═NO(C1-C6-alkyl);
and
R17 as a substituent on a cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl or polycarbocyclyl ring is additionally selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, wherein the three last-mentioned aliphatic radicals may be unsubstituted, partially or fully halogenated and/or may carry 1 or 2 substituents selected from the group consisting of CN, C3-C4-cycloalkyl, C3-C4-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and oxo;
each R18 is independently selected from the group consisting of hydrogen, cyano, —Si(R14)3, C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, wherein the three last-mentioned aliphatic radicals may be unsubstituted, partially or fully halogenated and/or may carry 1 or 2 radicals selected from the group consisting of C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C20-alkoxy, C1-C20-haloalkoxy, C1-C20-alkylthio, C1-C20-haloalkylthio, C1-C20-alkylsulfinyl, C1-C20-haloalkylsulfinyl, C1-C20-alkylsulfonyl, C1-C20-haloalkylsulfonyl and oxo;
C3-C8-cycloalkyl which may be unsubstituted, partially or fully halogenated and/or may carry 1 or 2 radicals selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, C3-C4-cycloalkyl, C3-C4-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, C1-C4-haloalkylthio, C1-C4-alkylsulfinyl, C1-C4-haloalkylsulfinyl, C1-C4-alkylsulfonyl, C1-C4-haloalkylsulfonyl and oxo;
aryl, heterocyclyl and heteroaryl, wherein the 3 last-mentioned radicals may be unsubstituted, partially or fully halogenated and/or carry 1, 2 or 3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl; and
R18 in the group S(O)mR18 is additionally selected from the group consisting of C1-C6-alkoxy, C1-C6-haloalkoxy, aryloxy, heterocyclyloxy and heteroaryloxy;
each R19 is independently selected from the group consisting of halogen, nitro, cyano, —OH, —SH, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, Si(R14)3;
C3-C8-cycloalkyl, C3-C8-halocycloalkyl, wherein the two last-mentioned cycloaliphatic radicals may carry one or more radicals selected from the group consisting of cyano, C1-C4-alkyl, C1-C4-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and oxo;
aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy, wherein the 6 last mentioned radicals may be unsubstituted, partially or fully halogenated and/or carry 1, 2 or 3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl;
each R20 is independently defined as R18;
R21, R21a and R21b, independently of each other and independently of each occurrence, are selected from the group consisting of hydrogen, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, wherein the four last-mentioned aliphatic and cycloaliphatic radicals may be partially or fully halogenated,
aryl, aryl-C1-C4-alkyl, heterocyclyl, and heteroaryl, where the rings in the 4 last mentioned radicals may be substituted with 1, 2, 3, 4, or 5 substituents R15;
or R21a and R21b, together with the nitrogen atom to which they are bound, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic, inclusive heteroaromatic, ring, where the ring may further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from the group consisting of O, S, N, SO, SO2, C═O and C═S as ring members, wherein the heterocyclic ring may be substituted with 1, 2, 3, 4 or 5 independent R15 substituents;
each R22 is independently defined as R16;
each R23 is independently selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, and phenyl, optionally substituted with 1, 2, 3, 4, or 5 radicals selected from the group consisting of halogen, cyano, nitro, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy and C1-C6-haloalkoxy; and
m is 0, 1 or 2;
where the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl and mixed alkenyl/alkynyl groups R1, R3 and R4, and the aryl, heteroaryl, benzyl, vinyl and alkyl groups R2 can carry one or more substituents.
17. The method as claimed in claim 13, where the transition metal catalyzed C—C-coupling reaction is a C—C coupling reaction involving C—H activation in which an aromatic or heteroaromatic halogenide or sulfonate is coupled with an aromatic or heteroaromatic compound in the presence of a transition metal catalyst and in case that an aromatic or heteroaromatic chloride, bromide or iodide is used, optionally also in the presence of a water-soluble silver(I) salt;
where the aromatic or heteroaromatic halogenide or sulfonate is a compound of formula R2—Z, where R2 is an aryl or heteroaryl group, Z is a halogen atom or a sulfonate group, and the aromatic or heteroaromatic is a compound of formula R1—H, where R1 is an aryl or heteroaryl group,
where the aryl and heteroaryl groups R1 and R2 can carry one or more substituents.
18. The method as claimed in claim 13, where the transition metal catalyzed C—C-coupling reaction is a Stille reaction, where an organotin compound (organostannane) is reacted with an alkenyl, aryl, heteroaryl or acyl halide, sulfonate or phosphate in the presence of a transition metal catalyst and optionally also in the presence of a base,
where the organostannane compound is a compound of the formula R1—Sn(Ra)3, where R1 is a an alkenyl, aryl or heteroaryl group and Ra is an alkyl group, and
the alkenyl, aryl, heteroaryl or acyl halide, sulfonate or phosphate is a compound of the formula R2—(Z)n, where R2 is an alkenyl, aryl, heteroaryl or acyl group, Z is a halogen atom, a sulfonate group or a phosphate group, and n is 1, 2, 3 or 4,
where the alkenyl, aryl and heteroaryl groups R1 and R2 can carry one or more substituents.
19. The method as claimed in claim 13, where the transition metal catalyzed C—C-coupling reaction is a Negishi reaction.
20. The method as claimed in claim 13, where the transition metal catalyzed C—C-coupling reaction is a Grubbs olefin metathesis, where two olefinic compounds R1R2C═CR3R4 and R5R6C═CR7R8 are reacted with each other in the presence of a Grubbs catalyst,
where R1, R2, R3, R4, R5, R6, R7 and R8, independently of each other, are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, hetaryl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13 and —Si(R14)3; where R11, R12a, R12b, R13 and R14 are independently as defined in claim 17;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl and heteroaryl groups R1, R2, R3, R4, R5, R6, R7 and R8 can carry one or more substituents.
21. The method as claimed in claim 13, where the transition metal catalyzed C—C coupling reaction is a 1,4-addition of an organoborane compound to an α,β-olefinically unsaturated carbonyl compound in the presence of a transition metal catalyst, where the organoboron compound is a compound of formula R1—BY2, where R1 is an alkyl, alkenyl, alkynyl, aryl or heteroaryl group and Y is an alkyl, O-alkyl or hydroxyl group, or the two substituents Y form together with the boron atom they are bound to a mono-, bi- or polycyclic ring; or the organoboron compound is a compound of formula R1—BF3M, where M is a metal equivalent, and
the α,β-olefinically unsaturated carbonyl compound is a compound of formula R2R3C═CR4—C(═O)—R5, where R2, R3 and R4, independently of each other, are hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and R5 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, OH, SH, alkoxy, alkylthio, NH2, alkylamino or dialkylamino,
where the alkyl (also as part of alkoxy, alkylthio, alkylamino or dialkylamino), alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups R1, R2, R3, R4 and R5 can carry one or more substituents.
22. The method as claimed in claim 13, where the transition metal catalyzed C—C-coupling reaction is a cyclopropanation, where an olefinically unsaturated compound is reacted with a diazo compound in the presence of a transition metal catalyst, where the olefinically unsaturated compound is a compound of formula R1R2C═CR3R4 and the diazo compound is a compound of formula N2═CR5R6, where R1, R2, R3, R4, R5 and R6, independently of each other, are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, hetaryl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13 and —Si(R14)3; where R11, R12a, R12b, R13 and R14 are independently as defined in claim 17;
where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl and heteroaryl groups R1, R2, R3, R4, R5 and R6 can carry one or more substituents.
23. The method as claimed in claim 1, where the transition metal catalyzed reaction is a transition metal catalyzed reaction involving C—O bond formation, where the transition metal catalyzed reaction involving C—O bond formation is an Au-catalyzed cyclodehydratization of alkyne diols, an Au-catalyzed cyclization of alkynenols, an Au-catalyzed cyclization of alkynones, an Au-catalyzed cyclization of allenones, or is the formation of alcohols or ethers via C—O coupling.
24. The method as claimed in claim 23, where the transition metal catalyzed reaction involving C—O bond formation is an Au-catalyzed cyclodehydratization of an alkyne (I) carrying in α- and β-position to the alkyne group two OH groups to the corresponding furane (II):
where R1, R2 and R3 are independently of each other H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl,
where the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl groups R1, R2 and R3 can carry one or more substituents.
25. The method as claimed in claim 23, where the transition metal catalyzed reaction involving C—O bond formation is the formation of alcohols or ethers via C—O coupling,
where an aromatic or heteroaromatic compound R1—X, where R1 is an aryl or heteroaryl group and X is a halogen atom or a pseudohalide group, is reacted with a metal hydroxide to yield an alcohol R1—OH; or is reacted with a hydroxyl compound R2—OH, where R2 is alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl, to yield an ether R1—O—R2,
where the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl groups R1 and R2 can carry one or more substituents.
26. The method as claimed in claim 1, where the transition metal catalyzed reaction is a transition metal catalyzed reaction involving C—B bond formation, where the transition metal catalyzed reaction involving C—B bond formation is a Miyaura borylation,
where a halogenide or sulfonate R2—(Z)n, where R2 is an alkenyl, aryl or heteroaryl group, Z is a halogenide or sulfonate group and n is 1, 2, 3 or 4, is reacted with a tetraalkoxydiboron (R1O)2B—B(OR1)2, where R1 is alkyl or two R1 bound on oxygen atoms bound in turn to the same B atom form together —C(CH3)3—C(CH3)2— (so that B(OR1)2 is the pinacolon ester of boronic acid), in the presence of a transition metal catalyst, and optionally also of a base, where the alkyl, alkenyl, aryl or heteroaryl groups R1 and R2 can carry one or more substituents.
27. The method as claimed in claim 1, where the transition metal catalyzed reaction is a transition metal catalyzed reaction involving C-halogen bond formation, in which an aromatic or heteroaromatic compound R1—H, where R1 is aryl or heteroaryl, is reacted with a halogenating agent in the presence of a transition metal catalyst, to yield a compound R1—X, where X is a halogen atom,
where the aryl or heteroaryl group R1 can carry one or more substituents.
28. The method as claimed in claim 1, where the organic reaction is a C—C coupling reaction not requiring transition metal catalysis, and is selected from the group consisting of reactions of carbonyl or nitrile compounds and pericyclic reactions.
29. The method as claimed in claim 28, where the C—C coupling reaction not requiring transition metal catalysis is a Wittig reaction in which a phosphorous ylene or ylide (I) is reacted with a carbonyl compound (II) to an olefinically unsaturated compound (III) and a phosphorus oxide (IV)
where
R1 is an aryl group;
R2 and R3, independently of each other, are hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, CN, C(O)R13, C(S)R13 or S(O)2R11, where R11 and R13 are as defined in claim 17; and
R4 and R5 are independently of each other hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl;
where the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl and heteroaryl groups R1, R2, R3, R4 and R5 can carry one or more substituents.
30. The method as claimed in claim 28, where the C—C coupling reaction not requiring transition metal catalysis is a Diels-Alder reaction in which a conjugated diene is reacted with a dienophile to a cyclohexene derivative.
31. The method as claimed in claim 28, where the C—C coupling reaction not requiring transition metal catalysis is a Baylis-Hillman reaction in which an α,β-olefinically unsaturated carbonyl compound (I) is reacted with an aldehyde or an activated ketone or derivative thereof (II) in the presence of a nucleophilic catalyst and optionally in the presence of a metal-derived Lewis acid to a compound (III):
or in which α,β-olefinically unsaturated nitrile (IV) compound is reacted with a an aldehyde or an activated ketone or derivative thereof (II) in the presence of a nucleophilic catalyst and optionally in the presence of a metal-derived Lewis acid to a compound (V):
where R1, R2 and R3 are independently of each other H, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl, or R1 and R2 form together with the carbon atom they are bound to a carbocyclic or heterocyclic ring;
X is OR or N(R)2, where R is H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
Y is O or N substituted with an electron-withdrawing group, and
the nucleophilic catalyst is selected from the group consisting of tertiary amines and tertiary phosphines;
where the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl and heteroaryl groups R1, R2, R3 and R can carry one or more substituents.
32. The method as claimed in claim 1, where the organic reaction is a nucleophilic substitution reaction, where a compound R1—X is reacted with an alcohol R2—OH, a thiol R2—SH, a primary amine R3NH2 or a secondary amine R3(R4)NH to a compound R1—O—R2, R1—S—R2, R1—NH—R3 or R1—N(R4)—R3, or a compound R1(X)2 is reacted with a primary amine R3NH2 to a cyclic compound;
where R1, R2, R3 and R4, independently of each other, are an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl group; and
X is a halogenide or sulfonate group;
where the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl groups R1, R2, R3 and R4 can carry one or more substituents.
33. The method as claimed in claim 1, where the organic reaction is a nucleophilic aromatic substitution reaction, where a compound R1—X is reacted with an alcohol R2—OH, a thiol R2—SH, a primary amine R3NH2 or a secondary amine R3(R4)NH, where R1 is a mono-, bi- or polycyclic aryl or heteroaryl group;
X is a halide, and
R2, R3 and R4 are independently of each other an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl group,
where the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups R1, R2, R3 and R4 can carry one or more substituents.
34. The method as claimed in claim 1, where the organic reaction is the reduction of nitro compounds to the corresponding amino compounds via reduction with a base metal, optionally in acidic solution; with a metal hydride, with a complex hydride, or with a borane; or via catalytic hydrogenation.
35. The method as claimed in claim 34, where an aromatic or heteroaromatic nitro compound R1—NO2, where R1 is a mono-, bi- or polycyclic aryl or heteroaryl group, is reduced with Zn or Fe in acidic solution; or is reduced via catalytic hydrogenation in the presence of a hydrogenation catalyst, where the hydrogenation catalyst comprises at least one metal of group VIII and/or VIIa selected from the group consisting of ruthenium, cobalt, rhodium, nickel, palladium, platinum and rhenium, where the hydrogenation catalyst is a heterogeneous hydrogenation catalyst in which the metal is used in finely divided form, as a metal sponge or as a supported catalyst, or where the catalyst is a homogeneous hydrogenation catalysts;
where the aryl or heteroaryl group R1 can carry one or more substituents.
36. The method as claimed in claim 1, where the organic reaction is the reduction of C—C double bonds.
37. The method as claimed in claim 1, where the organic reaction is a reductive amination, where a primary or secondary amine is reacted with an aldehyde or ketone in the presence of a reduction agent to an amino compound.
38. The method as claimed in claim 1, which is additionally carried out in the presence of a surfactant different from the cellulose derivative as defined in claim 1, where the surfactant is selected from the group consisting of anionic, cationic, nonionic and amphoteric surfactants, block polymers, polyelectrolytes, and mixtures thereof.
39. The method as claimed in claim 38, where the surfactant is a polyoxyethanyl-α-tocopheryl succinate derivative.
40. The method as claimed in claim 1, where after completion of the organic reaction the cellulose derivative is precipitated by heating or by adding an inorganic salt, where the inorganic salt is selected from the group consisting of sodium sulfate, potassium sulfate, magnesium sulfate, ammonium sulfate, sodium phosphate, potassium phosphate, sodium hydrogenphosphate, potassium hydrogenphosphate and sodium chloride; where precipitation of the cellulose derivative can be carried out before or after removing the reaction product and, if present, unreacted starting compounds, and where the precipitated cellulose derivative, after a reactivation step, can be reused in the method as claimed in claim 1.
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40
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 16/742,523, filed Jan. 14, 2020, which is a continuation of U.S. patent application Ser. No. 16/434,900, filed Jun. 7, 2019, which is a continuation of U.S. patent application Ser. No. 15/417,806, filed Jan. 27, 2017, which claims the benefit of U.S. Patent Application No. 62/288,890, filed Jan. 29, 2016, and International Patent Application No. PCT/EP2016/053238, filed Feb. 16, 2016, the contents of all of which are fully incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to a method of carrying out an organic reaction in aqueous solution in the presence of a hydroxyalkyl(alkyl)cellulose or an alkylcellulose.
BACKGROUND OF THE INVENTION
With the growing concern for environmental protection, chemical synthesis and process chemistry are increasingly scrutinized with respect to sustainability. The term “green chemistry” illustrates the goal to provide a more resource-efficient and inherently safer design of molecules, materials, products, and processes. One goal is to provide chemical processes which minimize the use of substances which do not origin from renewable sources and/or cause disposal problems. Especially reducing or avoiding the use of organic solvents is the primary objective, as these account for the major part of the feedstock used in many chemical processes. Most organic solvents are of mineral origin and thus not from a renewable source. They are rather expensive, not only because of their production costs, but also because of the costs related with their disposal. They often pose significant risks to the environment and humans handling them, being mostly flammable or even explosive, and need to be handled and stored with precaution.
Many efforts have therefore been made to replace at least a part of the organic solvents with water. Water is readily available, cheap, neither flammable nor explosive, and non-toxic. Unfortunately however, it has only poor solubility for most organic compounds, so that reaction times and yields are generally inefficient. Many reactants agglomerate in aqueous medium, which hampers their efficient reaction and makes their processing, especially stirring, difficult.
To enhance conversion rates and reduce reaction times in aqueous medium, surfactants and emulsifiers are often used.
Lipshutz and coworkers developed surfactants based on polyoxyethanyl-α-tocopheryl succinate (TPGS-750-M and TPGS-1000) or sebacate (PTS-600) which in aqueous solution forms micelles in which organic reactions can take place. TPGS-750-M, which is the most promising, is a polyoxyethanyl-α-tocopheryl succinate derivative of following formula:
The use of these micelle-forming surfactants is described, for example, in J. Org. Chem., 2011, 76 (11), 4379-4391 or Green Chem. 2014, 16, 3660-3679, where the authors report the performance of various reactions, including Heck, Suzuki-Miyaura, Sonogashira, and Negishi-like couplings, as well as aminations, C—H activations, and olefin metathesis reactions in water in the presence of TPGS-750-M.
While the results obtained with this surfactant are impressive, TPGS-750-M as well as the other polyoxyethanyl-α-tocopheryl derivatives are a rather expensive and sophisticated material. Moreover, they tend to agglomerate in the aqueous reaction medium, which hampers the efficient reaction of the reactants and makes their processing, especially stirring, difficult.
Cellulose and its derivatives are inexpensive and biodegradable. Organic reactions in water catalyzed by a transition metal and carried out in the presence of cellulosic material have been reported.
Cellulose as such is not water-soluble or swellable and thus cannot act as a surfactant. It is used as carrier for transition metal catalysts; see for example
Baruah et al., Catalysis Commun. 2015, 69, 68-71, where cellulose-supported copper nanoparticles are used as a catalyst for the protodecarboxylation and oxidative decarboxylation of aromatic acids; water or acetonitrile being used as solvents;
Baruah et al., Tetrahedron Lett. 2015, 56, 2543-2547, where cellulose-supported copper nanoparticles are used as a catalyst for the selective oxidation of alcohols to aldehydes; water or acetonitrile being used as solvents;
Baruah et al., RSC Adv. 2014, 4, 59338-59343, where cellulose-supported copper nanoparticles are used as a catalyst for the deprotection of oximes, imines and azines to carbonyl; water being used as solvent;
Chavan et al., RSC Adv. 2014, 4, 42137-42146, where cellulose-supported CuI nanoparticles are used as a catalyst for the one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles in water; and
Jamwal et al., Internat. J. Biol. Macromolecules 2011, 49, 930-935, where cellulose-supported Pd(0) is used as a catalyst for Suzuki coupling and aerobic oxidation of benzyl alcohols in water.
Modified celluloses are also used as carriers for transition metal catalysts; see for example
Bhardwaj et al., where Pd(0) nanoparticles supported on ethylene diamine functionalized silica cellulose is used as a catalyst for C—C and C—S coupling reactions in water;
Faria et al., RSC Adv. 2014, 4, 13446-13452, where cellulose acetate-supported Pd(0) nanoparticles are used as a catalyst for Suzuki reactions in water,
Xiao et al., Appl. Organometal Chem. 2015, 29, 646-652, where carboxymethyl cellulose-supported Pd nanoparticles are used as a catalyst for Suzuki and Heck couplings in water;
Huang et al., Beilstein J. Org. Chem. 2013, 9, 1388-1396, where Au nanoparticles covalently bonded to thiol-functionalized nanocrystalline cellulose films are used as a catalyst for A3 coupling in water;
Keshipour et al., Cellulose 2013, 20, 973-980, where Pd(0) nanoparticles supported on ethylene diamine functionalized cellulose is used as a catalyst for Heck and Sonogashira couplings in water;
Harrad et al., Catalysis Commun. 2013, 32, 92-100, where colloidal Ni(0) carboxymethyl cellulose particles are used as a catalyst for hydrogenation of nitro aromatic compounds and carbonyl compounds in aqueous medium;
Zhang et al., Catal. Sci. Technol. 2012, 2, 1319-1323, where sodium carboxymethyl cellulose-stabilized Pd is used as a catalyst for the selective hydrogenation of acetylene in water;
Azetsu et al., Catalysis 2011, 1, 83-96, where Au/Pd bimetallic nanoparticles supported on TEMPO-oxidized cellulose nanofibers are used as a catalyst in the aqueous reduction of 4-nitrophenol; and
Lam et al., Nanoscale 2012, 4, 997, where Au nanoparticles supported on poly(diallyldimethylamoniumchloride)-coated nanocrystalline cellulose are used as a catalyst in the aqueous reduction of 4-nitrophenol.
These documents do however not use the modified celluloses as surfactants.
It was the object of the present invention to provide a surfactant which allows the performance of organic reactions in water with good yields and short reaction times, but which is less expensive than TPGS-750-M and the other polyoxyethanyl-α-tocopheryl derivatives described above, and which is readily available. Moreover, this surfactant should not be restricted to the application in transition metal-catalyzed reactions, but should be widely applicable. Furthermore, the surfactant should be easily separable from the reaction medium after completion of the reaction.
The present invention is based on the finding that hydroxyalkyl(alkyl)celluloses and alkylcelluloses solve this task.
SUMMARY OF THE INVENTION
The invention relates to a method of carrying out an organic reaction in a solvent containing at least 90% by weight, in particular at least 97% by weight, based on the total weight of the solvent, of water, which method comprises reacting the reagents in said solvent in the presence of a cellulose derivative which is selected from the group consisting of cellulose modified with one or more alkylene oxides or other hydroxyalkyl precursors, and alkylcellulose;
where the organic reaction is not a polymerization or oligomerization reaction of olefinically unsaturated compounds.
The invention also relates to the use of a cellulose derivative which is selected from the group consisting of cellulose modified with one or more alkylene oxides or other hydroxyalkyl precursors, and alkylcellulose, as a surfactant in organic reactions carried out in a solvent containing at least 90% by weight, in particular at least 97% by weight, based on the total weight of the solvent, of water,
where the organic reactions are not a polymerization or oligomerization reaction of olefinically unsaturated compounds.
DETAILED DESCRIPTION
The below remarks and details of suitable and preferred or particular embodiments of the method of the invention are valid both alone, taken per se, and in particular in any conceivable combination with one another.
“Carrying out an organic reaction in a solvent containing at least 90% by weight, in particular at least 97% by weight, based on the total weight of the solvent, of water” means that at least the principal reaction step of the organic reaction is carried out in said aqueous medium. The aqueous medium is not limited to be used in a work-up or purification or separation step.
Work-up, separation and purification can however encompass the use of organic solvents.
The term “organic reaction” relates to all types of chemical reactions involving at least one organic compound. Organic compounds in turn are gaseous, liquid, or solid chemical compounds whose molecules contain carbon. Exceptions are carbides, carbonates (in the sense of salts of carbonic acid), carbon oxides (CO and CO2), and cyanides (in the sense of salts of HCN), which for historical reasons are considered as inorganic. The basic types of organic reactions are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. Further details will become evident in the detailed description below.
In terms of the present invention, the organic reactions do not include polymerization or oligomerization reactions of olefinically unsaturated compounds, such as the polymerization of olefins (e.g. ethylene) to polyolefins (e.g. polyethylene), of acrylic acid (esters) to polyacrylates etc. In particular, in the present invention, the organic reactions do not include any type of polymerization or oligomerization, be it the polymerization of olefinically unsaturated molecules, polycondensations (like the formation of polyesters from diols and diacids or derivatives thereof, or of polyamides from diamines and diacids or derivatives thereof), or polyadditions (like the formation of polyurethanes). Polymerizations are reactions in which polymers are formed. Polymers in turn are high molecular mass compounds formed by polymerization of monomers and contain repeating units of the same or similar structure. In terms of the present invention, polymers are compounds formed of at least 11 monomers in polymerized form. Oligomers, too, are formed by polymerization of monomers and contain repeating units of the same or similar structure. They differ from polymers in being shorter-chained. In terms of the present invention, oligomers contain 3 to 10 monomers in polymerized form.
Organic reactions which do not include any polymerization or oligomerization reaction yield compounds with a discrete (i.e. well-defined) molar mass. In contrast thereto, oligomers and polymers do not have a discrete molar mass, but a mass distribution. The ratio of weight-average molecular weight and number average molecular weight Mw/Mn for polymers and oligomers is >1. Thus, the particular embodiment of the present method which excludes any type of polymerization or oligomerization, yields compounds with a well-defined molar mass, and not with a molar mass distribution.
Apart from not including polymerization and oligomerization reactions of olefinically unsaturated compounds and especially not including any type of polymerization and oligomerization reactions at all, one other limiting factor imposed to the organic reactions which can be used in the method of the present invention is reactants, intermediates and products which are too hydrolabile, i.e. which are too easily deteriorated (e.g. hydrolyzed) by water to give satisfactory yields (as compared to non-aqueous systems) under the given reaction conditions. Thus, the present method does not include organic reactions using or yielding compounds which are easily deteriorated by water under the given reaction conditions. It has has however to be noticed that not all reactions usually known to use or yield hydrolabile compounds are excluded: Surprisingly, the method of the invention leads to good yields in a number of reactions which a skilled person would normally have carried out under the exclusion of water. Another limiting factor imposed to the organic reactions which can be used in the method of the present invention is reaction temperatures distinctly below 0° C. (it has to be mentioned that the addition of salts such as NaCl may allow to carry out the reactions at temperatures somewhat below 0° C. as they lower the freezing point, e.g. to as low as −5° C. or even −10° C.) as well as above the gelling or gelation point of the cellulose derivative used (if this has a gelation point at all) under the respective reaction conditions (especially concentration of the cellulose derivative). When the solutions of certain cellulose derivatives heat up to a critical temperature, the solutions congeal into a non-flowable, semi-flexible mass and the reactions cannot proceed in an optimum way. Thus, the present method does not include organic reactions mandatorily and inevitably requiring reaction temperatures of distinctly below 0° C. (i.e. of below −10° C. or in particular of below −5° C. or specifically of below 0° C.) or above the gelling point of the cellulose derivative used (of course only if the respective cellulose derivative has a gelling point under the given reaction conditions, especially the concentration in which the cellulose derivative is used).
“Solvent” is a liquid substance that dissolves a solute (a chemically different liquid, solid or gas), resulting in a solution. In terms of the present invention, the solvent is not restricted to a compound or medium which dissolves the reagents in the proper sense: This compound or medium may be more generally a dispersing medium, and thus the “solution” might be a suspension, emulsion or solution in the proper sense (solution in the proper sense being a homogeneous mixture composed of two or more substances, where the particles of the solute cannot be seen by naked eye and which does not scatter light).
As a matter of course, the term “solvent” in the terms of the present invention does not include the stoichiometric amounts of liquid reactants (i.e. those amounts theoretically needed for the reaction with respect to the amount of the other reactant(s)) which may principally act as a solvent for other reagent(s). By way of example, in a Heck reaction of 1 mole of chlorobenzene and 1 mole of methylacrylate, chlorobenzene may principally act as solvent for the acrylate. However, this 1 mole of chlorobenzene is not considered as belonging to the solvent in the terms of the present invention and thus is not part of the 10% by weight or in particular 3% by weight of the solvent which may be different from water. The term “solvent” in the terms of the present invention does moreover not include the excess amount of any liquid reactant which may principally act as a solvent for other reagent(s). For instance, if in the above example chlorobenzene is used in excess, for example here in an amount of 1.2 mole, this excess of 0.2 mole is not considered as part of the solvent, although chlorobenzene may principally act as solvent for the acrylate, and thus is not part of the 10% by weight or in particular 3% by weight of the solvent which may be different from water. See however the below restrictions.
The term “solvent” in the terms of the present invention does furthermore not include auxiliary reagents (other than reactants; i.e. reagents which do not appear in the net reaction equation) which are liquid and can principally act as solvents, such as liquid bases (e.g. liquid amines or basic N-heterocycles, e.g. triethylamine, pyridine or lutidine). See however the below restrictions.
If the solvent contains, apart from water, a supplementary solvent, this is usually present because it is necessary for bringing one or more reagents into the reaction vessel, e.g. if these are oily and stick to the container in which they are kept before being introduced into the reaction. The supplementary solvent is generally chosen for its property to bring the reagent(s) into the reaction vessel and of course for being inert in the reaction mixture, i.e. for not interfering with the desired reaction. Generally, water miscible solvents which do not interfere with the reaction are preferred. Examples are protic solvents, such as C1-C3-alkanols, e.g. methanol, ethanol, propanol or isopropanol, or glycols, such as ethylene glycol, diethylene glycol, triethylene glycol or polyethyleneglycol, and polar aprotic solvents, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), 1,4-dioxane, acetone, methylethylketone or acetonitrile. If these polar solvents are however not useful for the intended purpose, i.e. for bringing the reagents into the reaction vessel, less polar solvents can be used, too.
In some very few instances the presence of a supplementary solvent might be useful for improving the yield of the reaction. In such cases the solvent can be selected from any solvent type useful for the specific surface.
These supplementary solvents are of course used in such an amount that their amount does not exceed 10% by weight, preferably does not exceed 3% by weight, of the total weight solvent (composed of water and optionally said supplementary solvent).
The term “solvent” in the terms of the present invention is thus restricted to water and optionally another solvent which is inert in the reaction and generally has no other role but to bring one or more reagents into the reaction vessel.
In particular, the amount of optionally present excess liquid reactant suitable to act as solvent for the other reagent(s) plus the amount of optionally present liquid auxiliary reagent(s) plus the amount of optionally present supplementary solvent does not exceed 35% by weight, preferably does not exceed 30% by weight, in particular does not exceed 25% by weight, more particularly does not exceed 20% by weight, specifically does not exceed 15% by weight, very specifically does not exceed 10% by weight, more specifically does not exceed 8% by weight, of the total weight of water plus excess liquid reactant suitable to act as solvent for the other reagent(s) plus liquid auxiliary reagent(s) plus supplementary solvent.
In terms of the present invention, “cellulose modified with one or more alkylene oxides or other hydroxyalkyl precursors” relates to hydroxyalkylcelluloses; i.e. to celluloses in which a part of the hydrogen atoms of the OH groups is replaced by hydroxyalkyl groups. In these hydroxyalkylcelluloses another part of the hydrogen atoms of the OH groups may be replaced by alkyl groups. Such derivatives are termed hydroxyalkyl(alkyl)celluloses.
The term “alkylcellulose” relates to celluloses in which a part of the hydrogen atoms of the OH groups are replaced by alkyl groups. In terms of the present invention, in alkylcelluloses, hydrogen atoms of the OH groups are not replaced by hydroxyalkyl groups.
The term “reagents” means starting compounds (also termed starting materials or reactants), and also catalysts, catalyst ligands, coupling agents and other compounds which do not appear in the net reaction equation. The cellulose derivative is however not considered as a reagent. Generally, the solvent is not considered a reagent, either, except in cases where it is consumed, such as water in a hydrolyzation reaction.
The term “starting compound” or “starting material” or “reactant” relates to those substances which are consumed in the course of a chemical reaction and which are indispensable yet for the “paper” or net reaction (e.g. alcohol and acid or acid derivative for an esterification, amine and acid or acid derivative for an amide synthesis, diene and dienophile for a Diels-Alder reaction, organoboron compound and halide or sulfonate compound for a Suzuki reaction, etc.). Thus, catalysts, catalyst ligands, coupling agents and the like are no “starting compounds” or “starting materials” or “reactants” in the terms of the present invention.
The method of the invention is suitable for reactions in which all the reagents are water-miscible or water-soluble under the given reaction conditions (e.g. reaction temperature, degree of dilution of the reagents, etc.); its advantages become however especially manifest in reactions in which at least one of the reagents is not or only scarcely water-soluble or water-miscible. “Miscible” generally refers to two liquids; thus the term water miscibility relates to liquid reagents. “Soluble” generally refers to a property of a gas or a solid in a liquid; thus the term water-solubility relates to gaseous or solid reagents. In the present invention, however, the term “water solubility” is used indiscriminately both for water miscibility and solubility, and thus independently of the physical state of the reagent(s).
In one embodiment, at least one of the reagents has a water solubility of at most 100 g per 1 l of water, in particular at most 50 g per 1 l of water, more particularly at most 10 g per 1 l of water, and specifically at most 5 g per 1 l of water at 20° C.+/−20% and 101325 Pascal+/−20%. In another embodiment, at least one of the starting compounds has a water solubility of at most 100 g per 1 l of water, in particular at most 50 g per 1 l of water, more particularly at most 10 g per 1 l of water, and specifically at most 5 g per 1 l of water at 20° C.+/−20% and 101325 Pascal+/−20%.
Cellulose Derivative
Without wishing to be bound by theory, it is assumed that the cellulose derivatives form in the aqueous medium a three-dimensional hollow structure inside which or at the interface (phase boundary) of which at least a part of the organic reaction takes place.
As said above, “cellulose modified with one or more alkylene oxides or other hydroxyalkyl precursors” relates to hydroxyalkylcelluloses; i.e. to celluloses in which a part of the hydrogen atoms of the OH groups is replaced by a hydroxyalkyl group, in particular by a C2-C4-hydroxyalkyl group, especially by a C2-C3-hydroxyalkyl group. Suitable alkylene oxides for modifying celluloses are ethylene oxide and 1,2-propylene oxide. Other hydroxyalkyl precursors are for example tetrahydrofuran. Preferably, ethylene oxide and/or 1,2-propylene oxide and especially 1,2-propylene oxide are used for modifying cellulose, and thus the cellulose modified with one or more alkylene oxides or other hydroxyalkyl precursors is preferably a hydroxyethylcellulose, a 2-hydroxypropylcellulose or a mixed hydroxyethyl-2-hydroxypropylcellulose; i.e. a cellulose in which a part of the hydrogen atoms of the OH groups is replaced by hydroxyethyl- and/or 2-hydroxypropyl groups.
In these hydroxyalkylcelluloses another part of the hydrogen atoms of the OH groups may be replaced by alkyl groups, especially by C1-C3-alkyl groups, such as methyl, ethyl or propyl groups, especially by methyl or ethyl groups. Such derivatives are termed “hydroxyalkyl(alkyl)celluloses”. Derivatives in which another part of the hydrogen atoms of the OH groups is indeed replaced by alkyl groups are termed “hydroxyalkylalkylcelluloses”.
The term “alkylcellulose” relates to celluloses in which a part of the hydrogen atoms of the OH groups are replaced by alkyl groups, especially by C1-C3-alkyl groups, such as methyl, ethyl or propyl groups, especially by methyl groups. In terms of the present invention, in order to distinguish them from hydroxyalkylalkylcelluloses, in alkylcelluloses, hydrogen atoms of the OH groups are not replaced by hydroxyalkyl groups.
Alkylcelluloses can be prepared by reacting cellulose, generally after a pretreatment with a base, with an alkylation agent, such as a methyl, ethyl or propyl halide, e.g. methyl chloride, bromide or iodide, dimethyl sulfate, ethyl chloride, bromide or iodide, diethyl sulfate and the like.
Hydroxyalkylcelluloses can be prepared by reacting cellulose, generally after a pretreatment with a base, with an alkylene oxide, such as ethylene oxide or 1,2-propylene oxide, or with another hydroxyalkyl precursors, such as tetrahydrofuran.
Hydroxyalkylalkylcelluloses can be prepared by reacting alkylcelluloses, generally after a pretreatment with a base, with an alkylene oxide, such as ethylene oxide or 1,2-propylene oxide, or with another hydroxyalkyl precursors, such as tetrahydrofuran, or by reacting cellulose, also generally after a pretreatment with a base, with an alkylene oxide, such as ethylene oxide or 1,2-propylene oxide, or with another hydroxyalkyl precursors, such as tetrahydrofuran, and simultaneously with an alkylation agent, such as a methyl, ethyl or propyl halide, e.g. methyl chloride, bromide or iodide, dimethyl sulfate, ethyl chloride, bromide or iodide, diethyl sulfate and the like.
Under the reaction conditions alkylene oxides or other hydroxyalkyl precursors might react with hydroxyalkyl groups already bound to the celluloses, thus yielding oligoether groups terminated by OH. Such compounds are also enclosed in the present cellulose derivatives, more precisely in the terms “hydroxyalkylcelluloses”, “hydroxyalkyl(alkyl)celluloses” and “hydroxyalkylalkylcelluloses”.
The cellulose derivatives may also be used in quaternized form; i.e. may contain an ammonium or (di/tri)alkylammonium group. Such ammonium groups may for example be introduced by reacting a hydroxyl group of the cellulose derivative with an epoxide containing an ammonium group or an amino group which is then quaternized via alkylation.
Cellulose derivatives are generally characterized by their size and the degree of substitution. The cellulose derivatives are generally macromolecules, and thus their size or weight has to be determined by methods suitable for characterizing polymers. Generally, cellulose derivatives are characterized by their viscosity. Viscosity can be determined by various methods, for example with a Brookfield LV or RV, Höppler falling ball, Haake Rotovisco, and the like. If not indicated otherwise, in the present invention, viscosity values of up to (and including) 70 mPa·s are values obtained with a 2% by weight solution of the cellulose derivative in water, relative to the weight of water, at 25° C., as determined when using a Malvern Instruments Viscosizer 200 and an uncoated glass capillary (Art.-Nr. PRY2007, Malvern Instruments) and applying following protocol:
Pressure
Duration
Step
Solution
(mBar)
(min)
wash
3% Mucasol ™
2000
1
universal detergent
rinse
water
2000
4
fill
water
2000
1
reset baseline
water
1000
1
load sample
sample
1000
auto
dip (clean inlet)
water
0
0.15
ran
water
1000
auto
A 1 mg/mL caffeine in water solution is used as viscosity reference at 0.8905 mPa·s. Raw data is fitted using the trailing region of the detector trace with a sampling interval of 55 and peak region threshold of 30%.
If not indicated otherwise, in the present invention, viscosities of above 70 mPa·s and up to (and including) 4000 mPa·s are values obtained with a 2% by weight solution of the cellulose derivative in water, relative to the weight of water, at 25° C., as determined when using a falling-sphere viscosimeter: First, sample density is determined with an Anton Paar DMA 4100 densitometer. Sample density is used to determine dynamic viscosity with an Anton Paar AMVn viscosimeter equipped with an 1.8 mm capillary or an Anton Paar Lovis 2000 ME viscosimeter equipped with a 2.5 mm capillary. Measurements are performed as quadruplicates at 25° C. with capillaries tilted to 70°.
If not indicated otherwise, in the present invention, viscosities of above 4000 mPa·s are values obtained with a 2% by weight solution of the cellulose derivative in water, relative to the weight of water, at 20° C., as described in European Pharmacopoeia 8.6, 01/2016:0348, Chapter “Hypromellose”, Method 2, using a single-cylinder type spindle viscosimeter. For viscosities below 9500 mPa·s, following specifications apply: rotor number: 4; revolutions. 60 r/min; calculation multiplier: 100; for viscosities of from 9500 to <99500 mPa·s, following specifications apply: rotor number 4; revolutions. 6 r/min; calculation multiplier: 1000; and for viscosities of 99500 mPa·s and above, following specifications apply: rotor number: 4; revolutions. 3 r/min; calculation multiplier: 2000.
In a preferred embodiment, the cellulose derivative has a viscosity of from 1 to 150000 mPa·s, more preferably 2 to 100000 mPa·s, in particular 2 to 10000 mPa·s, more particularly 2 to 6000 mPa·s, even more particularly 2 to 1000 mPa·s, specifically 2 to 100 mPa·s, more specifically 2 to 80 mPa·s, very specifically 3 to 70 mPa·s, determined as a 2% by weight aqueous solution, relative to the weight of water, at the temperature and with the method as described above (viscosities of 1 to 70 mPa·s determined at 25° C. with a Malvern Instruments Viscosizer 200 according to the above-described method; viscosities of >70 to 4000 mPa·s determined at 25° C. with a falling-sphere viscosimeter according to the above-described method; viscosities of >4000 mPa·s determined at 20° C. with a single-cylinder type spindle viscosimeter according to the above-described method (in the case of viscosities of >4000 mPa·s as given by the respective suppliers). In a specific embodiment, the cellulose derivative has a viscosity of from 2 to 7 mPa·s, specifically from 3 to 6 mPa·s, very specifically from 3.5 to 6 mPa·s or from 3.8 to 5 mPa·s, determined as a 2% by weight aqueous solution, relative to the weight of water, at 25° C. with a Malvern Instruments Viscosizer 200 according to the above-described method. In another specific embodiment, the cellulose derivative has a viscosity of from 10 to 20 mPa·s, determined as a 2% by weight aqueous solution, relative to the weight of water, at 25° C. with a Malvern Instruments Viscosizer 200 according to the above-described method. In another specific embodiment, the cellulose derivative has a viscosity of from 30 to 70 mPa·s, specifically from 40 to 60 mPa·s, very specifically from 40 to 50 mPa·s, determined as a 2% by weight aqueous solution, relative to the weight of water, at 25° C. with a Malvern Instruments Viscosizer 200 according to the above-described method. In another specific embodiment, the cellulose derivative has a viscosity of from 70 to 150 mPa·s, specifically from 75 to 120 or 75 to 100 mPa·s, determined as a 2% by weight aqueous solution, relative to the weight of water, at 25° C. with a falling-sphere viscosimeter according to the above-described method. In another specific embodiment, the cellulose derivative has a viscosity of from 100 to 600 mPa·s, specifically from 100 to 500 mPa·s, determined as a 2% by weight aqueous solution, relative to the weight of water, at 25° C. with a falling-sphere viscosimeter according to the above-described method. In another specific embodiment, the cellulose derivative has a viscosity of from 2000 to 6000 mPa·s, specifically from 2500 to 5700 mPa·s, very specifically from 3000 to 4000 mPa·s, determined at 20° C. with a single-cylinder type spindle viscosimeter according to the above-described method. 1 mPa·s is 1 cP (cP=centipoise; also abbreviated as cps).
In an alternatively preferred embodiment, the cellulose derivative has a molecular weight of from 5000 to 1500000, more preferably from 6000 to 1000000, in particular from 7000 to 500000, more particularly from 8000 to 250000, even more particularly from 8000 to 100000, specifically from 8000 to 50000 Dalton. The molecular weight values relate to the weight average molecular weight.
The degree of substitution is the average level of alkyl and/or hydroxyalkyl substitution on the cellulose chain. The degree of substitution is often expressed in percentages.
In a preferred embodiment, in the cellulose derivative 5 to 70%, in particular 10 to 60%, specifically 15 to 50%, more specifically 20 to 45%, very specifically 25 to 45% of the hydrogen atoms in the hydroxyl groups of the cellulose on which the cellulose derivative is based are replaced by a hydroxyalkyl and/or alkyl group.
In particular, the cellulose derivative is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose and methylcellulose, and especially from hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylcellulose. Particularly, however, the cellulose derivative is a hydroxyalkylcellulose. Thus, more particularly, the cellulose derivative is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, ethylhydroxyethylcellulose and hydroxyethylcellulose and especially from hydroxypropylmethylcellulose and hydroxyethylcellulose.
Specifically, the cellulose derivative is hydroxypropylmethylcellulose.
Various viscosities and substitution degrees of the above hydroxyalkyl(alkyl)-celluloses and alkylcelluloses are commercially available.
In a preferred embodiment, the cellulose derivative is used in an amount of from 0.01 to 15% by weight, in particular 0.05 to 10% by weight, more particularly 0.1 to 7% by weight, specifically 0.2 to 5% by weight, based on the weight of the solvent.
In another preferred embodiment, the cellulose derivative is used in an amount of from 0.01 to 15% by weight, in particular 0.05 to 10% by weight, more particularly 0.1 to 7% by weight, specifically 0.2 to 5% by weight, based on the weight of water (water being the only solvent or making up at least 90% by weight of the solvent, in particular at least 97% by weight of the solvent, the percentages being based on the total weight of the solvent).
In a preferred embodiment, the weight ratio of the cellulose derivative and all reagents is of from 1:1 to 1:200, in particular 1:1 to 1:100, more particularly 1:2 to 1:70, specifically 1:5 to 1:60. The term “reagents” is as defined above, i.e. it includes catalysts, catalyst ligands, coupling agents and other compounds which do not appear in the net reaction equation.
In a preferred embodiment, the weight ratio of the cellulose derivative and the starting compounds, i.e. those compounds indispensable for the respective reaction (e.g. alcohol and acid or acid derivative for an esterification, amine and acid or acid derivative for an amide synthesis, diene and dienophile for a Diels-Alder reaction, organoboron compound and halide or sulfonate compound for a Suzuki reaction, etc.), i.e. exclusive of any catalysts, ligands therefor, coupling agents and other compounds which do not appear in the net reaction equation, is of from 1:1 to 1:150, in particular 1:1 to 1:100, more particularly 1:2 to 1:50, specifically 1:2 to 1:30.
In cases in which high dilution is not important (high dilution is for example advantageous in intramolecular reactions, like lactone or lactam formation, in order to suppress competing intermolecular reactions), it is preferred to carry out the present organic reactions in rather high concentration. Preferably the reaction is carried out in such a way that the reactant used in substoichiometric amounts is present in the reaction medium in a concentration of from 0.1 to 5 mol per l of solvent, more preferably from 0.2 to 4 mol per l of solvent, in particular from 0.3 to 3 mol per l of solvent, more particularly from 0.5 to 3 mol per l of solvent and specifically from 0.8 to 3 mol per l of solvent. In case that the reactants are used in equimolar amounts, the above concentrations apply of course simply to one of these reactants. Alternatively preferably the reaction is carried out in such a way that the overall concentration of all reagents (i.e. reactants, catalysts, ligands, coupling agents) is of from 0.2 to 10 mol per l of solvent, more preferably from 0.4 to 8 mol per l of solvent, in particular from 0.8 to 6 mol per l of solvent and specifically from 1 to 4 mol per l of solvent.
Reaction Temperature
As indicated above, the limiting factor of reaction temperature is on the lower side the temperature at which the reaction mixture solidifies (0° C. or somewhat lower, e.g. −10° C. or −5° C.) and on the upper side the gelation point, i.e. the temperature at which the reaction mixture gels, or, if the cellulose derivative does not gel, the boiling point of the reaction mixture at the given pressure. Preferably the reaction is carried out at of from 5° C. to 80° C., more preferably from 10° C. to 70° C., in particular from 20° C. to 70° C., more particularly from 20° C. to 65° C. and specifically from 20° C. to 55° C., e.g. at from 20 to 25° C. or at from 45 to 55° C. or at from 48 to 52° C. The reaction temperature will be chosen according to the specific aim of the specific reaction. Higher reaction temperatures, e.g. around 50° C. to 70° C., will generally shorten reaction times significantly, but lower temperatures might lead to a more selective formation of the desired product, which advantage may overweigh longer reaction times.
Organic Reactions
As said above, basic types of organic reactions are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. Thus, in one aspect, the organic reactions of the present invention are selected from the group consisting of addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions.
Addition Reactions:
In this reaction type two or more molecules combine to form a larger one (the adduct). Addition reactions are limited to chemical compounds that have multiple bonds, such as molecules with carbon-carbon double bonds (alkenes, alkadienes, cycloalkenes, cycloalkadienes and other olefinic compounds) or triple bonds (alkynes, alkadiynes, cycloalkynes etc.), or with carbon-heteroatom double bonds, like carbonyl (C═O) groups or imine (C═N) groups or carbon-heteroatom triple bonds, like cyano (C≡N). Addition can take place by initial attack of a nucleophile, an electrophile or a free radical. Examples are the addition of hydrogen halides, other acids, like sulfuric acid or carboxylic acids, halogens, hydrogen, water, alcohols, hydrogen sulfide, thiols, ammonia, amines, hydroazoic acid to C—C double or triple bonds, the addition of hydrogen to C═O, C═N or C≡N bonds to give the reduced species, pericyclic reactions like Diels-Alder and various other cycloadditions, and many more. See for example J. March, Advanced Organic Chemistry, 3rd ed., John Wiley & Sons, p. 657 et seq.
Elimination Reactions:
In this reaction type two substituents are removed from a molecule in either a one or two-step mechanism. Examples are dehydration (α,β-hydro-hydroxy elimination), α,β-hydro-alkoxy elimination, α,β-hydro-halo elimination, intramolecular condensation reactions etc. Elimination in α,β-position normally leads to unsaturated compounds, e.g. olefins, alkynes or aromatic compounds. Intramolecular condensation normally leads to a cyclic system, e.g. to a lactone or lactam.
Substitution Reactions
In substitution reactions one functional group in a chemical compound is replaced by another functional group. Depending on the substituent type, substitution reactions are classified as nucleophilic (SN), electrophilic (SE) or radical (SR). Examples are SN1 and SN2 reactions of aliphatic or cycloaliphatic compounds, SE, SN reactions on (hetero)aromatic compounds, SR on aromatic compounds like the Sandmeyer reaction, transition metal catalyzed C—C, C—O, C—N or C—S coupling reactions, etc.
Pericyclic Reactions
In pericyclic reactions the transition state of the molecule has a cyclic geometry, the reaction progresses in a concerted fashion and no radical or ionic intermediates are formed. Examples are concerted cycloadditions, like Diels-Alder reaction, Paterno Büchi reactions or 1,3-cycloadditons; sigmatropic rearrangements, cheletropic reactions etc.
Rearrangement Reactions
In rearrangement reactions, the carbon skeleton of a molecule is rearranged to give a structural isomer of the original molecule. Often a substituent moves from one atom to another atom in the same molecule.
Photochemical Reactions
In photochemical reactions, a chemical reaction is caused by absorption of ultraviolet (wavelength from 100 to 400 nm), visible light (400-750 nm) or infrared radiation (750-2500 nm). Examples are [2+2] and other thermally forbidden cycloadditions, di-pi-methane rearrangement, Norrish type I and II reactions, photoredox reactions etc.
Redox Reactions
Redox reactions encompass oxidations and reductions.
As many reactions cannot be categorized to belong to only one of the above types, in the following other categories will be used.
Thus, the organic reactions of the present invention are in particular selected from the group consisting of
transition metal catalyzed reactions, especially transition metal catalyzed C—C coupling reactions, and transition metal catalyzed reactions involving C—N, C—O, C—S, C—B or C-halogen bond formation,
C—C coupling reactions not requiring transition metal catalysis, such as the Wittig reaction, pericyclic reactions like the Diels-Alder reaction or photochemically induced reactions like [2+2] cycloaddition or cyclopropanation reactions, or reaction of carbonyl compounds with CH acidic compounds, such as in the aldol reaction or the Knoevenagel reaction or Michael addition and the like,
reactions involving C—N bond formation and not requiring transition metal catalysis, such as carboxamide bond formation (amidation; synthesis of amides/peptides), urea formation, carbamate formation (formation of C(O)—N bond in the carbamate), amination (in the sense of nucleophilic substitution), reductive amination, Michael addition with N nucleophiles or nitration,
reactions involving C—O bond formation and not requiring transition metal catalysis, such as esterification or etherification or carbamate formation (formation of C(O)—O bond in the carbamate) or Michael addition with O nucleophiles,
reactions involving C-halogen bond formation and not requiring transition metal catalysis, such as halogenation of e.g. aromatic compounds,
reactions involving S—N bond formation and not requiring transition metal catalysis, such as sulfonamide bond formation (synthesis of sulfonamides) or Michael addition with S nucleophiles,
substitution reactions, such as (cyclo)aliphatic nucleophilic substitution, aromatic nucleophilic, electrophilic or radical substitution,
reductions and oxidations (redox reactions),
protection and deprotection reactions,
photochemically induced reactions, and
combined forms of the above reaction types.
The method of the invention also allows to carry out a chain of different organic reactions as a one pot reaction, such as protection of a functional group, reaction at another functional group, deprotection and, where expedient, further reaction of the deprotected functional group.
Transition Metal-Catalyzed Reactions
In one particular embodiment of the invention, in the organic reaction a transition metal catalyst is used; i.e. the organic reaction is a transition metal-catalyzed reaction.
Transition metal-catalyzed reactions are all organic reactions which involve the use of one or more transition metals as catalysts. Typically, they result in C—C, C—N, C—O, C—S, C—B or C-halogen bond formation. C—C bond formation is also called coupling reaction. If the two substrates to be coupled are different, the coupling reaction is termed cross coupling, while in case of identical substrates it is termed homocoupling.
Most transition metals are useful as catalysts; however, due to their availability and acceptable toxicity, the following metals are mostly used: Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, and Zn. Thus, in a preferred embodiment, the transition metal is selected from the group consisting of Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, and Zn. In particular, the transition metal is selected from the group consisting of Ru, Rh, Ni, Pd, Pt, Cu and Au. In another particular embodiment, the transition metal is Fe.
Transition metals can be used with an oxidation state of 0 or in oxidized form. In an oxidation state of 0, the transition metals are generally used as complexes to make their homogeneous distribution in the reaction medium possible. Alternatively they can be used as such (i.e. in elementary form), advantageously in a finely divided form, or supported on a carrier, to act as a heterogeneous catalyst. In oxidized form, the transition metals can be used in form of their salts, oxides or, mostly, in form of their complexes. The transition metal catalysts can also be used in form of their precursors, i.e. the active form forms in situ. For instance, in reactions requiring the metal in an oxidation state of 0 the transition metal can be introduced into the reaction in oxidized form and be reduced before or in the course of the reaction by a reduction agent present in the reaction.
In a particular embodiment, the transition metal catalyst is not a catalyst supported on a cellulose derivative or on cellulose.
In another particular embodiment the catalyst is used as a catalyst complex. Suitable complex ligands are well known and often contain phosphorus. Examples for phosphorus ligands are di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP; Mo-Phos), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-Bu XPhos, tBuXPhos, tert-Butyl XPhos), 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf), 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,4-bis(diphenylphosphino)butane (dppb), (2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (diop), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) (Amphos), (2S,3S)-(−)-bis(diphenylphosphino)butane (Chiraphos), di-(tert-butyl)phenylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), [1,1′-biphenyl]-2-diisopropyl phosphine, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos), 4,5-bis-(di-1-(3-methylindolyl)-phosphoramidit)-2,7,9,9-tetramethylxanthene (MeSkatOX), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-phos), 2-(2-dicyclohexyl-phosphanylphenyl)-N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine (C-phos), 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine, [(4R)-(4,4′-bis-1,3-benzodioxole)-5,5′-diyl]bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]((R)-DTBM-SEGPHOS®), (R)- or (S)-3,5-Xyl-MeO-BIPHEP, (R,S)- or (S,R)-PPF-P(t-Bu)2, the Josiphos ligands, triphenylphosphite, tri-(2-(1,1-dimethylethyl)-4-methoxy-phenyl)-phosphite, tricyclohexylphosphine, tri(tert-butyl)phosphine, butyldi-1-adamantylphosphine (cataCXium), 1,6-bis(diphenylphosphino)hexane (DPPH), 2,6-bis(2,5-dimethylphenyl)-1-octyl-4-phenylphosphacyclohexan (PCH), tris(3-sulfophenyl)phosphine trisodium salt (TPPTS) and the like.
Non-phosphorus ligands are for example bis(dibenzylideneacetone) (dba), acetonitrile, bisoxazoline and the like. Further, Pd catalysts with non-phosphorus ligands are for example the PEPPSI catalysts (PEPPSI=Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation)
in which R is a small organic fragment, e.g. methyl, ethyl, isopropyl, isopentyl, or isoheptyl. The corresponding catalysts are labeled as PEPPSI-IMes, PEPPSI-IEt, PEPPSI-IPr, PEPPSI-IPent, and PEPPSI-IHept respectively, with or without “Pd-” added in front.
Also new generation PEPPSI catalysts are suitable:
Here, too, R is a small organic fragment, e.g. methyl, ethyl, isopropyl, isopentyl, or isoheptyl.
Other suitable non-phosphorus ligands are for example porphyrins, such as shown in the following formula. They are mostly used with Fe, Ru, Rh or Ir as central metal, but Zn may also be used.
Generally, at least one of Ra, Rb, Rc and Rd is an aromatic group, such as phenyl, optionally substituted by 1, 2 or 3 substituents selected from the group consisting of methyl, methoxy, hydroxyl, amino, alkylcarbonyl, alkoxycarbonyl and the like. For sterically selective reactions, expediently, at least one of Ra, Rb, Rc and Rd is a chiral group, such as a BINAP radical, a phenyl ring carrying one or more chiral substituents or a phenyl ring fused to one or more rings resulting in a chiral system. Radicals Ra, Rb, Rc and Rd which are not an aromatic group are generally selected from the group consisting of alkyl groups, alkoxy groups, alkyl carbonyl groups and alkoxycarbonyl groups. They can however also be hydrogen.
Transition metal complexes of these porphyrin ligands, in particular complexes with Fe, Ru, Rh or Ir as central metal, are especially useful in cyclopropanation reactions.
Other suitable ligands are the following semicorrin or bis-oxazolin (BOX and PyBOX) ligands:
R can have various meanings, such as C1-C4-alkyl, C1-C4-alkyl substituted by OH, tri-C1-C4-alkyl-silyloxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl or phenyl; C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl or phenyl. Each R′ is generally independently H or C1-C4-alkyl, in particular H or methyl.
These ligands are generally used with Cu as central metal. Copper complexes of these ligands are especially useful in cyclopropanation reactions.
a) C—C Coupling Reactions
In a particular embodiment, the transition metal catalyzed reaction is a C—C coupling reaction. Transition metal catalyzed C—C coupling reactions are well known, and are often named reactions. Examples are the Suzuki-Miyaura reaction (or Suzuki-Miyaura coupling or just Suzuki reaction or just Suzuki coupling), Negishi coupling, Heck reaction, C—C coupling reactions involving C—H activation (different from Heck reaction), Sonogashira coupling, Stille coupling, Grubbs olefin metathesis, 1,4-additions of organoborane compounds to α,β-olefinically unsaturated carbonyl compounds, in particular Rh-catalyzed 1,4-additions, Kumada coupling, Hiyama coupling, Ullmann reaction, Glaser coupling (inclusive the Eglinton and the Hay coupling), Cadiot-Chodkiewicz coupling, the Fukuyama coupling, hydroformylations or cyclopropanations.
The Suzuki reaction is a cross coupling reaction in which an organoboron compound is reacted with an organic halogenide or sulfonate [the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate (trifluoromethylsulfonate) or nonaflate (nonafluorobutylsulfonate)], e.g. with an alkyl, alkenyl, alkynyl, aryl or heteroaryl halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate), in the presence of a transition metal catalyst, mostly a Pd or Ni catalyst, and in general also of a base.
The Negishi reaction is a cross coupling reaction in which an organozinc compound is reacted with an organic halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate), e.g. with an alkyl, alkenyl, alkynyl, aryl or heteroaryl halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate), in the presence of a transition metal catalyst, mostly a Pd or Ni catalyst. Organoaluminum or organozirconium compounds can be used instead of the organozinc compound.
In Heck reactions an aryl, heteroaryl, benzyl, vinyl or alkyl halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate, nonaflate or tosylate) (the alkyl group must not contain any β-hydrogen atoms) is reacted with an olefinically unsaturated compound in the presence of a transition metal catalyst, mostly a Pd catalyst, and generally also in the presence of a base.
C—C coupling reactions involving C—H activation are coupling reactions in which one of the reactants reacts via a C—H bond and not via a specific activating group. The Heck reaction is such a reaction involving C—H activation. In the present case, in the C—C coupling reactions involving C—H activation two aromatic or heteroaromatic compounds are coupled.
The Sonogashira reaction is a cross coupling reaction in which an aryl, heteroaryl or vinyl halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) is reacted with a terminal alkyne in the presence of a transition metal catalyst, mostly a Pd catalyst, generally also of a base and optionally of a Cu(I) salt (also in catalytic amounts).
The Stille reaction, also termed Migita-Kosugi-Stille coupling, is a cross coupling reaction in which an organotin compound (organostannane) is reacted with an alkenyl, aryl, heteroaryl or acyl halide, sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) or phosphate in the presence of a Pd catalyst.
Grubbs olefin metathesis is an olefin metathesis in which a Grubbs catalyst is used. An olefin metathesis is an organic reaction that entails the redistribution of fragments of alkenes (olefins) by the scission and regeneration of carbon-carbon double bonds. Grubbs catalysts are Ruthenium carbene complexes. For further details see below.
Rh-catalyzed 1,4-additions in the terms of the present invention are 1,4 additions of organoborane compounds, in particular of aryl or heteroaryl boronic acids, to α,β-olefinically unsaturated carbonyl compounds, in particular to α,β-unsaturated carboxylic acids or acid derivatives, in the presence of a rhodium catalyst to give 3-(het)arylpropionic acids or acid derivatives. However, Pd and Ru catalysts are principally also suitable for such 1,4 additions of organoborane compounds to α,β-olefinically unsaturated carbonyl compounds.
The Kumada reaction is a cross coupling reaction in which a vinyl halide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) is reacted with a Grignard reagent or a lithium organyl in the presence of a transition metal catalyst, mostly a Pd or Ni catalyst.
The Hiyama reaction is cross-coupling reaction in which an aryl, heteroaryl, alkenyl or alkynyl silane is reacted with an organic halide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate), e.g. an alkyl, alkenyl, alkynyl, aryl or heteroaryl halide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate), in the presence of a transition metal catalyst, mostly a Pd catalyst.
The Ullmann reaction or Ullmann coupling is a cross coupling or homocoupling reaction in which two aryl or heteroaryl halides or pseudohalogenides (e.g. —SCN) are reacted to biaryl compounds in the presence of copper, a Cu(I) salt or a Ni catalyst.
The Glaser coupling is homocoupling reaction in which a terminal alkyne is treated with a copper(I) salt and oxidized to give a symmetrical conjugated diyne. The original Glaser reaction was carried out in aqueous ammonia, and air or oxygen was used as oxidation agent, but in terms of the present invention the Glaser coupling comprises all variants of Cu-catalyzed homocoupling of terminal alkynes, e.g. the use of CuCl2 or K3Fe(CN)6 as oxidizing agents, the Eglinton variant (Eglinton coupling), in which Cu(II) acetate and methanolic pyridine is used, or the Hay variant (Hay coupling), in which tertiary amines, like pyridine, or TMEDA are used as complexing agents for the Cu(I) salt, and air or oxygen is used as oxidizing agent.
The Cadiot-Chodkiewicz coupling is a cross coupling in which a terminal alkyne and an 1-bromoalkyne are reacted in the presence of a Cu(I) catalyst and an aliphatic amine.
The Fukuyama coupling is a cross coupling reaction in which a thioester and an organozinc halide are reacted in the presence of a transition metal catalyst, mostly a Pd catalyst, to give a ketone.
In a transition metal catalyzed cyclopropanation an olefinically unsaturated compound is reacted with a diazo compound to a cyclopropane in the presence of a transition metal catalyst. The reaction is formally a [1+2] ring forming reaction of a carbene (formed after N2 elimination) and an olefin; therefore cyclopropanations are herein formally considered as a pericyclic reaction.
In a hydroformylation, also known as oxo synthesis or oxo process, formally a formyl group (CHO) and a hydrogen atom add to a carbon-carbon double bond, thus giving an aldehyde. The reaction is generally catalyzed by a Rh or Ru catalyst, mostly by a homogeneous Rh or Ru catalyst.
Particularly, the transition metal catalyzed C—C coupling reaction is selected from the group consisting of the Suzuki-Miyaura reaction (or just Suzuki reaction), Negishi coupling, Heck reaction, C—C coupling reactions involving C—H activation other than Heck reaction (see above and below definition), Sonogashira coupling, Stille coupling, Grubbs olefin metathesis, 1,4-additions of organoborane compounds to α,β-olefinically unsaturated carbonyl compounds, in particular Rh-catalyzed 1,4-additions, hydroformylations and cyclopropanations. Specifically, the transition metal catalyzed C—C coupling reaction is selected from the group consisting of the Suzuki-Miyaura reaction (or just Suzuki reaction), Heck reaction, C—C coupling reactions involving C—H activation other than Heck reaction, Sonogashira coupling, Stille coupling, Grubbs olefin metathesis, Rh-catalyzed 1,4-additions and cyclopropanations. In another specific embodiment the transition metal catalyzed C—C coupling reaction is selected from the group consisting of the Suzuki-Miyaura reaction (or just Suzuki reaction), Heck reaction, C—C coupling reactions involving C—H activation other than Heck reaction, Sonogashira coupling, Stille coupling, Grubbs olefin metathesis and Rh-catalyzed 1,4-additions.
Suzuki-Miyaura Reaction
In a particular embodiment the transition metal catalyzed C—C coupling reaction is a Suzuki-Miyaura reaction. As said, in Suzuki reactions an organoboron compound is reacted with an organic halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate), in particular with a halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) R2—(Z)n, where R2 is an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl group, Z is a halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) group, especially Cl, Br, I, triflate or nonaflate, and n is 1, 2, 3 or 4, in the presence of a transition metal catalyst, mostly a Pd or Ni catalyst, and in general also of a base.
Preferably, the organoboron compound is a compound of formula R1—BY2, where R1 is an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl group and Y is an alkyl, O-alkyl or hydroxyl group, or the two substituents Y form together with the boron atom they are bound to a mono-, bi- or polycyclic ring; or the organoboron compound is a compound of formula R1—BF3M, where M is a metal equivalent. The reaction of the organoboron compound with R2—(Z)n yields a compound (R1)n—R2. Examples of suitable organoboron compounds R1—BY2 are R1—B(OH)2, R1—B(O—C1-C4-alkyl)2, R1—B(C1-C4-alkyl)2, or the MIDA ester of R1—B(OH)2 (MIDA=N-methyliminodiacetic acid; HO—C(═O)—CH2—N(CH)—CH2—C(═O)—OH; i.e. the two Y form together —O—C(═O)—CH2—N(CH3)—CH2—C(═O)—O—). The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl halide or sulfonate can contain more than one halide or sulfonate group (when n is 2, 3 or 4), so that multiply coupled compounds can form, especially if the organoboron compound is used in excess. For instance, a difunctional compound R2—(Z)2 can yield a twofold coupled compound R1—R2—R1. In case that n is 2, 3 or 4 and the reaction is intended to couple 2, 3 or 4 organic radicals deriving from the organoboron compound (e.g. 2, 3 or 4 R1 deriving from R1—BY2), Z in (Z)n is preferably always the same; i.e. all groups Z in R2—(Z)n have the same meaning.
Due to the tolerance of the Suzuki reaction to a wide variety of functional groups, the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 can carry one or more substituents, e.g. halogen (provided that this not more reactive than the halogen atom or sulfonate group on the desired reaction site of the R2—(Z)n compound), cyano, nitro, azido, —SCN, —SF5, OR11 (provided that this not more reactive than the halogen atom or sulfonate group on the desired reaction site of the R2—(Z)n compound), S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13, —Si(R14)3, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, where the five last-mentioned cyclic substituents may carry one or more substituents selected from R15; aryl which may be substituted by one or more radicals R15; heterocyclyl which may be substituted by one or more radicals R15; heteroaryl which may be substituted by one or more radicals R15; oxo (═O), ═S, or ═NR12a;
and in case of cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl groups R1 and R2, optional substituents on these groups can additionally be alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl and mixed alkenyl/alkynyl, where these six radicals may in turn be substituted by one or more radicals, e.g. by halogen (provided that this not more reactive than the halogen atom or sulfonate group on the desired reaction site of the R2—(Z)n compound), cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13, —Si(R14)3, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, where the five last-mentioned cyclic substituents may carry one or more substituents selected from R15; aryl which may be substituted by one or more radicals R15; heterocyclyl which may be substituted by one or more radicals R15; heteroaryl which may be substituted by one or more radicals R15; oxo (═O), ═S, and ═NR12a; where
each R11 is independently selected from the group consisting of hydrogen, cyano, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, where the aliphatic and cycloaliphatic moieties in the 11 last-mentioned radicals may be partially or fully halogenated and/or may be substituted by one or more radicals R17,
-alkyl-C(═O)OR18, -alkyl-C(═O)N(R12a)R12b,
-alkyl-C(═S)N(R12a)R12b, -alkyl-C(═NR12)N(R12a)R12b,
—Si(R14)3, —S(O)mR18, —S(O)mN(R12a)R12b, —N(R12a)R12b, —N═C(R16)2, —C(═O)R13,
—C(═O)N(R12a)R12b, —C(═S)N(R12a)R12b, —C(═O)OR18,
aryl, optionally substituted with one or more substituents R15;
heterocyclyl, optionally substituted with one or more substituents R15; and
heteroaryl, optionally substituted with one or more substituents R15; and
R11 in the group —S(O)mR11 is additionally selected from the group consisting of alkoxy and haloalkoxy;
R12, R12a and R12b, independently of each other and independently of each occurrence, are selected from the group consisting of hydrogen, cyano, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, wherein the 11 last-mentioned aliphatic and cycloaliphatic radicals may be partially or fully halogenated and/or may be substituted by one or more, preferably 1, 2 or 3, in particular 1, substituents R19,
—OR20, —NR21aR21b, —S(O)mR20, —C(═O)N(R21aR21b), —C(═O)NR21N(R21aR21b), —Si(R14)3, —C(═O)R13,
aryl which may be substituted with 1, 2, 3, 4, or 5, preferably 1, 2 or 3, in particular 1, substituents R15,
heterocyclyl which may be substituted with one or more, preferably 1, 2 or 3, in particular 1, substituents R15; and
heteroaryl which may be substituted with one or more, preferably 1, 2 or 3, in particular 1, substituents R15; and
or R12a and R12b, together with the nitrogen atom to which they are bound, form a saturated, partially unsaturated or maximally unsaturated heterocyclic or heteroaromatic ring, where the ring may further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from the group consisting of O, S, N, SO, SO2, C═O and C═S as ring members, wherein the heterocyclic or heteroaromatic ring may be substituted with 1, 2, 3, 4 or 5, preferably 1, 2 or 3, in particular 1, substituents independently selected from R15;
or R12a and R12b together form a group ═C(R22)2, ═S(O)m(R20)2, ═NR21a or ═NOR20;
each R13 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, where the aliphatic and cycloaliphatic moieties in the 11 last-mentioned radicals may be partially or fully halogenated and/or may be substituted by one or more radicals R17; aryl, optionally substituted with one or more radicals R15; heterocyclyl, optionally substituted with one or more radicals R15; heteroaryl, optionally substituted with one or more radicals R15; OR20, —S(O)mR20, —N(R21a)R21b, —C(═O)N(R21a)R21b,
—C(═S)N(R21a)R21b and —C(═O)OR20;
each R14 is independently selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, and phenyl, optionally substituted with 1, 2, 3, 4, or 5 radicals R15;
each R15 is independently selected from the group consisting of halogen, azido, nitro, cyano, —OH, —SH, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, —Si(R23)3;
C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkapolyenyl, C2-C20-alkynyl, C2-C20-alkapolyynyl, mixed C2-C20-alkenyl/alkynyl, wherein the six last-mentioned aliphatic radicals may be partially or fully halogenated and/or may carry one or more radicals selected from the group consisting of OH, C1-C20-alkoxy, C1-C20-haloalkoxy, SH, C1-C20-alkylthio, C1-C20-haloalkylthio, C1-C20-alkylsulfinyl, C1-C20-haloalkylsulfinyl, C1-C20-alkylsulfonyl, C1-C20-haloalkylsulfonyl, —Si(R23)3, oxo, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, C8-C20-cycloalkynyl, mixed C3-C20-cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl and heteroaryl, wherein the 8 last-mentioned cyclic radicals may in turn be partially or fully halogenated and/or may carry one or more radicals selected from the group consisting of OH, C1-C20-alkoxy, C1-C20-haloalkoxy, SH, C1-C20-alkylthio, C1-C20-haloalkylthio, C1-C20-alkylsulfinyl, C1-C20-haloalkylsulfinyl, C1-C20-alkylsulfonyl, C1-C20-haloalkylsulfonyl, —Si(R23)3, oxo, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, C8-C20-cycloalkynyl, mixed C3-C20-cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl and heteroaryl, wherein the 8 last mentioned radicals may in turn be unsubstituted, partially or fully halogenated and/or carry 1, 2 or 3 substituents selected from the group consisting of cyano, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl; C3-C8-cycloalkyl, C3-C8-cycloalkenyl, C8-C20-cycloalkynyl, mixed C3-C20-cycloalkenyl/cycloalkynyl, polycarbocyclyl, wherein the 5 last-mentioned cycloaliphatic radicals may be partially or fully halogenated and/or may carry one or more radicals selected from the group consisting of cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and oxo;
aryl, O-aryl, heterocyclyl, O-heterocyclyl, heteroaryl and O-heteroaryl, wherein the cyclic moieties in the 6 last mentioned radicals may be unsubstituted, partially or fully halogenated and/or carry 1, 2 or 3, in particular 1, substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl;
or
two R15 present together on the same atom of an unsaturated or partially unsaturated ring may be ═O, ═S, ═N(C1-C6-alkyl), ═NO(C1-C6-alkyl), ═CH(C1-C4-alkyl) or ═C(C1-C4-alkyl)C1-C4-alkyl;
or
two R15 on two adjacent carbon or nitrogen atoms form together with the carbon or nitrogen atoms they are bonded to a 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated, including heteroaromatic, ring, wherein the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members, and wherein the ring optionally carries one or more, preferably 1, 2 or 3, in particular 1, substituents selected from the group consisting of halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;
each R16 is independently selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl and C2-C6-haloalkynyl, wherein the six last-mentioned aliphatic radicals may carry 1 or 2 radicals selected from the group consisting of CN, C3-C4-cycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and oxo;
each R17 is independently selected from the group consisting of cyano, nitro, —OH, —SH, —SCN, —SF5, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, —Si(R14)3,
C3-C8-cycloalkyl which may be unsubstituted, partially or fully halogenated and/or may carry 1 or 2 radicals selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and oxo;
aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy, where the cyclic moiety in the 6 last-mentioned radicals may be unsubstituted, partially or fully halogenated and/or carry 1, 2, 3, 4 or 5 substituents R15; or
two R17 present on the same carbon atom (of an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl or polycarbocyclyl, group) may together be ═O, ═CH(C1-C4-alkyl), ═C(C1-C4-alkyl)C1-C4-alkyl, ═N(C1-C6-alkyl) or ═NO(C1-C6-alkyl);
and
R17 as a substituent on a cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl or polycarbocyclyl ring is additionally selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, wherein the three last-mentioned aliphatic radicals may be unsubstituted, partially or fully halogenated and/or may carry 1 or 2 substituents selected from the group consisting of CN, C3-C4-cycloalkyl, C3-C4-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and oxo;
each R18 is independently selected from the group consisting of hydrogen, cyano, —Si(R14)3,
C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, wherein the three last-mentioned aliphatic radicals may be unsubstituted, partially or fully halogenated and/or may carry 1 or 2, in particular 1, radicals selected from the group consisting of C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C20-alkoxy, C1-C20-haloalkoxy, C1-C20-alkylthio, C1-C20-haloalkylthio, C1-C20-alkylsulfinyl, C1-C20-haloalkylsulfinyl, C1-C20-alkylsulfonyl, C1-C20-haloalkylsulfonyl and oxo;
C3-C8-cycloalkyl which may be unsubstituted, partially or fully halogenated and/or may carry 1 or 2, in particular 1, radicals selected from the group consisting of C1-C4-alkyl, C1-C4-haloalkyl, C3-C4-cycloalkyl, C3-C4-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, C1-C4-haloalkylthio, C1-C4-alkylsulfinyl, C1-C4-haloalkylsulfinyl, C1-C4-alkylsulfonyl, C1-C4-haloalkylsulfonyl and oxo;
aryl, heterocyclyl and heteroaryl, wherein the 3 last-mentioned radicals may be unsubstituted, partially or fully halogenated and/or carry 1, 2 or 3, preferably 1 or 2 in particular 1, substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl; and
R18 in the group S(O)mR18 is additionally selected from the group consisting of C1-C6-alkoxy, C1-C6-haloalkoxy, aryloxy, heterocyclyloxy and heteroaryloxy;
each R19 is independently selected from the group consisting of halogen, nitro, cyano, —OH, —SH, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C3-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, Si(R14)3;
C3-C8-cycloalkyl, C3-C8-halocycloalkyl, wherein the two last-mentioned cycloaliphatic radicals may carry one or more radicals selected from the group consisting of cyano, C1-C4-alkyl, C1-C4-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and oxo;
aryl, aryloxy, heterocyclyl, heterocyclyloxy, heteroaryl and heteroaryloxy, wherein the 6 last mentioned radicals may be unsubstituted, partially or fully halogenated and/or carry 1, 2 or 3, in particular 1, substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl;
each R20 is independently defined as R18;
R21, R21a and R21b, independently of each other and independently of each occurrence, are selected from the group consisting of hydrogen, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, wherein the four last-mentioned aliphatic and cycloaliphatic radicals may be partially or fully halogenated, and/or the four last-mentioned aliphatic and cycloaliphatic radicals carry one or more substituents selected from the group consisting of cyano, OH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino;
aryl, aryl-C1-C4-alkyl, heterocyclyl, and heteroaryl, where the rings in the 4 last mentioned radicals may be substituted with 1, 2, 3, 4, or 5 substituents R15;
or R21a and R21b, together with the nitrogen atom to which they are bound, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic, inclusive heteroaromatic, ring, where the ring may further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from the group consisting of O, S, N, SO, SO2, C═O and C═S as ring members, wherein the heterocyclic ring may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from R15;
each R22 is independently defined as R16;
each R23 is independently selected from the group consisting of hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, and phenyl, optionally substituted with 1, 2, 3, 4, or 5 radicals selected from the group consisting of halogen, cyano, nitro, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy and C1-C6-haloalkoxy; and
m is 0, 1 or 2.
In the above radicals, all functional groups, especially halogen atoms and sulfonyloxy groups, have to be less reactive towards the organoboron compound than the halogen atom or sulfonate group on the desired reaction site of the R2—(Z)n compound.
Specifically, R1 and R2 are aryl or heteroaryl groups, Y is OH or forms a MIDA ester, Z is a halide, especially Cl or Br, and n is 1 or 2.
The organoboron compounds are either commercially available or can be prepared by known methods; see e.g. the below-described Miyaura borylation.
The organoboron compound and the halogenide or sulfonate can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In case of di- or polyfunctional halides or sulfonates, the molar ratio relates of course to the number of halide or sulfonate groups in the molecule. The organoboron compounds are however generally used in at least equimolar amount (in case of di- or polyfunctional halides or sulfonates, the at least equimolar amount refers of course to the amount of halide or sulfonate groups; i.e. for 1 mol of Z—R2—Z at least 2 mol of R1—BY2 are used), e.g. from equimolar amount to a fivefold or in particular threefold or especially twofold excess or 1.5-fold excess (again, in case of di- or polyfunctional halides or sulfonates, the excess amount refers of course to the amount of halide or sulfonate groups; i.e. for 1 mol of Z—R2—Z 10 mol of R1—BY2 are used for a fivefold excess). If however the halide or sulfonate is more easily available and/or less expensive than the organoboron compound, this can instead be used in excess, e.g. in a fivefold or threefold or twofold or 1.5-fold excess. Especially in case that the organoboron compound is a MIDA ester, the organoboron compound and the halide or sulfonate can be used in approximately equimolar amounts.
The Pd catalyst can generally either be used as a salt (e.g. Pd(II) acetate or Na2PdCl4) or, more often, as a Pd(II) complex which is either preformed or prepared in situ from a Pd(II) salt (e.g. Pd(II)acetate or PdCl2) and the respective ligand. The same applies to Ni catalysts. Suitable ligands for the complex often contain phosphorus. Examples for phosphorus ligands are di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)-phosphine (cBRIDP; Mo-Phos), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-Bu XPhos, tBuXPhos, tert-Butyl XPhos), 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf), 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,4-bis(diphenylphosphino)butane (dppb), (2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (diop), bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine) (Amphos), (2S,3S)-(−)-bis(diphenylphosphino)butane (Chiraphos), di-(tert-butyl)phenylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), [1,1′-biphenyl]-2-diisopropyl phosphine, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos), 4,5-bis-(di-1-(3-methylindolyl)-phosphoramidit)-2,7,9,9-tetramethylxanthene (MeSkatOX), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-phos), 2-(2-dicyclohexylphosphanylphenyl)-N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine (C-phos), 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine, [(4R)-(4,4′-bis-1,3-benzodioxole)-5,5′-diyl]bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine] ((R)-DTBM-SEGPHOS®), (R)- or (S)-3,5-Xyl-MeO-BIPHEP, (R,S)- or (S,R)-PPF-P(t-Bu)2, the Josiphos ligands, triphenylphosphine, triphenylphosphite, tri-(2-(1,1-dimethylethyl)-4-methoxy-phenyl)-phosphite, tricyclohexylphosphine, tri(tert-butyl)phosphine, butyldi-1-adamantylphosphine (cataCXium), 1,6-bis(diphenylphosphino)hexane (DPPH), 2,6-bis(2,5-dimethylphenyl)-1-octyl-4-phenylphosphacyclohexan (PCH), tris(3-sulfophenyl)phosphine trisodium salt (TPPTS) and the like.
Non-phosphorus ligands are for example bis(dibenzylideneacetone) (dba), acetonitrile, bisoxazoline and the like. Further, examples for Pd catalysts with ligands without phosphorus are the above-mentioned PEPPSI catalysts (inclusive the new generation).
Examples for catalysts are Pd(Cl)2(dtbpf), PdCl2(dppf), Pd(PPh3)4, Pd(Cl)2(t-Bu2PPh)2, Pd(Cl)2(Amphos)2, Pd(OAc)2-TPPTS, (OAc=acetate, Ph=phenyl), Pd(dba)2, the above PEPPSI catalysts (inclusive the new generation), Ni(Cl)2(dtbpf), Ni(Cl)2(dppf), Ni(Cl)2(dppp), and the like.
Suitable bases can be inorganic or organic. Examples for suitable inorganic bases are alkali metal carbonates, e.g. Li2CO3, Na2CO3, K2CO3 or Cs2CO3, alkali metal hydroxides, e.g. LiOH, NaOH or KOH, or phosphates, e.g. Li3PO4, Na3PO4, K3PO4 or Cs3PO4. Examples for suitable organic bases are open-chained amines, e.g. trimethylamine, triethylamine, tripropylamine, ethyldiisopropylamine and the like, basic N-heterocycles, such as morpoline, pyridine, lutidine, DABCO, DBU or DBN, alkoxylates, e.g. sodium or potassium methanolate, ethanolate, propanolate, isopropanolate, butanolate or tert-butanolate, especially sterically hindered alkoxylates, such as sodium or potassium tert-butanolate, silanolates, like sodium or potassium trimethylsilanolate ((CH3)3SiO−) or triisopropylsilanolate ((CH(CH3)2)3SiO−), phosphazene bases (superbases), such as BEMP and t-Bu-P4
or phenolates, especially sterically hindered phenolates, like the sodium or potassium salts of the following hydroxyaromatic compounds:
wherein R is H or optionally substituted C1-C2-alkyl, e.g. methyl, CH2—N(CH3)2 or CH2CH2—C(O)—O—C18H21.
The alkoxylates, phenolates and silanolates are either commercially available or can be prepared shortly before starting the reaction or in situ by reaction of the respective alcohol/hydroxyaromatic compound/silanol with NaOH or KOH.
Specifically, the present method relates to a Suzuki reaction in which an aromatic or heteroaromatic halide R2—(Z)n, where R2 is a mono-, bi- or polycyclic, especially a mono-, bi- or tricyclic aryl or heteroaryl group, Z is a halogen atom, especially Cl, Br or I, and n is 1 or 2, is reacted with an aromatic or heteroaromatic boron compound R1—BY2, wherein R1 is a mono-, bi- or polycyclic, especially a mono-, bi- or tricyclic aryl or heteroaryl group and Y is OH or the two Y form together a group —O—C(═O)—CH2—N(CH3)—CH2—C(═O)—O—, in the presence of a Pd catalyst, specifically of PdCl2(dtbpf), and in the presence of a base, specifically of an organic base, very specifically an amine.
In a particular embodiment aryl groups R1 and R2 are mono-, bi- or tricyclic and are specifically selected from the group consisting of phenyl and naphthyl; and heteroaryl groups R1 and R2 are in particular mono-, bi- or tricyclic and are specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1 and R2 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1 and R2 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 and R2 are selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 and R2 are selected from the group consisting of fluorine, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 25° C. to 55° C. and very specifically from 40° C. to 50° C.
If n is 1, R2—(Z)n and R1—BY2 are in particular used in a molar ratio of from 0.8:1 to 1:4, more particularly from 1:1 to 1:3 and specifically from 1:1 to 1:2. If n is 2, R2—(Z)n and R1—BY2 are in particular used in a molar ratio of from 1:1.5 to 1:8, more particularly from 1:2 to 1:6 and specifically from 1:2 to 1:5.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.1 mol per mol of that reactant which not used in excess (here mostly the compound R2—(Z)n), in particular 0.005 to 0.07 mol per mol of the reactant not used in excess, specifically 0.01 to 0.05 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The base is generally used in excess, i.e. in overstoichiometric amounts with respect to that reactant not used in excess, e.g. in an amount of from 1.5 to 5 mol per mol of the reactant not used in excess, in particular 2 to 4 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for Suzuki reactions, e.g. by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s) and base, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Sonogashira Reaction
In another particular embodiment the transition metal catalyzed C—C coupling reaction is a Sonogashira reaction. In Sonogashira reactions an aryl, heteroaryl or vinyl halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) is reacted with a terminal alkyne. Preferably, a halogenide or sulfonate R2—(Z)n, where R2 is an alkenyl (especially a terminal alkenyl; i.e. Z is bound to a carbon atom of a C—C double bond), aryl or heteroaryl group, Z is a halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) group and n is 1, 2, 3 or 4, is reacted with a terminal alkyne H—C≡C—R1, where R1 is hydrogen or an alkyl, alkenyl, alkapolyenyl, alkynyl (provided that the C—C triple bond is not terminal), alkapolyynyl (provided there is no terminal C—C triple bond (—C≡C—H) in this radical), mixed alkenyl/alkynyl (provided there is no terminal C—C triple bond (—C≡C—H) in this radical), cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl or silyl group Si(R14)3, in the presence of a transition metal catalyst, mostly a Pd catalyst, optionally of a copper(I) salt, and in general also of a base. Each R14′ has independently one of the meanings given above in context with the Suzuki reaction for R14. Classically, the Sonogashira coupling involves the use of a copper salt. In the present invention, however, the term “Sonogashira reaction” or “Sonogashira coupling” is also used for the coupling of an aryl, heteroaryl or vinyl halogenide or sulfonate with a terminal alkyne in the presence of a transition metal catalyst, mostly a Pd catalyst, and in general also of a base, but without copper (salts/complexes).
The reaction of the terminal alkyne with R2—(Z)n yields a compound (R1)n—R2. The alkenyl, aryl or heteroaryl halide or sulfonate can contain more than one halide or sulfonate group (when n is 2, 3 or 4), so that multiply coupled compounds can form, especially if the alkyne compound is used in excess. For instance, a difunctional compound R2—(Z)2 can yield a twofold coupled compound R1—R2—R1.
Due to the tolerance of the Sonogashira reaction to a wide variety of functional groups, the alkyl, alkenyl, alkapolyenyl, alkynyl, mixed alkenyl/alkynyl, alkapolyynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl groups R1 and R2 can carry one or more substituents. Suitable substituents for the alkyl, alkenyl, alkapolyenyl, alkynyl, mixed alkenyl/alkynyl, alkapolyynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups R1 and R2 correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups, especially halogen atoms and sulfonyloxy groups, have to be less reactive towards the alkyne compound than the halogen atom or sulfonate group on the desired reaction site of the R2—(Z)n compound.
Suitable Pd catalysts (inclusive ligands) are those mentioned above in context with the Suzuki coupling.
Suitable Cu(I) salts are CuI and CuBr.
Suitable bases are those mentioned above in context with the Suzuki coupling.
Specifically, the present method relates to a Sonogashira reaction in which an aromatic or heteroaromatic halogenide R2—(Z)n, where R2 is a mono-, bi- or polycyclic aryl or heteroaryl group, Z is a halogen atom, especially Cl, Br or I, more specifically Br or I, and n is 1, is reacted with a terminal alkyne H—C≡C—R1, where R1 is a mono-, bi- or polycyclic aryl or heteroaryl group, in the presence of a Pd catalyst, specifically of PdCl2(CH3CN)2 or PdCl2(X-Phos)2, and in the presence of a base, specifically of an alkali metal carbonate, very specifically Cs2CO3, or an organic base, specifically an amine.
In a particular embodiment aryl groups R1 and R2 are mono-, bi- or tricyclic and are specifically selected from the group consisting of phenyl and naphthyl; and heteroaryl groups R1 and R2 are in particular mono-, bi- or tricyclic and are specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1 and R2 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1 and R2 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 and R2 are selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 and R2 are selected from the group consisting of fluorine, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
Very specifically, R1 and R2 are selected from the group consisting of phenyl and naphthyl, where phenyl and naphthyl may carry 1, 2 or 3, specifically 1 or 2 substituents as defined above.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C. and very specifically from 20° C. to 30° C.
The halogenide or sulfonate and the terminal alkyne can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In case of di- or polyfunctional halides or sulfonates, the molar ratio relates of course to the number of halide or sulfonate groups in the molecule. If n is 1, R2—(Z)n and H—C≡C—R1 are preferably used in a molar ratio of from 2:1 to 1:2, more preferably from 1.5:1 to 1:1.5 and specifically in approximately equimolar amounts. If n is 2, R2—(Z)n and H—C≡C—R1 are preferably used in a molar ratio of from 1:1 to 1:4, more preferably from 1:1.5 to 1:3 and specifically in a molar ratio of ca. 1:2. “ca.” and “approximately” include weighing errors of +/−10%.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.1 mol per mol of that reactant which is not used in excess, in particular 0.005 to 0.07 mol per mol of the reactant not used in excess, specifically 0.005 to 0.05 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The base is generally used in excess, i.e. in overstoichiometric amounts with respect to that reactant not used in excess, e.g. in an amount of from 1.5 to 5 mol per mol of the reactant not used in excess, in particular 1.5 to 4 mol per mol of the reactant not used in excess, specifically 1.5 to 3 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for Sonogashira reactions, e.g. by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s) and base, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Heck Reaction
In another particular embodiment the transition metal catalyzed C—C coupling reaction is a Heck reaction. In Heck reactions an aryl, heteroaryl, benzyl, vinyl or alkyl halogenide or sulfonate (the alkyl group must not contain any β-hydrogen atoms) is reacted with an olefinically unsaturated compound in the presence of a transition metal catalyst, mostly a Pd catalyst, and generally also in the presence of a base. The sulfonate is in particular a fluorinated alkylsulfonate or tosylate, specifically triflate, nonaflate or tosylate.
Preferably, a halogenide or sulfonate R2—(Z)n, where R2 is an aryl, heteroaryl, benzyl, vinyl or alkyl group (the alkyl group must however not contain any β-hydrogen atoms), Z is a halogen atom or a sulfonate group (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate, nonaflate or tosylate), preferably a Cl, Br, I, triflate, nonaflate or tosylate group, and n is 1, 2, 3 or 4, is reacted with an olefin R1(H)C═C(R3)(R4) where R1, R3, and R4, independently of each other, are hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, or are one of the substituents listed in context with the Suzuki reaction as suitable radicals on alkyl, alkenyl, alkapoyenyl, alkynyl, alkapolyynyl or mixed alkenyl/alkynyl groups (however except for oxo (═O), ═S, and ═NR12a), in the presence of a transition metal catalyst, mostly a Pd catalyst, and in general also of a base. More precisely, R1, R3 and R4, independently of each other, are hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13 or —Si(R14)3; where R11, R12a, R12b, R13, R14 and R15 are independently as defined above in context with the Suzuki reaction. The reaction yields a compound (R1)n—R2. The halogenide or sulfonate can contain more than one halogenide or sulfonate group (when n is 2, 3 or 4), so that multiply coupled compounds can form, especially if the olefinic compound is used in excess. For instance, a difunctional compound R2—(Z)2 can yield a twofold coupled compound R1—R2—R1.
Due to the tolerance of the Heck reaction to a wide variety of functional groups, the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, benzyl, vinyl groups R1, R2, R3 and R4 can carry one or more substituents. Suitable substituents for the on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups correspond to those listed above in context with substituents on the alkyl, alkenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Specifically, the cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl and heteroaryl groups R1, R3 and R4 may be substituted by one or more radicals R15.
In these substituents, however, all functional groups, especially halogen atoms and sulfonyloxy groups, have to be less reactive towards the olefinic compound than the halogen atom or sulfonate group on the desired reaction site of the R2—(Z)n compound. Analogously, if in the olefinic compound R1(H)C═C(R3)(R4) the radicals R1, R3, and/or R4 contain C—C double (or also triple) bonds, these have to be less reactive towards Z than the C—C double bond at the desired reaction site of R1(H)C═C(R3)(R4).
Suitable Pd catalysts (inclusive ligands) are those mentioned above in context with the Suzuki coupling.
Suitable bases are those mentioned above in context with the Suzuki coupling.
Specifically, the present method relates to a Heck reaction in which an aromatic or heteroaromatic halogenide R2—(Z)n, where R2 is a mono-, bi- or polycyclic aryl or heteroaryl group, Z is a halogen atom, especially Cl, Br or I, more specifically Br or I, and n is 1, is reacted with an olefinic compound R1(H)C═C(R3)(R4) where R1 and R3 are H and R4 is hydrogen, alkyl, or is one of the substituents listed in context with the Suzuki reaction as suitable radicals on alkyl, alkenyl and alkynyl groups (and is more precisely hydrogen, alkyl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13 or —Si(R14)3), in the presence of a Pd catalyst, specifically of Pd(t-Bu3P)2, and in the presence of a base, specifically an amine.
In a particular embodiment the aryl group R2 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl group R2 is in particular mono-, bi- or tricyclic and is specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R2 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R2 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R2 are selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R2 are selected from the group consisting of fluorine, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
Particular groups R4 are halogen (provided that this not more reactive than the halogen atom or sulfonate group on the desired reaction site of the R2—(Z)n compound) cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13, —Si(R14)3, alkyl, optionally substituted by one or more radicals R17; cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, where the 5 last-mentioned substituents may carry one or more substituents selected from R15; aryl which may be substituted by one or more radicals R15, heterocyclyl may be substituted by one or more radicals R15; and heteroaryl which may be substituted by one or more radicals R15; where R11, R12a, R12b, R13, R14, R15 and R17 are as defined above in context with the Suzuki reaction. Specifically, R4 is C(═O)R13, where R13 is alkyl or alkoxy, specifically C1-C6-alkyl or C1-C6-alkoxy and very specifically C1-C6-alkoxy.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 25° C. to 55° C. and very specifically from 40° C. to 50° C.
The halogenide or sulfonate and the olefinically unsaturated compound can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In case of di- or polyfunctional halogenides or sulfonates, the molar ratio relates of course to the number of halogenide or sulfonate groups in the molecule. If n is 1, R2—(Z)n and R1(H)C═C(R3)(R4) are preferably used in a molar ratio of from 0.8:1 to 1:4, more preferably from 1:1 to 1:3 and specifically from 1:1 to 1:2. If n is 2, R2—(Z)n and R1(H)C═C(R3)R4) are preferably used in a molar ratio of from 1:1.5 to 1:8, more preferably from 1:2 to 1:6 and specifically from 1:2 to 1:5.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.1 mol per mol of that reactant which is not used in excess, in particular 0.005 to 0.07 mol per mol of the reactant not used in excess, specifically 0.01 to 0.05 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The base is generally used in excess, i.e. in overstoichiometric amounts with respect to that reactant not used in excess, e.g. in an amount of from 1.5 to 5 mol per mol of the reactant not used in excess, in particular 1.5 to 4 mol per mol of the reactant not used in excess, specifically 2 to 4 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for Heck reactions, e.g. by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s) and base, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
C—C Coupling Reactions Involving C—H Activation
In another particular embodiment the transition metal catalyzed C—C coupling reaction is C—C coupling reaction involving C—H activation. Such reactions are coupling reactions in which one of the reactants reacts via a C—H bond and not via a specific activating group. The Heck reaction is such a reaction involving C—H activation. In the present case however, in the C—C coupling reactions involving C—H activation two aromatic or heteroaromatic compounds are coupled.
In a particular embodiment of the present invention, a halogenide or sulfonate R2—Z, where R2 is an aryl or heteroaryl group, Z is a halogen atom (Cl, Br and I being preferred) or a sulfonate group (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate, nonaflate or tosylate), and is preferably I, is reacted with a compound R1—H, where R1 is an aryl or heteroaryl group, in the presence of a transition metal catalyst, mostly a Pd catalyst, often under acidic conditions. If Z is Cl, Br or I, it may be advantageous to carry out the reaction in the presence of a water-soluble silver(I) salt, which precipitates the eliminated chloride, bromide or iodide ion as AgCl, AgBr or AgI and draws the reaction to the product side. The reaction yields a compound R1—R2. Preferably, R1 carries in ortho position to the shown hydrogen atom a heteroatom-directing group. This group helps the transition metal to coordinate to the substrate. Such heteroatom-directing groups are for example amino groups, carbonylamino groups, urea groups, carbonyl groups, carboxyl groups, carboxylic ester groups, carboxamide groups and the like. Particularly useful are urea groups, especially urea groups with electron-donating groups, e.g. alkyl-substituted urea groups, such as (C1-C4-alkyl)2N—C(O)—NH—.
In a particular embodiment aryl groups R1 and R2 are mono-, bi- or tricyclic and are specifically selected from the group consisting of phenyl and naphthyl; and heteroaryl groups R1 and R2 are in particular mono-, bi- or tricyclic and are specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1 and R2 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1 and R2 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction.
In these substituents, however, all functional groups, especially halogen atoms and sulfonyloxy groups, have to be less reactive towards the alkyne compound than the halogen atom or sulfonate group on the desired reaction site of the R2—Z compound.
In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 and R2 are selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 and R2 are selected from the group consisting of fluorine, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
Very specifically, R1 and R2 are selected from the group consisting of phenyl and naphthyl, where phenyl and naphthyl may carry 1, 2 or 3, specifically 1 or 2 substituents as defined above. As said, preferably, R1 carries in ortho position to the shown hydrogen atom a heteroatom-directing group.
Suitable Pd catalysts (inclusive ligands) are those mentioned above in context with the Suzuki coupling. Particularly, however, the Pd catalyst is used in form of a salt, e.g. as PdCl2 or, in particular Pd(OAc)2 (OAc=acetate).
The Ag salt, if present, is in particular used as a water-soluble salt, e.g. AgNO3 or, in particular, AgOAc.
The reaction is preferably carried out in acidic medium, so that the electrophilic attack on the (het)aryl ring is facilitated. Suitable acids are for example HBF4, trifluoroacetic acid, toluenesulfonic acid and acetic acid.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C. and very specifically from 20° C. to 30° C.
The halogenide or sulfonate and the C—H compound can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5; preferably from 4:1 to 1:4, in particular from 3:1 to 1:3 and specifically from 2:1 to 1:2.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of that reactant which is not used in excess, in particular 0.01 to 0.5 mol per mol of the reactant not used in excess, specifically 0.05 to 0.3 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The silver(I) salt is preferably used in such an amount that it can precipitate all the theoretically eliminated halide ions. Accordingly, it is preferably used in at least equimolar amounts with respect to the halide R2—Z, e.g. in a weight ratio of Ag salt to halide of from 1:1 to 2:1, in particular 1:2 to 1.5:1 and specifically in approximately equimolar amounts “Approximately” includes weighing errors of +/−10%.
The acid is generally used in excess, i.e. in overstoichiometric amounts with respect to that reactant not used in excess, e.g. in an amount of from 1.5 to 5 mol per mol of the reactant not used in excess, in particular 1.5 to 4 mol per mol of the reactant not used in excess, specifically 2 to 4 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for C—C coupling reactions reactions involving C—H activation, e.g. by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s), silver salt, if used, acid, if used, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Negishi Reaction
In another particular embodiment the transition metal catalyzed C—C coupling reaction is a Negishi reaction. In classical Negishi reactions an organozinc compound is reacted with a halogenide, sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) or acetate in the presence of a transition metal catalyst, mostly a Pd or Ni catalyst, where the Pd catalyst is often better suited. The reaction does not need the presence of a further booster, such as the base in the Suzuki coupling. Instead of organozinc compounds organoaluminum or organozirconium compounds can be used. If these are not reactive enough they can be transmetallated to the corresponding zinc compounds by addition of zinc salts (“double metal catalysis”).
In the present case, however, the organozinc compound (or the organoaluminum or organozirconium compound) need not be preformed. Instead the precursor halide (of which the organozinc compound would normally be formed), the other halogenide, sulfonate or acetate, a transition metal catalyst (mostly a Pd or Ni catalyst, better a Pd catalyst) and Zn dust or powder are mixed in water in the presence of the cellulose derivative. It is assumed that the corresponding organozinc compound is formed in situ and reacts then with the halogenide, sulfonate or acetate. Preferably, a halide R1—Z, where R1 is an alkyl, alkenyl, alkynyl, aryl or heteroaryl group and Z is a halogen atom, especially Cl, Br or I, is reacted with a compound R2—(Z)n, where R2 is an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, Z is a halogen atom, a sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) or an acetate group and n is 1, 2, 3 or 4, in the presence of a transition metal catalyst, mostly a Pd or Ni catalyst, where the Pd catalyst is often better suited, Zn powder or dust to a compound (R1)n—R2. The halogenide, sulfonate or acetate can contain more than one halogenide, sulfonate or acetate group (when n is 2, 3 or 4), so that multiply coupled compounds can form, especially if the organozine compound is used in excess. For instance, a difunctional compound R2—(Z)2 can yield a twofold coupled compound R1—R2—R1. In a particular embodiment the reaction is moreover carried out in the presence of TMEDA (tetramethylethylendiamine), which presumably activates the Zn surface.
Due to the tolerance of the Negishi reaction to a wide variety of functional groups, the alkyl, alkenyl, alkynyl, aryl or heteroaryl groups R1 and R2 can carry one or more substituents. Suitable substituents correspond to those listed above in context with substituents on the alkyl, alkenyl, alkynyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups, especially halogen atoms and sulfonyloxy groups, have to be less reactive towards the organozinc compound (formed in situ) than the halogen atom or sulfonate or acetate group on the desired reaction site of the R1—Z and R2—(Z)n compounds.
Suitable Pd and Ni catalysts (inclusive ligands) are those mentioned above in context with the Suzuki coupling.
The precursor halide (of which the organozinc compound would normally be formed) or the organizing compound, if preformed, and the other halogenide, sulfonate or acetate can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In case of di- or polyfunctional halogenides, sulfonates or acetates, the molar ratio relates of course to the number of halogenide, sulfonate or acetate groups in the molecule.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.1 mol per mol of that reactant which is not used in excess, in particular 0.005 to 0.07 mol per mol of the reactant not used in excess, specifically 0.01 to 0.05 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Stille Coupling
In another particular embodiment the transition metal catalyzed C—C coupling reaction is a Stille reaction. In the Stille reaction, also termed Migita-Kosugi-Stille coupling, an organotin compound (organostannane) is reacted with an alkenyl, aryl, heteroaryl or acyl halide, sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) or phosphate in the presence of a transition metal catalyst, mostly a Pd catalyst, and sometimes also in the presence of a base.
Preferably, the organostannane compound is a compound of formula R1—Sn(Ra)3, where R1 is a an alkenyl, aryl or heteroaryl group and Ra is an alkyl group, mostly butyl. The alkenyl, aryl, heteroaryl or acyl halide, sulfonate or phosphate is preferably a compound R2—(Z)n, where R2 is an alkenyl, aryl, heteroaryl or acyl group, Z is a halogen atom, sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) or phosphate group, preferably a Cl, Br, I, triflate, nonaflate or phosphate group, and n is 1, 2, 3 or 4. The reaction yields a compound (R1)n—R2. The halogenide, sulfonate or phosphate can contain more than one halogenide, sulfonate or phosphate group (when n is 2, 3 or 4), so that multiply coupled compounds can form, especially if the organostannane compound is used in excess. For instance, a difunctional compound R2—(Z)2 can yield a twofold coupled compound R1—R2—R1.
Due to the tolerance of the Stille reaction to a wide variety of functional groups, the alkenyl, aryl and heteroaryl groups R1 and R2 can carry one or more substituents. Suitable substituents correspond to those listed above in context with substituents on the alkyl, alkenyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups, especially halogen atoms and sulfonyloxy groups, have to be less reactive towards the organotin compound than the halogen atom or sulfonate or phosphate group on the desired reaction site of the R2—(Z)n compound.
Suitable Pd catalysts (inclusive ligands) are those mentioned above in context with the Suzuki coupling.
Suitable bases are those mentioned above in context with the Suzuki coupling.
Specifically, the present method relates to a Stille reaction in which an aromatic or heteroaromatic halogenide R2—(Z)n, where R2 is a mono-, bi- or polycyclic aryl or heteroaryl group, Z is a halogen atom, especially Cl, Br or I, more specifically Br or I, and n is 1, is reacted with an organostannane R1—Sn(Ra)3, where R1 is an aryl or in particular an alkenyl group and Ra is butyl, a Pd catalyst, specifically of Pd(t-Bu3P)2, and in the presence of a base, specifically a basic heterocycle.
In a particular embodiment aryl groups R1 and R2 are mono-, bi- or tricyclic and are specifically selected from the group consisting of phenyl and naphthyl; and heteroaryl groups R1 and R2 are in particular mono-, bi- or tricyclic and are specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1 and R2 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1 and R2 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 and R2 are selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 and R2 are selected from the group consisting of fluorine cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
The alkenyl group R1 may be substituted as described above in context of the Suzuki reaction for alkenyl groups R1 and R2. In particular, the alkenyl group has a terminal C—C double bond; i.e. Sn is bound to a C—C double bond. This C—C double bond may be substituted as described above in context of the Suzuki reaction for alkenyl groups R1 and R2. Examples for suitable substituents on this C—C double bond or on alkenyl in general are halogen (provided that this not more reactive than the group Z in the R2—(Z)n compound) cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13, —Si(R14)3, alkyl, optionally substituted by one or more radicals R17; cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, where the 5 last-mentioned substituents may carry one or more substituents selected from R15; aryl which may be substituted by one or more radicals R15, heterocyclyl may be substituted by one or more radicals R15; and heteroaryl which may be substituted by one or more radicals R15; where R11, R12a, R12b, R13, R14, R15 and R17 are as defined above in context with the Suzuki reaction. Specifically, the substituent on the alkenyl group R1 is OR11, where R13 is alkyl, specifically C1-C6-alkyl.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., and specifically from 20° C. to 50° C.
The halogenide, sulfonate or phosphate and the organostannane compound can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In case of di- or polyfunctional halogenides, sulfonates or phosphates, the molar ratio relates of course to the number of halogenide, sulfonate or phosphate groups in the molecule. If n is 1, R2—(Z)n and R1—Sn(Ra)3 are preferably used in a molar ratio of from 0.8:1 to 1:2, more preferably from 1:1 to 1:1.5 and specifically from 1:1 to 1:1.2. If n is 2, R2—(Z)n and R1—Sn(Ra)3 are preferably used in a molar ratio of from 0.4:1 to 1:4, more preferably from 0.5:1 to 1:3 and specifically from 0.5:1 to 1:2.5.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.1 mol per mol of that reactant which is not used in excess, in particular 0.005 to 0.07 mol per mol of the reactant not used in excess, specifically 0.007 to 0.05 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The base is generally used in excess, i.e. in overstoichiometric amounts with respect to that reactant not used in excess, e.g. in an amount of from 1.1 to 5 mol per mol of the reactant not used in excess, in particular 1.2 to 4 mol per mol of the reactant not used in excess, specifically 1.3 to 2 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for Stille reactions, e.g. by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s) and base, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Grubbs Olefin Metathesis
In another particular embodiment the transition metal catalyzed C—C coupling reaction is a Grubbs olefin metathesis. Olefin metathesis is an organic reaction in which fragments of alkenes (olefins) are redistributed by the scission and regeneration of carbon-carbon double bonds, as illustrated below (the regio- and steric arrangement of the groups is not necessarily as shown; Ra and Re as well as Rb and Rg can be trans to each other, or an olefin RaRdC═CRfRg+an olefin RbRcC═CReRh can be formed instead of the below couple):
Olefin metathesis, which includes i.a. cross metathesis (CM), ring opening metathesis (ROM), ring closing metathesis RCM), acyclic diene metathesis (ADMET) and ethanolysis, is catalyzed by various transition metal catalysts, the most known being the Schrock and Grubbs metathesis catalysts. In the present case, the olefin metathesis is a Grubbs olefin metathesis, which means that it is catalyzed by a Grubbs catalyst. Grubbs catalysts are Ruthenium carbene complexes, especially complexes of the following formulae:
First generation Grubbs catalyst:
This first generation catalyst is e.g. prepared from RuCl2(PPh3)4 and diphenylcyclopropene.
The second generation catalyst has following formula:
The Hoveyda Grubbs first generation catalyst has following formula:
The Hoveyda Grubbs second generation catalyst has following formula:
The Hoveyda Grubbs third generation catalyst has following formula:
Grubbs catalysts in terms of the present invention also include the Hoveyda Grubbs I and II analogous catalysts from Zannan Pharma Ltd. with a sulfonamide on the phenyl ring:
In a preferred embodiment, two olefinic compounds R1R2C═CR3R4 and R5R6C═CR7R8 are reacted with each other in the presence of a Grubbs catalyst, especially the Grubbs second generation catalyst. R1, R2, R3, R4, R5, R6, R7 and R8, independently of each other, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl or are one of the substituents listed in context with the Suzuki reaction as suitable radicals on alkyl, alkenyl and alkynyl groups (however except for oxo (═O), ═S and ═NR12a). More precisely, R1, R2, R3, R4, R5, R6, R7 and R8, independently of each other, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13 or —Si(R14)3; where R11, R12a, R12b, R13 and R14 are independently as defined above in context with the Suzuki reaction. The alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl groups R1, R2, R3, R4, R5, R6, R7 and R8 can in turn carry one or more substituents. Suitable substituents for the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl groups correspond to those listed above in context with substituents on the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In particular R3, R4, R7 and R8 are hydrogen and at least one of R1, R2, R5 and R6 is not hydrogen. More particularly, R3, R4, R7 and R8 are hydrogen, one of R1 and R2 is not hydrogen and one of R5 and R6 is not hydrogen. In particular, the two radicals not being hydrogen are selected from the group consisting of halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13, —Si(R14)3, alkyl, optionally substituted by one or more radicals R17; aryl which may be substituted by one or more radicals R15, and a 3-, 4-, 5-, 6- 7-, 8-, 9- or 10-membered saturated, partially unsaturated or maximally unsaturated (inclusive heteroaromatic) heteromonocyclic or heterobicyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members, where the heteromonocyclic or heterobicyclic ring may be substituted by one or more radicals R15; where R11, R12a, R12b, R13, R14, R15 and R17 are as defined above in context with the Suzuki reaction. Specifically, one of R1 and R2 is alkyl, optionally substituted by one or more radicals R17; and one of R5 and R6 is C(═O)R13. More specifically one of R1 and R2 is C1-C4-alkyl substituted with an aryl group which may carry one or more substituents R15 as defined in context with the Suzuki reaction, and one of R5 and R6 is C(═O)R13, where R13 is C1-C6-alkoxy.
The olefins R1R2C═CR3R4 and R5R6C═CR7R8 are used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or 5:1 to 1:5, preferably 4:1 to 1:4, in particular 3:1 to 1:3 and specifically from 2:1 to 1:2.
The catalyst is generally used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.0001 to 0.1 mol per mol of that reactant which is not used in excess, in particular 0.001 to 0.05 mol per mol of the reactant not used in excess, specifically 0.002 to 0.01 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
It may be advantageous to carry out the reaction in the presence of a weak acid, such as acetic acid, citric acid, malic acid, oxalic acid or succinic acid. The acid is generally used in substoichiometric amounts, e.g. in an amount of from 0.0001 to 0.1 mol per mol of that reactant which is not used in excess, in particular 0.001 to 0.05 mol per mol of the reactant not used in excess, specifically 0.002 to 0.01 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of acid apply of course to either of the reactants.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C. and very specifically from 20° C. to 30° C.
The reaction can be carried out by standard proceedings for olefin metathesis reactions, e.g. by mixing all reagents, inclusive catalyst, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Although Grubbs catalysts are rather stable to oxidation by air, the reaction is nevertheless preferably carried out in an inert atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
1,4-Additions of an Organoborane Compounds to α,β-olefinically Unsaturated Carbonyl Compounds
In another particular embodiment the transition metal catalyzed C—C coupling reaction is a 1,4-addition of an organoborane compound to an α,β-olefinically unsaturated carbonyl compound. This addition reaction resembles the well-known Michael addition, uses however an organoboron compound as nucleophile instead of a CH-acidic compound, and uses transition metal catalysis. Suitable catalysts are Pd, Ru and especially Rh catalysts.
Preferably, the organoboron compound is a compound of formula R1—BY2, where R1 is an alkyl, alkenyl, alkynyl, aryl or heteroaryl group and Y is an alkyl, O-alkyl or hydroxyl group, or the two substituents Y form together with the boron atom they are bound to a mono-, bi- or polycyclic ring; or the organoboron compound is a compound of formula R1—BF3M, where M is a metal equivalent. Examples of suitable organoboron compounds R1—BY2 are R1—B(OH)2, R1—B(O—C1-C4-alkyl)2, R1—B(C1-C4-alkyl)2, or the MIDA ester of R1—B(OH)2 (MIDA=N-methyliminodiacetic acid; HO—C(═O)—CH2—N(CH3)—CH2—C(═O)—OH; i.e. the two Y form together —O—C(═O)—CH2—N(CH3)—CH2—C(═O)—O—).
The α,β-olefinically unsaturated carbonyl compound is preferably a compound of formula R2R3C═CR4—C(═O)—R5, where R2, R3 and R4, independently of each other, are hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and R5 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, OH, SH, alkoxy, alkylthio, NH2, alkylamino or dialkylamino. The alkyl (also as part of alkoxy, alkylthio, alkylamino or dialkylamino), alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups R1, R2, R3, R4 and R5 can carry one or more substituents. Suitable substituents for the alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups correspond to those listed above in context with substituents on the alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups have to be less reactive towards the organoboron compound than the desired reaction site on the C—C double bond of the α,β-olefinically unsaturated carbonyl compound.
Reaction of the organoboron compound with R2R3═CR—C(═O)—R5 yields a compound R1—(R2)(R)3C—CHR4—C(═O)—R5.
Specifically R1 is an aryl or heteroaryl group which may be substituted as described above in context with the Suzuki reaction.
In a particular embodiment the aryl group R1 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl group R1 is in particular mono-, bi- or tricyclic and is specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkycarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of fluorine, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
In particular at least one of R2 and R3 is H. If one of R2 and R3 is not H, this is specifically alkyl. Specifically, R4 is H. Specifically R5 is alkoxy.
Suitable Pd catalysts correspond to those mentioned above in context with the Suzuki reaction.
Like Pd, Rh may be introduced as a salt into the reaction and converted in situ into a complex by reaction with suitable ligands. It is however more expedient to use preformed Rh catalysts.
Suitable Rh catalysts are e.g. [RhCl(C2H4)2]2, [RhCl2(C2H4)2], [Rh(nbd)]2BF4 (nbd=norbornadiene), [Rh(nbd)]2CF3SO3, [Rh(cod)(CH3CN)2]BF4 (cod=cyclooctadiene), [Rh(cod)2]PF6, [Rh(cod)2]SbF6, [Rh(cod)2]BF4, [Rh(cod)2]CF3SO3, [Rh(OH)(cod)]2, acetylacetonatobis(ethylene)rhodium(I), (acetylacetonato)(1,5-cyclooctadiene)rhodium(I), (acetylacetonato)dicarbonylrhodium(I), (acetylacetonatoxnorbornadiene)rhodium(I), (bicyclo[2.2.1]hepta-2,5-diene)[1,4-bis(diphenylphosphino)butane]rhodium(I) tetrafluoroborate, bicyclo[2.2.1]hepta-2,5-diene-rhodium(I) chloride dimer, [(bisacetonitrile)(norbornadiene)]rhodium(I) hexafluoroantimonate, bis(2,2-dimethylpropanoato)(4-methylphenyl)bis[tris[4-(trifluoromethyl)phenyl]phosphine]rhodium, [1,4-bis(diphenylphosphino)butane](1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, bis(triphenylphosphine)rhodium(I) carbonyl chloride, chlorobis(cyclooctene)rhodium(I) dimer, and the like.
The organoboron compound and the unsaturated carbonyl compound can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. The organoboron compounds are however generally used in at least equimolar amount, e.g. from equimolar amount to a fivefold or in particular threefold or especially twofold or 1.5-fold excess. If however the carbonyl compound is more easily available and/or less expensive than the organoboron compound, this can instead be used in excess, e.g. in a fivefold or threefold or twofold or 1.5-fold excess. Especially in case that the organoboron compound is a MIDA ester, the organoboron compound and the carbonyl compound can be used in approximately equimolar amounts.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.1 mol per mol of that reactant which not used in excess (here mostly the α,β-olefinically unsaturated carbonyl compound), in particular 0.005 to 0.07 mol per mol of the reactant not used in excess, specifically 0.01 to 0.07 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for transition metal-catalyzed 1,4-coupling reactions, e.g. by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s), water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air, the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Cyclopropanation
In another particular embodiment the transition metal catalyzed C—C coupling reaction is a cyclopropanation. Cyclopropanations without transition metal catalysis are also well-known reactions, but in this context, only transition metal catalyzed cyclopropanations are discussed. As said, in a transition metal catalyzed cyclopropanation an olefinically unsaturated compound is reacted with a diazo compound to a cyclopropane in the presence of a transition metal catalyst. The olefinically unsaturated compound is preferably a compound of formula R1R2C═CR3R4, and the diazo compound is preferably a compound of formula N2═CR5R6; where R1, R2, R3, R4, R5 and R6, independently of each other, are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, hetaryl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13 and —Si(R14)3; where R11, R12a, R12b, R13 and R14 are independently as defined above in context with the Heck reaction; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl and heteroaryl groups R1, R2, R3, R4, R5 and R6 can carry one or more substituents. Suitable substituents for the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl and heteroaryl groups correspond to those listed above in context with substituents on the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Specifically, the cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl and heteroaryl groups R1, R2, R3 and R4 may be substituted by one or more radicals R15.
Suitable catalysts are all those customarily used for cyclopropanations, such as the following copper(II) complexes of Schiff's bases
or the above-described semicorrin, bisoxazolin or porphyrin complexes. Among the above semicorrin and bis-oxazolin complexes, preference is given to following complexes of copper:
L is a simple ligand, such as Cl, or two L form together a usual bidentate ligand, such as acetylacetonate or methyl acetylacetate.
Preferably however, porphyrin complexes are used, in particular porphyrin complexes with Fe, Ru, Rh or Ir as central metal, but Zn may also be used.
The porphyrin ligand has preferably following structure:
Generally, at least one of Ra, Rb, Rc and Rd is an aromatic group, such as phenyl, optionally substituted by 1, 2 or 3 substituents selected from the group consisting of methyl, methoxy, hydroxyl, amino and the like. For sterically selective reactions, expediently, at least one of Ra, Rb, Rc and Rd is a chiral group, such as a BINAP radical, a phenyl ring carrying one or more chiral substituents or a phenyl ring fused to one or more rings resulting in a chiral system. Radicals Ra, Rb, Rc and Rd which are not an aromatic group are generally selected from the group consisting of alkyl groups, alkoxy groups, alkyl carbonyl groups and alkoxycarbonyl groups. They can however also be hydrogen. In a specific embodiment, Ra, Rb, Rc and Rd are phenyl, and the central atom is Fe, in particular Fe(III). The charge of the central metal is generally neutralized by a halide, especially chloride, an acetate or other anions customary in such complexes.
In a particular embodiment, in the olefinically unsaturated compound R1R2C═CR3R4 the radicals R1, R2, R3 and R4 are not electron-withdrawing groups and are preferably selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl and hetaryl, where these groups (apart from hydrogen, of course) may be substituted as described above. Specifically, the present method relates to a cyclopropanation reaction wherein in the olefinically unsaturated compound R1R2C═CR3R4 in two or three of R1, R2, R3 and R4 are hydrogen and the other is/are C1-C4-alkyl, C3-C6-cycloalkyl or aryl, specifically phenyl, where the alkyl, cycloalkyl and aryl radical may carry one or more substituents. Suitable substituents correspond to those listed above in context with substituents on the alkyl, cycloalkyl or aryl groups R1 and R2 in the Suzuki coupling. Very specifically, three of R1, R2, R3 and R4 are hydrogen and the other is phenyl which may be substituted as described above, specific substituents being selected from the group consisting of CN, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C3-C6-cycloalkyl, C3-C6-halocycloalkyl and phenyl.
In the diazo compound N2═CR5R6, R5 is specifically H and R6 is a C1-C4-alkoxycarbonyl group.
The diazocompound is prepared by known means, such as reaction of the C1-C4-alkyl ester of glycine with a nitrite, generally sodium nitrite, often in the presence of an acid. Suitable acids are inorganic acids which do not interfere with the diazonium formation, such as hydrochloric acid, and organic acids, such as acetic acid, trifluoroacetic acid, toluene sulfonic acid and the like. The diazo compound can be prepared in situ before the olefinic compound is added, i.e. in the aqueous solvent used in the method of the invention in the presence of the cellulose derivative, or, preferably, in the presence of the olefinic compound. For example, the olefinic compound, the C1-C4-alkyl ester of glycine, the transition metal catalyst, if desired the acid, water and the cellulose derivative are mixed and sodium nitrite is added. If desired, the reaction mixture can be heated before, during or after addition of sodium nitrite, e.g. to 30 to 60° C. or 35 to 50° C. or to 35 to 45° C.
The diazo compound is generally used in at least equivalent amounts, preferably in excess, with respect to the olefinic compound, the molar ratio of diazo compound and olefinic compound being preferably of from 1:1 to 10:1, in particular from 1.1:1 to 5:1 and specifically from 1.5:1 to 3:1.
The nitrite is generally used in at least equivalent amounts, often in slight excess, with respect to the diazo compound, the molar ratio of nitrite and diazo compound being preferably of from 1:1 to 5:1, in particular from 1:1 to 2:1 and specifically from 1.1:1 to 1.5:1.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.1 mol per mol of that reactant which not used in excess (here mostly the olefinic compound), in particular 0.005 to 0.07 mol per mol of the reactant not used in excess, specifically 0.005 to 0.05 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
Workup proceedings will be described below, as they are similar for most reactions.
b) C—N Coupling Reactions
In a particular embodiment, the transition metal catalyzed reaction is a C—N coupling reaction. Transition metal catalyzed C—N coupling reactions are well known. Examples are the Buchwald-Hartwig reaction and Au-catalyzed cyclodehydratizations of alkynes carrying in α-position to the alkyne group an OH group and in β-position a primary or secondary amino group to give pyrroles.
Buchwald-Hartwig Reaction
In a particular embodiment the transition metal catalyzed C—N coupling reaction is a Buchwald-Hartwig reaction. The Buchwald-Hartwig reaction is a transition metal-catalyzed, mostly a Pd catalyzed, C—N or C—O bond formation between an aryl or heteroaryl halogenide or sulfonate and a primary or secondary amine, carboxamide, sulfonamide, imide, urea or urethane (for C—N bond formation) or an alcohol (for C—O bond formation), generally in the presence of a base. In context with C—N coupling reactions, the Buchwald-Hartwig reaction is understood as a transition metal-catalyzed, mostly a Pd catalyzed, C—N bond formation between an aryl or heteroaryl halogenide or sulfonate (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) and a primary or secondary amine, carboxamide, sulfonamide, imide, urea or urethane, generally in the presence of a base.
Preferably, a halogenide or sulfonate R2—(Z)n, where R2 is an aryl or heteroaryl group, Z is a halogenide or sulfonate group (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) and n is 1, 2, 3 or 4, is reacted with a compound H—N(R1)R3, where R1 is H, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl, heteroaryl or —C(O)—R4, and R3 is H, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl, heteroaryl, —C(O)—R4, —S(O)2—R4, —C(O)—O—R4 or —C(O)—N(R4)R5, where R4 and R5 are independently H, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl, heterocyclyl or heteroaryl, or R4 and R5 form together with the nitrogen atom they are bound to a mono- bi- or polycyclic heterocyclic ring; or R1 and R3 form together with the nitrogen atom they are bound to a mono-, bi- or polycyclic heterocyclic ring. The reaction of the halogenide or sulfonate R2—(Z)n and the amine (derivative) H—N(R1)R3 yields a compound (R3(R1)N)n—R2. The aryl or heteroaryl halide or sulfonate can contain more than one halide or sulfonate group (when n is 2, 3 or 4), so that multiply coupled compounds can form, especially if the amine compound is used in excess. For instance, a difunctional compound R2—(Z)2 can yield a twofold C—N coupled compound R3(R1)N—R2—N(R1)R3.
Due to the tolerance of the Buchwald-Hartwig reaction to a wide variety of functional groups, the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl groups R1, R2, R3, R4, and R5, as well as the mono- bi- or polycyclic heterocyclic ring formed by R4 and R5 or R1 and R3 together with the nitrogen atom they are bound to, can carry one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups and for the mono- bi- or polycyclic heterocyclic ring formed by R4 and R5 together with the nitrogen atom they are bound to or by R1 and R3 together with the nitrogen atom they are bound to correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups, especially halogen atoms and sulfonyloxy groups, have to be less reactive than the halogen atom or sulfonate group on the desired reaction site of the R2—(Z)n compound; amino groups have to be less reactive than the amino group on the desired reaction site of the H—N(R1)R3 compound.
Suitable Pd catalysts (inclusive ligands) are those mentioned above in context with the Suzuki coupling.
Suitable bases are those mentioned above in context with the Suzuki coupling.
Specifically, the present method relates to a Buchwald-Hartwig reaction in which an aromatic or heteroaromatic halogenide R2—(Z)n, where R2 is an optionally substituted mono-, bi- or polycyclic aryl or heteroaryl group, Z is a halogen atom, especially Cl, Br or I, and n is 1, is reacted with an amine (derivative) H—N(R1)R3, where R1 is H and R3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(O)—R4, —S(O)2—R4, —C(O)—O—R4 or —C(O)—N(R4)R5, where R4 and R5 are independently of each other alkyl, optionally substituted aryl or optionally substituted heteroaryl, or R4 and R5 form together with the nitrogen atom they are bound to a monocyclic heterocyclic ring, in the presence of a Pd catalyst, specifically of a Pd catalyst with cBRIDP or t-BuXPhos as ligand, and in the presence of a base, specifically of an alkali metal alcoholate, especially an alkali metal tert-butanolate, or a silanolate, especially an alkali metal triisopropylsilanolate.
In a particular embodiment the aryl groups R1, R2, R3, R4, and R5 are mono-, bi- or tricyclic and are specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl groups R1, R2, R3, R4, and R5 are in particular mono-, bi- or tricyclic and are specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1, R2, R3, R4, and R5 are are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1, R2, R3, R4, and R5 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1, R2, R3R4, and R5 are selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected the group consisting of from fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1, R2, R3, R4, and R5 are selected from the group consisting of fluorine, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl.
In a more specific embodiment an aromatic or heteroaromatic halogenide R2—(Z)n, where
R2 is a mono- or bicyclic aryl group (i.e. phenyl or naphthyl) or is a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where the mono- or bicyclic aryl group and the heteroaromatic monocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl,
Z is a halogen atom, especially Cl, Br or I, and
n is 1,
is reacted with an amine (derivative) H—N(R1)R3, where
R1 is H and
R3 is optionally substituted C1-C6-alkyl, a mono- or bicyclic aryl group (i.e. phenyl or naphthyl), a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where the mono- or bicyclic aryl group and the heteroaromatic monocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl; —C(O)—R4, —S(O)2—R4, —C(O)—O—R4 or —C(O)—N(R4)R5, where the optional substituents on C1-C6-alkyl are selected from the group consisting of a mono- or bicyclic aryl group (i.e. phenyl or naphthyl) and a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where the mono- or bicyclic aryl group and the heteroaromatic monocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl; and
R4 and R5 are independently of each other hydrogen, C1-C6-alkyl, a mono- or bicyclic aryl group (i.e. phenyl or naphthyl) or a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where the mono- or bicyclic aryl group and the heteroaromatic monocyclic ring may carry 1, 2 or 3 substituents selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl; or R4 and R5 form together with the nitrogen atom they are bound to a 3-, 4-, 5-, 6- or 7-membered monocyclic saturated heterocyclic ring,
in the presence of a Pd catalyst, specifically of a Pd catalyst with cBRIDP or t-BuXPhos as ligand, and in the presence of a base, specifically of an alkali metal alcoholate, especially an alkali metal tert-butanolate, or a silanolate, especially an alkali metal triisopropylsilanolate.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C.
The halogenide or sulfonate and the amine (derivative) can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In case of di- or polyfunctional halides or sulfonates, the molar ratio relates of course to the number of halide or sulfonate groups in the molecule. If n is 1, R2—(Z)n and H—N(R1)R3 are preferably used in a molar ratio of from 3:1 to 1:3, in particular from 2:1 to 1:2. If n is 2, R2—(Z)n and H—N(R1)R3 are preferably used in a molar ratio of from 1.5:1 to 1:6, more preferably from 1:1 to 1:4. Specifically, the amine (derivative) H—N(R1)R3 is used in slight excess, e.g. in a 2-fold or 1.5-fold or 1.2-fold excess with respect to the n groups Z.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of that reactant which is not used in excess, in particular 0.002 to 0.3 mol per mol of the reactant not used in excess, specifically 0.003 to 0.2, more specifically 0.005 to 0.1 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The base is generally used in at least equimolar amount and mostly in excess, i.e. in overstoichiometric amounts, with respect to that reactant not used in excess, e.g. in an amount of from 1 to 5 mol per mol of the reactant not used in excess, in particular 1.2 to 3 mol per mol of the reactant not used in excess, specifically 1.3 to 2 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for Buchwald-Hartwig reactions, e.g. by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s) and base, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Au-Catalyzed Cyclodehydratizations of Aminoalcohols
α,β-amino alcohols containing an appropriately positioned alkynyl residue (C—C triple bond) can undergo gold-catalyzed ring closure/dehydration (cyclodehydration). For instance, an alkyne carrying in α-position to the alkyne group an OH group and in β-position a primary or secondary amino function undergoes cyclodehydration to the corresponding pyrrole, as shown in the scheme below; an alkyne carrying in β-position to the alkyne group an OH group and in γ-position a primary or secondary amino function undergoes cyclodehydration to the corresponding dihydropyridine, etc.
R1, R2, R3 and R4 are independently of each other H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl.
The alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl groups R1, R2, R3 and R4 can carry one or more substituents. Suitable substituents for alkyl, cycloalkyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, cycloalkyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In a specific embodiment, R2 and R3 are H, alkyl, cycloalkyl, in particular alkyl, specifically C1-C6-alkyl, and R1 is aryl or heteroaryl, where aryl and heteroaryl may carry one or more substituents. Suitable substituents correspond to those listed above in context with aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In a particular embodiment the aryl group R1 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl group R1 is in particular mono-, bi- or tricyclic and is specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,3,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
Suitable Au catalysts are Au(III) salts and Au complexes. Examples for suitable Au salts are AuCl3, AuBr3 or Au(triflate)3. Suitable complexes are for example (Ph3P)AuCl, [c-Hex2(o-biphenyl)]PAuCl or [t-Bu2(o-biphenyl)]PAuCl.
Ag salts or complexes can be use as co-catalysts. Examples are Ag(I) triflate or AgNO3.
The Au catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of aminoalcohol, in particular 0.005 to 0.2 mol per mol of aminoalcohol, specifically 0.005 to 0.1 per mol of aminoalcohol, more specifically 0.01 to 0.05 mol per mol of aminoalcohol.
Also the Ag co-catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of aminoalcohol, in particular 0.005 to 0.2 mol per mol of aminoalcohol, specifically 0.005 to 0.1 per mol of aminoalcohol, more specifically 0.01 to 0.05 mol per mol of aminoalcohol.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C.
The reaction can be carried out, e.g., by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s), water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air, the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
c) C—O Coupling Reactions
In a particular embodiment, the transition metal catalyzed reaction is a C—O coupling reaction. Transition metal catalyzed C—O coupling reactions are well known. Examples are Au-catalyzed cyclodehydratizations of alkyne diols, cyclizations of alkynenols, of alkynones or of allenones or the formation of alcohols or ethers via C—O coupling in analogy to the Ullmann biaryl ether synthesis.
Au-Catalyzed Cyclodehydratizations of Diols
α,β-diols containing an appropriately positioned alkynyl residue (C—C triple bond) can undergo gold-catalyzed ring closure/dehydration (cyclodehydration). For instance, an alkyne carrying in α- and β-position to the alkyne group two OH groups undergoes cyclodehydration to the corresponding furane, as shown in the scheme below; an alkyne carrying in β- and γ-position to the alkyne group two OH groups undergoes cyclodehydration to the corresponding pyrane, etc.
R1, R2 and R3 are independently of each other H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl.
The alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl groups R1, R2 and R3 can carry one or more substituents. Suitable substituents for alkyl, cycloalkyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, cycloalkyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In a specific embodiment, R2 and R3 are H, alkyl or cycloalkyl, in particular alkyl, specifically C1-C6-alkyl, and R1 is aryl or heteroaryl, where aryl and heteroaryl may carry one or more substituents. Suitable substituents correspond to those listed above in context with aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In a particular embodiment the aryl group R1 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl group R1 is in particular mono-, bi- or tricyclic and is specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
Suitable Au catalysts are Au(III) salts and Au complexes. Examples for suitable Au salts are AuCl3, AuBr3 or Au(triflate)3. Suitable complexes are for example (Ph3P)AuCl, [c-Hex2(o-biphenyl)]PAuCl or [t-Bu2(o-biphenyl)]PAuCl.
Ag salts or complexes can be use as co-catalysts. Examples are Ag(I) triflate or AgNO3.
The Au catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of diol, in particular 0.005 to 0.2 mol per mol of diol, specifically 0.005 to 0.1 per mol of diol, more specifically 0.01 to 0.05 mol per mol of diol.
Also the Ag co-catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of diol, in particular 0.005 to 0.2 mol per mol of diol, specifically 0.005 to 0.1 per mol of diol, more specifically 0.01 to 0.05 mol per mol of diol.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C.
The reaction can be carried out, e.g., by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s), water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air, the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Cyclizations of Alkynenols
Alcohols containing an appropriately positioned alkenyl and alkynyl group (C—C triple bond) can undergo transition metal-catalyzed ring closure. For instance, an alkenyne carrying in α-position to the alkene group an OH group undergoes cyclization to the corresponding furane, as shown in the scheme below; an alkenyne carrying in β-position to the alkene group an OH group undergoes cyclization to the corresponding pyrane, etc.
R1, R2, R3 and R4 are independently of each other H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl.
The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups R1, R2, R3 and R4 can carry one or more substituents. Suitable substituents for alkyl, cycloalkyl, aryl or heteroaryl groups R1, R2, R3 and R4 correspond to those listed above in context with substituents on the alkyl, cycloalkyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups R1, R2, R3 and R4 correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
Suitable catalysts are for example Ru, Pd, Ag and Au catalysts, among which Au catalysts generally give the best results.
Suitable Au catalysts are Au(III) salts and Au complexes. Examples for suitable Au salts are AuCl3, AuBr3 or Au(triflate)3. Suitable complexes are for example (Ph3P)AuCl, [c-Hex2(o-biphenyl)]PAuCl or [t-Bu2(o-biphenyl)]PAuCl.
Ag salts or complexes can be use as co-catalysts. Examples are Ag(I) triflate or AgNO3.
The Au catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of diol, in particular 0.005 to 0.2 mol per mol of alkenynol, specifically 0.005 to 0.1 per mol of alkenynol, more specifically 0.01 to 0.05 mol per mol of alkenynol.
Also the Ag co-catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of alkenynol, in particular 0.005 to 0.2 mol per mol of alkenynol, specifically 0.005 to 0.1 per mol of alkenynol, more specifically 0.01 to 0.05 mol per mol of alkenynol.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C.
The reaction can be carried out, e.g., by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s), water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air, the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Cyclization of Alkynones
Carbonyl compounds, especially aldehydes or ketones, containing an appropriately positioned alkynyl group (C—C triple bond) can undergo transition metal-catalyzed ring closure. For instance, an alkyne carrying in β-position to the alkyne group a C(O) group undergoes cyclization to the corresponding furane, as shown in the scheme below; an alkyne carrying in γ-position to the alkene group a C(O) group undergoes cyclization to the corresponding pyrane, etc.
R1, R2 and R3 are independently of each other H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl.
The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups R1, R2 and R3 can carry one or more substituents. Suitable substituents for alkyl, cycloalkyl, aryl or heteroaryl groups R1, R2 and R3 correspond to those listed above in context with substituents on the alkyl, cycloalkyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups R1, R2 and R3 correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
Suitable catalysts are for example Ru, Pd, Ag and Au catalysts, among which Au catalysts generally give the best results.
Suitable Au catalysts are Au(III) salts and Au complexes. Examples for suitable Au salts are AuCl3, AuBr3 or Au(triflate)3. Suitable complexes are for example (Ph3P)AuCl, [c-Hex2(o-biphenyl)]PAuCl or [t-Bu2(o-biphenyl)]PAuCl.
Ag salts or complexes can be use as co-catalysts. Examples are Ag(I) triflate or AgNO3.
The Au catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of alkynone, in particular 0.005 to 0.2 mol per mol of alkynone, specifically 0.005 to 0.1 per mol of alkynone, more specifically 0.01 to 0.05 mol per mol of alkynone.
Also the Ag co-catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of alkynone, in particular 0.005 to 0.2 mol per mol of alkynone, specifically 0.005 to 0.1 per mol of alkynone, more specifically 0.01 to 0.05 mol per mol of alkynone.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C.
The reaction can be carried out, e.g., by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s), water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air, the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Cyclization of Allenones
Carbonyl compounds, especially aldehydes or ketones, containing an appropriately positioned allene group can undergo transition metal-catalyzed ring closure. For instance, an allene carrying in α-position to the allene group a C(O) group undergoes cyclization to the corresponding furane, as shown in the scheme below; an allene carrying in β-position to the allene group a C(O) group undergoes cyclization to the corresponding pyrane, etc.
R1, R2 and R3 are independently of each other H, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl.
The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups R1, R2 and R3 can carry one or more substituents. Suitable substituents for alkyl, cycloalkyl, aryl or heteroaryl groups R1, R2 and R3 correspond to those listed above in context with substituents on the alkyl, cycloalkyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups R1, R2 and R3 correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
Suitable catalysts are for example Ru, Pd, Ag and Au catalysts, among which Au catalysts generally give the best results.
Suitable Au catalysts are Au(III) salts and Au complexes. Examples for suitable Au salts are AuCl3, AuBr3 or Au(triflate)3. Suitable complexes are for example (Ph3P)AuCl, [c-Hex2(o-biphenyl)]PAuCl or [t-Bu2(o-biphenyl)]PAuCl.
Ag salts or complexes can be use as co-catalysts. Examples are Ag(I) triflate or AgNO3.
The Au catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of allenone, in particular 0.005 to 0.2 mol per mol of allenone, specifically 0.005 to 0.1 per mol of allenone, more specifically 0.01 to 0.05 mol per mol of allenone.
Also the Ag co-catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.5 mol per mol of allenone, in particular 0.005 to 0.2 mol per mol of allenone, specifically 0.005 to 0.1 per mol of allenone, more specifically 0.01 to 0.05 mol per mol of allenone.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C.
The reaction can be carried out, e.g., by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s), water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air, the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Formation of Alcohols or Ethers Via C—O Coupling
The copper-mediated synthesis of biaryl ethers by reaction of an aromatic halide or pseudohalide and a hydroxyaromatic compound to a biaryl ether is known as the Ullmann biaryl ether synthesis or condensation. In the method of the present invention, the use of Cu is however not mandatory; any transition metal catalyst can be used. Mostly a Pd catalyst is used.
Moreover, the oxygen source is not limited to an aromatic hydroxyl compound, but can be any compound with a nucleophilic OH group. Thus, an aromatic or heteroaromatic compound R1—X, where R1 is an aryl or heteroaryl group and X is a halogen atom or a pseudohalide group, such as SCN, and is in particular Cl, Br, I or SCN, is reacted with a metal hydroxide, such as alkali metal hydroxide, e.g. LiOH, NaOH or KOH, or an earth alkaine metal hydroxide, such as Mg(OH)2 or Ca(OH)2, to yield an alcohol R1—OH; or with a hydroxyl compound R2—OH, where R2 is alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl, to yield an ether R1—O—R2.
In a particular embodiment the aryl group R1 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl group R1 is in particular mono-, bi- or tricyclic and is specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction.
In these substituents, however, all functional groups, especially halogen atoms, pseudohalogen groups and sulfonyloxy groups, have to be less reactive towards the hydroxide or hydroxyl compound than the halogen atom or pseudohalide group on the desired reaction site of the R1—X compound.
In a particular embodiment, the substituents are selected from the group consisting of halogen (provided this is less reactive than X in the C—O coupling reaction), cyano (provided this is less reactive than X in the C—O coupling reaction), nitro, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkythio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl. Specifically, the substituents are selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl and C3-C8-halocycloalkyl-C1-C6-alkyl.
Very specifically, R1 is selected from the group consisting of phenyl and naphthyl, where phenyl and naphthyl may carry 1, 2 or 3, specifically 1 or 2 substituents as defined above.
The alkyl, alkenyl, alkapolyenyl, alkynyl, mixed alkenyl/alkynyl, alkapolyynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl groups R2 can carry one or more substituents. Suitable substituents correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups R2 correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
Suitable Pd catalysts (inclusive ligands) are those mentioned above in context with the Suzuki coupling.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C.
The halogenide or pseudohalogenide and the OH compound (metal hydroxide or hydroxyl compound) can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.1 mol per mol of that reactant which is not used in excess, in particular 0.005 to 0.07 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for such reactions, e.g. by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s), water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
d) C—B Coupling Reactions
In a particular embodiment, the transition metal catalyzed reaction is a C—B coupling reaction. Transition metal catalyzed C—B coupling reactions are well known. Examples are the Miyaura boration or borylation.
Miyaura Borylation
The Pd-catalyzed C—B coupling reaction of alkenyl, aryl or heteroaryl halides or sulfonates with tetraalkoxydiboron compounds is called Miyaura borylation. The resulting aryl boronic esters are valuable substrates for Suzuki coupling reactions, Ullmann biaryl ether syntheses and the above described 1,4 additions of organoborane compounds to α,β-olefinically unsaturated carbonyl compounds, such as the Rh-catalyzed 1,4-addition reactions.
Preferably, a halogenide or sulfonate R2—(Z)n, where R2 is an alkenyl, aryl or heteroaryl group, Z is a halogenide or sulfonate group (the sulfonate being in particular a fluorinated alkylsulfonate or tosylate, specifically triflate or nonaflate) and n is 1, 2, 3 or 4, is reacted with a tetraalkoxydiboron (R1O)2B—B(OR1)2, where R1 is alkyl or two R1 bound on oxygen atoms bound in turn to the same B atom form together —C(CH3)3—C(CH3)2— (so that B(OR1)2 is the pinacolon ester of boronic acid), in the presence of a transition metal catalyst, in particular of a Pd catalyst, and in general also of a base.
The reaction of the tetraalkoxydiboron (R1O)2B—B(OR1)2 with R2—(Z)n yields a compound (B(OR1)2)n—R2. The alkenyl, aryl or heteroaryl halide or sulfonate can contain more than one halide or sulfonate group (when n is 2, 3 or 4), so that multiply coupled compounds can form, especially if the tetraalkoxydiboron compound is used in excess. For instance, a difunctional compound R2—(Z)2 can yield a twofold coupled compound tetraalkoxydiboron (R1O)2B—R2—B(OR1)2.
Due to the tolerance of the Miyaura borylation to a wide variety of functional groups, the alkenyl, aryl or heteroaryl groups R2 can carry one or more substituents. Suitable substituents correspond to those listed above in context with substituents on the alkenyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups, especially halogen atoms and sulfonyloxy groups, have to be less reactive towards the diboron compound than the halogen atom or sulfonate group on the desired reaction site of the R2—(Z)n compound.
Suitable Pd catalysts (inclusive ligands) are those mentioned above in context with the Suzuki coupling.
Suitable bases can be inorganic or organic. Examples for suitable are those listed in context with the Suzuki reaction.
Specifically, the present method relates to a Miyaura borylation in which an aromatic or heteroaromatic halogenide R2—(Z)n, where R2 is a mono-, bi- or polycyclic aryl or heteroaryl group, Z is a halogen atom, especially Cl, Br or I, more specifically Br or I, and n is 1, is reacted with a tetraalkoxydiboron, specifically with bis(pinacolato)diboron, in the presence of a Pd catalyst, specifically of bis(tritert-butyl-butylphosphine) palladium(0), and in the presence of a base, specifically of an acetate, specifically sodium or potassium acetate.
In a particular embodiment the aryl group R2 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl group R2 is in particular mono-, bi- or tricyclic and is specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R2 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R2 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R2 are selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R2 are selected from the group consisting of fluorine, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C.
The halogenide or sulfonate and the tetraalkoxydiboron can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In case of di- or polyfunctional halides or sulfonates, the molar ratio relates of course to the number of halide or sulfonate groups in the molecule. If n is 1, R2—(Z)n and the tetraalkoxydiboron are preferably used in a molar ratio of from 2:1 to 1:2, more preferably from 1.5:1 to 1:1.5 and specifically from 1:1 to 1:1.5. If n is 2, R2—(Z)n and R1—BY2 are preferably used in a molar ratio of from 1:1 to 1:4, more preferably from 1:1.5 to 1:3 and specifically in a molar ratio of from 1:2 to 1:3.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.1 mol per mol of that reactant which is not used in excess, in particular 0.005 to 0.07 mol per mol of the reactant not used in excess, specifically 0.01 to 0.07 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The base is generally used in excess, i.e. in overstoichiometric amounts with respect to that reactant not used in excess, e.g. in an amount of from 1.5 to 5 mol per mol of the reactant not used in excess, in particular 1.5 to 4 mol per mol of the reactant not used in excess, specifically 1.5 to 3 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for Miyaura borylations, e.g. by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s) and base, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
e) C-Halogen Coupling
In this reaction a C—H bond is converted into a C-halogen bond by reaction with a halogenating agent in the presence of a transition metal catalyst. In a specific embodiment an aromatic or heteroaromatic compound R1—H, where R1 is aryl or heteroaryl, is reacted with a halogenating agent in the presence of a transition metal catalyst to yield a compound R1—X, where X is a halogen atom, especially Cl, Br or I, very specifically Cl or Br.
Suitable transition metal catalysts are those mentioned above. In particular, an Au or a Pd catalyst is used. Specifically an Au catalyst is used.
Suitable Au catalysts are Au(I) salts and Au complexes.
Suitable Pd catalysts (inclusive ligands) are those mentioned above in context with the Suzuki coupling.
Suitable halogenation reagents are for example the halogens, i.e. F2, Cl2, Br2 or I2, oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, sulfuryl chloride, sulfuryl bromide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), dichlorodimethylhydantoin, dibromodimethylhydantoin, trichlorisocyanuric acid, chloramine-T, PCl5, P(O)Cl3, sodium hypochlorite, monochloroamine (NH2Cl) and the like. In a specific embodiment NBS or NCS is used.
In a particular embodiment aryl group R1 is mono-, bi- or tricyclic and are specifically selected from the group consisting of phenyl and naphthyl; and heteroaryl group R1 is in particular mono-, bi- or tricyclic and are specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of fluorine, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C.
The (hetero)aromatic compound and the halogenating agent can be used in a molar ratio of from 10:1 to 1:10. More often, however, the halogenating agent is used in at least equimolar amounts, especially if a halogen is used as halogenating agent.
The catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.1 mol per mol of that reactant which is not used in excess, in particular 0.005 to 0.07 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for halogenations, e.g. by mixing all reagents, inclusive catalyst or catalyst precursor and ligand(s), water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process. If the halogenating agent is gaseous, e.g. fluorine or chlorine, generally all reagents but the gaseous halogen are mixed and the halogen gas is then bubbled through the reaction mixture. If the reaction is carried out at temperatures above or below ambient conditions, the mixture can be brought to the desired temperature before or during the introduction of the halogen gas.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions. If the halogenating agent is used in excess, this is generally neutralized before further workup.
C—C Coupling Reactions not Requiring Transition Metal Catalysis
In another particular embodiment of the invention, the organic reaction is a C—C coupling reaction not requiring transition metal catalysis. Such reactions are well known and often named reactions. Examples are various reactions of carbonyl compounds or nitrile compounds, e.g. with nucleophiles, e.g. with CH acidic compounds, like the Wittig reaction, the Baylis-Hillman reaction, the Aldol addition and condensation, the Knoevenagel condensation, the Michael addition, the Mannich reaction, the Perkin reaction, the Erlenmeyer reaction, the Darzens reaction, the acyloin condensation, Friedel Crafts alkylation and acylation, Grignard reaction etc; further pericyclic reactions like the Diels-Alder reaction, cyclopropanation reactions (without transition metal catalysis in this context) etc. In particular, the C—C coupling reaction not requiring transition metal catalysis is a Wittig reaction, a Diels-Alder reaction or a Baylis-Hillman reaction.
Wittig Reaction
In a particular embodiment, the C—C coupling reaction not requiring transition metal catalysis is a Wittig reaction. The formation of C—C double bonds from carbonyl compounds and phosphoranes (phosphorous ylides) is known as the Wittig reaction. In the below scheme both the phosphorous ylide and ylene mesomeric forms are shown:
The phosphorous ylide is generally prepared from a triaryl or trialkyl phosphine, mostly triphenyl phosphine, and an alkyl halide followed by deprotonation with a suitable base, such as BuLi, sodium hydride or sodium methanolate.
R1 is in general an aryl group, especially phenyl. R2 and R3 are generally independently of each other hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, CN, C(O)R13, C(S)R13 or S(O)2R11. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl and heteroaryl groups R1, R2 and R3 can carry one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. R11 and R13 are as defined above in context with the Suzuki coupling.
R4 and R5 are independently of each other hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl. Alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl can carry one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
Important variants of the Wittig reaction are
1) Horner-Wittig or Wittig-Horner reaction, in which the phosphorous ylides contain phosphine oxides in place of triarylphosphines or trialkylphosphines;
2) the Horner-Wadsworth-Emmons reaction, in which alkylphosphonicdiethylesters are the phosphorus reagents:
3) the Schlosser modification in which two equivalents of a Li-halide salt are present in the reaction mixture.
In the terms of the present invention the “Wittig reaction” encompasses all these variants.
In the proper Wittig reaction, the ylides can be stabilized, semi-stabilized or nonstabilized. In the stabilized ylides the alkylhalide component has at least one strong electron-withdrawing group (—COOR, C(O)R, S(O)2R, CN etc.) which stabilizes the formal negative charge on the C atom. In the semi-stabilized ylides the alkylhalide component has at least one alkenyl or aryl substituent (i.e. at least one of R2 and R3 is alkenyl or aryl). In the nonstabilized ylides the alkylhalide component has only alkyl substituent(s).
In particular, the C—C coupling reaction not requiring transition metal catalysis is a Wittig reaction in the proper sense. Preferably the ylide used is a stabilized ylide. In particular, one of R2 and R3 is a CN, C(O)R13, C(S)R13 or S(O)2R11 group and especially a C(O)OR20 group, where R11, R13 and R20 are as defined above in context with the Suzuki coupling. In particular, one of R2 and R3 is C1-C4-alkoxycarbonyl. The other radical is in particular hydrogen or C1-C4-alkyl.
In particular, one of R4 and R5 is hydrogen or C1-C4-alkyl and the other is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl can carry one or more substituents. Specifically, one of R4 and R5 is hydrogen or C1-C4-alkyl and the other is a mono-, bi- or polycyclic aryl or heteroaryl group which may carry one or more substituents.
In a particular embodiment the aryl group R4 or R5 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl group R4 or R5 is in particular mono-, bi- or tricyclic and is specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R4 or R5 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R4 or R5 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R4 or R5 are selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonylamino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R4 or R5 are selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
The carbonyl compound and the phosphorous ylide can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5, preferably from 3:1 to 1:3 and in particular from 2:1 to 1:2, e.g. 1.5:1 to 1:1.5.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 25° C. to 55° C. and very specifically from 40° C. to 50° C.
The reaction can be carried out by standard proceedings for Wittig reactions, e.g. by mixing all reagents, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Workup proceedings will be described below, as they are similar for most reactions.
Diels-Alder Reaction
In a particular embodiment, the C—C coupling reaction not requiring transition metal catalysis is a Diels-Alder reaction. The [4π+2π] cyclization of a conjugated diene with a dienophile, e.g. an alkene, to a cyclohexene derivative is called Diels-Alder cycloaddition or Diels-Alder reaction.
Besides alkenes (as shown in the above reaction scheme), alkynes, benzynes or allenes are also good dienophiles. The diene is usually electron rich and the dienophile is electron poor (this is called “normal electron-demand Diels-Alder reaction”). When the diene is electron poor and the dienophile electron rich, this is called “inverse electron-demand Diels-Alder reaction”. If the ring formed contains, apart from carbon ring atoms, one or more heteroatoms as ring member(s), this variant is called “hetero-Diels-Alder reaction”. Diels Alder reactions tolerate a wide variety of functional groups. Thus, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl, or are one of the substituents listed in context with the Suzuki as suitable radicals on alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl or mixed alkenyl/alkynyl groups (however except for oxo (═O), ═S and ═NR12a). More precisely, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10, independently of each other, are hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13 or —Si(R14)3; where R11, R12a, R12b, R13, R14 and R15 are independently as defined above in context with the Suzuki reaction.
The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups can in turn be substituted by one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Alternatively, R2 and R3 and/or R3 and R4 and/or R4 and R5 and/or R1 and R6 and/or R7 and R9 can form a mono-, bi- or polycyclic carbocyclic or heterocyclic ring. This ring(s) may in turn be substituted by one or more substituents. Suitable substituents correspond to those listed above in context with substituents on the aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are suitably chosen in such a way that the diene is electron rich and the dienophile is electron poor or inversely the diene is electron poor and the dienophile is electron rich. Groups which enhance the electron density on the double bond are for example alkyl groups, cycloalkyl groups, electron-rich heterocyclic rings, ether groups, amino groups, (di)alkyl amino groups. The alkyl, cycloalkyl or heterocyclic groups as well as the carbon atoms in the ether or (di)alkyl amino groups may be substituted as described above, as the electronic influence of optional substituents decreases drastically with the distance to the double bond of the diene or dienophile. Electron-withdrawing groups are for example carbonyl groups (be it in the form of formyl, keto, carbamoyl, carboxyl or ester groups), sulfonyl groups, CN, the nitro group or halogen atoms. Carbon and nitrogen atoms in these groups (i.e. in keto, amido, ester or sulfonyl groups) may be substituted as described above, as the electronic influence of optional substituents decreases drastically with the distance to the double bond of the diene or dienophile.
In a particular embodiment of the present invention, an electron-rich diene and an electron-poor alkene are reacted. Specifically, R1, R3, R4, R6, R7 and R9 are H, R7 and R9 are either both alkyl or one or R7 and R9 is H and the other is alkyl, where alkyl can carry a substituent, where suitable substituents correspond to those listed above in context with substituents on the alkyl groups R1 and R2 in the Suzuki coupling, and is specifically a OR11 group; and R8 and R10 are either both C(O)R13 or one of R8 and R10 is H and the other is C(O)R13, or R8 and R10 form together a bridging group —C(O)-A-C(O)—, where A is an alkylene bridge or O or NR12a, where R11, R12a and R13 areas defined above in context with the Suzuki coupling. Very specifically, R8 and R10 form together a bridging group —C(O)—N(R12a)—C(O)—, where R12a is as defined in context with the Suzuki coupling, and is specifically C1-C6-alkyl. R11 is very specifically a C1-C6-alkylcarbonyl group.
The diene and the dienophile can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5, preferably from 3:1 to 1:3 and in particular from 2:1 to 1:2, e.g. 1.5:1 to 1:1.5.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 25° C. to 55° C. and very specifically from 40° C. to 50° C.
The reaction can be carried out by standard proceedings for Diels-Alder reactions, e.g. by mixing all reagents, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Workup proceedings will be described below, as they are similar for most reactions.
Baylis-Hillman Reaction
In a particular embodiment, the C—C coupling reaction not requiring transition metal catalysis is a Baylis-Hillman reaction. Classically, in this reaction type, a C—C single bond between the α-position of conjugated carbonyl compounds, e.g. esters or amides, and carbon electrophiles, e.g. aldehydes or activated ketones, in the presence of a suitable nucleophilic catalyst is formed:
R1, R2 and R3 are independently H, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl, or R1 and R2 form together with the carbon atom they are bound to a carbocyclic or heterocyclic ring; X is OR or N(R)2, where R is for example H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and Y is O or N substituted with an electron-withdrawing group, such as an arylsulfonyl or an alkoxycarbonyl group. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups, as well as the carbocyclic or heterocyclic ring formed by R1 and R2 together with the carbon atom they are bound to, can be substituted by one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups and for the carbocyclic or heterocyclic ring formed by R1 and R2 together with the carbon atom they are bound to correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups have to be less reactive than the desired reaction sites for the desired reaction.
In terms of the present invention, the Baylis-Hillman reaction also encompasses also the reaction of a conjugated nitrile compound with a carbon electrophile, e.g. an aldehydes or an activated ketone, in the presence of a suitable nucleophilic catalyst:
R1, R2, R3 and Y are as defined above.
Nucleophilic catalysts are tertiary amines, e.g. trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, tributylamine, morpholine, DABCO, DBU, DBN or quinuclidine; and tertiary phosphines, e.g. trialkylphosphines, like trimethyl, triethyl-, tripropyl- or tributylphosphine.
In some cases it is advantageous to carry out the reaction in the presence of metal-derived Lews acids, such as AlCl3, FeCl3, TiCl4 and the like.
In a particular embodiment of the present invention, a conjugated nitrile compound, in which in the above scheme R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and is specifically H, is reacted with an aldehyde, i.e. in the above scheme Y is O, R2 is H and R is H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and is specifically aryl, where alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups can be substituted by one or more substituents. Suitable substituents for alkyl, cycloalkyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, cycloalkyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups have to be less reactive than the desired reaction sites for the desired reaction.
In a particular embodiment the aryl group R1 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl.
The aryl group R1 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl group R1 are selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl group R1 are selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
The nucleophilic catalyst is in particular a tertiary amine, more particularly a cyclic amine, such as DABCO, DBU, DBN or quinuclidine, and is specifically DABCO.
The conjugated carbonyl or nitrile compound and the carbon electrophile can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. Specifically, the carbon electrophile is used in excess, e.g. in a 10-fold or 7-fold or 5-fold or 2-fold excess.
The nucleophilic catalyst is generally used in catalytic amounts, i.e. in substoichiometric amounts with respect to that reactant not used in excess, e.g. in an amount of from 0.001 to 0.9 mol per mol of that reactant which is not used in excess, in particular 0.01 to 0.7 mol per mol of the reactant not used in excess, specifically 0.05 to 0.5 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C. and very specifically from 20° C. to 30° C.
The reaction can be carried out by standard proceedings for Baylis-Hillman reactions, e.g. by mixing all reagents, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Workup proceedings will be described below, as they are similar for most reactions.
Carboxamide or Sulfonamide Bond Formation not Requiring Transition Metal Catalysis
In another particular embodiment of the invention, the organic reaction is a carboxamide or sulfonamide bond formation (not requiring transition metal catalysis).
Carboxamide Bond Formation
For the synthesis of carboxamides, generally a carboxylic acid or a derivative of a carboxylic acid capable of amide formation, for instance an acid halide, acid anhydride or ester, is reacted with a primary or secondary amine.
R1, R2 and R3 are independently H, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl, or R2 and R3 form together with the nitrogen atom they are bound to a mono-, bi- or polycyclic heterocyclic ring; X is OH, OR4, O—C(O)—R1′ or a halogen atom, where R4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and R1′ is independently defined as R1. Alternatively, X is another common leaving group, for example thiophenyl or imidazolyl.
The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups, as well as the the mono- bi- or polycyclic heterocyclic ring formed by R2 and R3 together with the nitrogen atom they are bound to, can be substituted by one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups and for the mono- bi- or polycyclic heterocyclic ring formed by R2 and R3 together with the nitrogen atom they are bound to correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. If however these groups carry substituents which can compete in the reaction, e.g. further amino groups, it is expedient to protect these groups before the amidation reaction. For example, amino groups can be protected by standard N-protective groups, such as boc, benzyl, F-moc etc. Suitable protective groups are for example described in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999). Alike, when these groups carry a COY substituent, where Y is as defined as X, Y has to be converted into a group which is less reactive than X versus the amine. For instance, if X is OH, Y has to be converted into an alkoxy group, such as methoxy or ethoxy.
Amidation can be carried out by reacting the carboxylic acid (X=OH) with the amine under heating and removal of reaction water, but is preferably carried out by activation of the carboxylic acid with, e.g. oxalylchloride [(COCl)2] or thionylchloride (SOCl2) to the respective acid chloride (X=Cl), followed by reaction with amine.
Alternatively, amidation is carried out with the carboxylic acid in the presence of a coupling reagent. Suitable coupling reagent (activators) are well known and are for instance selected from the group consisting of carbodiimides, such as EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; also abbreviated as EDC), DCC (dicyclohexylcarbodiimide) and DIC (diisopropylcarbodiimide), benzotriazole derivatives, such as HOBt (1-hydroxybenzotriazole), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), HBTU ((O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) and HCTU (1H-benzotriazolium-1-[bis(dimethylamino)methylene]-5-chloro tetrafluoroborate), phosphonium-derived activators, such as BOP ((benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate), Py-BOP ((benzotriazol-1-yloxy)-tripyrrolidinphosphonium hexafluorophosphate) and Py-BrOP (bromotripyrrolidinphosphonium hexafluorophosphate), and others, such as COMU ((1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium-hexafluorophosphat). The above activators can also be used in combination with each other. Generally, the activator is used in at least equimolar amounts, with respect to that reactant not used in excess. The benzotriazole and phosphonium coupling reagents are generally used in a basic medium.
Suitable esters R1—COOR4 derive expediently from C1-C4-alkanols R4OH in which R4 is C1-C4-alkyl, such as methanol, ethanol, propanol, isopropanol, n-butanol, butan-2-ol, isobutanol and tert-butanol, preference being given to the methyl and ethyl esters (R4=methyl or ethyl). Suitable esters may also derive from C2-C6-polyols such as glycol, glycerol, trimethylolpropane, erythritol, pentaerythritol and sorbitol, preference being given to the glyceryl ester. When polyol esters are used, it is possible to use mixed esters, i.e. esters with different R4 radicals.
Alternatively, the ester R1—COOR4 is a so-called active ester, which is obtained in a formal sense by the reaction of the acid R1—COOH with an active ester-forming alcohol, such as p-nitrophenol, N-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide or OPfp (pentafluorophenol).
The acid anhydride R1—CO—O—OC—R1′ is either a symmetric anhydride R1—CO—O—OC—R1 (R1′═R1) or an asymmetric anhydride in which —O—OC—R1′ is a group which can be displaced easily by the amine HN(R2)R3. Suitable acid derivatives with which the carboxylic acid R1—COOH can form suitable mixed anhydrides are, for example, the esters of chloroformic acid, for example isopropyl chloroformate and isobutyl chloroformate, or of chloroacetic acid.
If X is a halogen atom, the reaction is generally carried out in the presence of a base. Suitable bases are those listed above in context with the Suzuki reaction.
In a particular embodiment of the present invention, a carboxylic acid (X=OH) is reacted with a primary or secondary amine in the presence of one or two coupling reagents, specifically of EDCI, HOBt or COMU or a combination thereof.
In a particular embodiment, R1 is alkyl or aryl, where the alkyl or aryl group may be substituted as described above. Specifically, R1 is C1-C10-alkyl which may carry a phenyl ring, which may in turn be substituted as described above and in particular by one or more R15, or may carry a group C(O)R13 or N(R12a)R12b, where R12a, R12b, R13 and R15 are as defined in context with the Suzuki reaction; or R1 is phenyl which may be substituted as described above and in particular by one or more R15. Specifically R13 is C1-C4-alkyl. Specifically R12a and R12b are H, but one of them is replaced by a protective group, such as boc, benzyl or F-moc.
In a particular embodiment, R2 is H and R3 is alky or aryl, where the alkyl or aryl group may be substituted as described above, or R2 and R3 form together with the nitrogen atom they are bound to a mono-, bi- or polycyclic ring, such as piperidine-1-yl, 1-alkyl-piperazin-4-yl, morpholinyl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, indolin-1-yl, indol-1-yl etc. Specifically, R3 is C1-C10-alkyl which may carry a phenyl ring, which may in turn be substituted as described above and in particular by one or more R15, or is C(O)R13, or is N(R12a)R12b, where R12a, R12b, R13 and R15 are as defined in context with the Suzuki reaction. Specifically R13 is C1-C6-alkyl. Specifically R12a and R12b are both C1-C10-alkyl or are both H, where however one of the hydrogen atoms is replaced by a protective group, such as boc, benzyl or F-moc.
The acid (derivative) and the amine can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In particular, they are used in a molar ratio of from 3:1 to 1:3, more particularly 2:1 to 1:2 and specifically from 1.5:1 to 1:1.5.
If the amidation is carried out in the presence of a coupling agent, this is generally used in at least equimolar amounts, with respect to that reactant not used in excess, e.g. in an amount of from 1 to 5 mol per mol of the reactant not used in excess, in particular 1 to 4 mol per mol of the reactant not used in excess, specifically 1.1 to 3 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of catalyst apply of course to either of the reactants.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C.
The reaction can be carried out by standard proceedings for carboxamide formation, e.g. by mixing all reagents, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Workup proceedings will be described below, as they are similar for most reactions.
Sulfonamide Bond Formation
For the synthesis of sulfonamides, generally a sulfonic acid or a derivative of a sulfonic acid capable of amide formation, for instance a sulfonic acid halide, anhydride or ester, is reacted with a primary or secondary amine:
R1, R2, R3 and X are as defined above in context with the carboxamide bond formation, except for R1 here not being H and except of X being in the anhydride alternative O—S(O)2—R1′ instead of O—C(O)—R1′. The above remarks on how to carry out the reaction, especially the various methods depending on X, apply here, too.
In a particular embodiment of the present invention, a sulfonic acid halide (X=halogen), especially a sulfonic acid chloride (X=Cl), is reacted with a primary or secondary amine in the presence of a base. Suitable bases are those listed above in context with the Suzuki reaction. In particular the base is an alkali metal hydroxide, e.g. LiOH, NaOH or KOH, an alkali metal carbonate, e.g. Li2CO3, Na2CO3, K2CO3 or Cs2CO3, or a silanolate, e.g. sodium or potassium trimethylsilanolate ((CH3)3SiO−) or triisopropylsilanolate ((CH(CH3)2)3SiO−).
In a particular embodiment, R1 is alky or aryl, where the alkyl or aryl group may be substituted as described above. Specifically, R1 is phenyl which may be substituted as described above and in particular by one or more R15, where R15 is as defined in context with the Suzuki reaction.
In a particular embodiment, R2 is H and R3 is alky or aryl, where the alkyl or aryl group may be substituted as described above, or R2 and R3 form together with the nitrogen atom they are bound to a mono-, bi- or polycyclic ring, such as piperidine-1-yl, 1-alkyl-piperazin-4-yl, morpholinyl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, indolin-1-yl, indol-1-yl etc. Specifically, R3 is C1-C10-alkyl which may carry a phenyl ring, which may in turn be substituted as described above and in particular by one or more R15, or is C(O)R13, or is N(R12a)R12b, where R12a, R12b, R13 and R15 are as defined in context with the Suzuki reaction; or, specifically, R2 and R3 form together with the nitrogen atom they are bound to a mono-, bi- or polycyclic ring, such as piperidine-1-yl, 1-alkyl-piperazin-4-yl, morpholinyl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, indolin-1-yl, indol-1-yl etc. Specifically R13 is C1-C4-alkyl. Specifically R12a and R12b are both C1-C10-alkyl or are both H, where however one of the hydrogen atoms is replaced by a protective group, such as boc, benzyl or F-moc.
The acid (derivative) and the amine can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In particular, they are used in a molar ratio of from 3:1 to 1:3, more particularly 2:1 to 1:2 and specifically from 1.5:1 to 1:1.5.
If the amidation is carried out in the presence of a base, this is generally used in excess, i.e. in overstoichiometric amounts with respect to that reactant not used in excess, e.g. in an amount of from 1.5 to 5 mol per mol of the reactant not used in excess, in particular 1.5 to 4 mol per mol of the reactant not used in excess, specifically 1.5 to 3 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C. and very specifically from 20° C. to 30° C.
The reaction can be carried out by standard proceedings for sulfonamide formation, e.g. by mixing all reagents, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Workup proceedings will be described below, as they are similar for most reactions.
In another particular embodiment of the invention, the organic reaction is the introduction of a protective group.
Introduction of Protective Groups
In certain reactions, some functional groups, such as NH, NH2, OH, SH or COOH, have to be protected in order to avoid their (competitive) reaction.
Protection of Primary or Secondary Amino Groups
Protective groups for amino groups are well known. Examples are C1-C4-alkylcarbonyl (e.g. acetyl, tert-butylcarbonyl), C1-C4-haloalkylcarbonyl (e.g. trifluoroacetyl), C3-C4-alkenylcarbonyl (e.g. allylcarbonyl), C1-C4-alkoxycarbonyl (e.g. tert-butyloxycarbonyl=Boc), C1-C4-haloalkoxycarbonyl, C3-C4-alkenyloxycarbonyl (e.g. allyloxycarbonyl=Alloc), fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Z or Cbz), C1-C4-alkylaminocarbonyl, di-(C1-C4-alkyl)-aminocarbonyl, C1-C4-alkylsulfonyl, C1-C4-haloalkylsulfonyl, benzyl or substituted benzyl (e.g. p-methoxybenzyl (=Mpm) or 2,3-dimethoxybenzyl). Suitable protective groups are for example described in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999). The (oxy)carbonyl and sulfonyl groups can be principally introduced in accordance with the above-described amidation reactions, especially via reaction of the amine with the respective (oxy)carboxylic chloride, (active) ester or anhydride or with the respective sulfonyl chloride, (Oxy)Carbonyl can moreover be introduced via reaction with the respective succinimidoester. The anhydride is generally a symmetric anhydride. With respect to the terms “active ester” and “symmetric anhydride”, reference is made to the above-described amidation reactions. The reagents used for introducing the protective group, such as boc anhydride for introducing boc, are termed in the following “protective group precursors”. (Oxy)carbonyl means carbonyl or oxycarbonyl.
Suitable (oxy)carbonylation/sulfonylation reagents (i.e. protective group precursors for introducing (oxy)carbonyl and sulfonyl protective groups) are well known. For example, boc is generally introduced via reaction with boc anhydride. Z is generally also introduced via the respective anhydride. Alkyl carbonyl groups are also often introduced via reaction with the symmetric anhydride, e.g. with acetanhydride or 2,2-dimethylacetanhydride. Benzyl or substituted benzyl is generally introduced via reaction of the amine with (substituted) benzyl chloride or bromide.
If the carbonylation/sulfonylation reagent is an acid chloride or an anhydride, the protection reaction is generally carried out in the presence of a base. Suitable bases are those listed in context with the Suzuki reaction.
In a particular embodiment, a primary or secondary amine R1(R2)NH is reacted with an alkylcarbonyl (e.g. acetyl), C1-C4-haloalkylcarbonyl (e.g. trifluoroacetyl), C3-C4-alkenylcarbonyl (e.g. allylcarbonyl), C1-C4-alkoxycarbonyl (e.g. tert-butyloxycarbonyl=Boc), C1-C4-haloalkoxycarbonyl, C3-C4-alkenyloxycarbonyl (e.g. allyloxycarbonyl=Alloc), fluorenylmethoxycarbonyl (Fmoc) or benzyloxycarbonyl (Z or Cbz) chloride, anhydride or succinimidoester. The anhydride is generally a symmetric anhydride. As said, if a chloride or an anhydride is used, the reaction is generally carried out in the presence of a base.
Specifically, a primary or secondary amine R1(R2)NH is reacted with boc anhydride.
In another specific embodiment, a primary or secondary amine R1(R2)NH is reacted with Z anhydride (dibenzyl dicarbonate).
In another specific embodiment, a primary or secondary amine R1(R2)NH is reacted with acetic anhydride.
R1 and R2, independently of each other, are alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenylcycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl, where R1 may additionally be hydrogen; or R1 and R2, together with the nitrogen atom they are bound to, form a mono-, bi- or polycyclic heterocyclic ring, which, apart from the compulsory nitrogen atom, may contain 1, 2 or 3 or 4 further heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO or SO2 as ring members.
The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups R1 and R2, as well as the mono-, bi- or polycyclic heterocyclic ring formed by R1 and R2 together with the nitrogen atom they are bound to, can be substituted by one or more substituents. Suitable substituents for the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl groups R1 and R2 correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups R1 and R2 and for the the mono-, bi- or polycyclic heterocyclic ring formed by R1 and R2 together with the nitrogen atom they are bound to correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups have to be less reactive than the desired reaction site towards the specific protective group precursor.
In a specific embodiment, R1 is hydrogen and R2 is an alkyl, alkenyl, alkynyl, cycloalkyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl group, where the alkyl, alkenyl, alkynyl, cycloalkyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl group may carry one or more substituents, where suitable substituents correspond to those listed above in context with substituents on the alkyl, alkenyl, alkynyl, cycloalkyl, polycarbocyclyl, heterocyclyl, aryl and heteroaryl groups R1 and R2 in the Suzuki coupling (suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling).
More specifically, R1 is hydrogen and R2 is heterocyclyl, in particular a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10- or 11-membered monocyclic or bicyclic saturated, partially unsaturated or maximally unsaturated heterocyclic (inclusive heteroaromatic) ring which may carry one or more substituents as defined above. In particular, the heterocyclyl ring R2 is a heteroaryl group. Heteroaryl groups R2 are in particular selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic heteroaryl groups R2 are for example furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”.
Suitable substituents on the heterocyclyl ring R2 are e.g. selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the heterocyclyl ring R2 are selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. In case of amino and C1-C4-alkylamino substituents, these may also react with the protective agent.
In another specific embodiment, R1 is hydrogen and R2 is aryl, specifically phenyl, which may carry one or more substituents as defined above. Suitable substituents on the aryl group R2 are e.g. selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C4-alkyl substituted by a radical selected from the group consisting of CN, OH, SH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino; C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl group R2 are selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C1-C4-alkyl substituted by a radical selected from the group consisting of CN, OH, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino and phenyl; C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Very specifically, the substituents on the aryl group R2 are selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C1-C4-alkyl substituted by a radical selected from the group consisting of CN, OH, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, and phenyl; C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl.
In another specific embodiment, R1 is hydrogen and R2 is polycarbocyclyl which may carry one or more substituents as defined above; preferably a 9- to 10-membered condensed saturated or partially unsaturated carbocyclic ring system, in particular selected from indanyl, tetrahydronaphthyl, hexahydronaphthyl, octahydronaphthyl and decahydronaphthyl, which may carry one or more substituents as defined above. In indanyl and tetrahydronaphthyl the attachment point to N is on the nonaromatic ring moiety. Suitable substituents on the polycarbocyclyl ring R2 are e.g. selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C4-alkyl substituted by a radical selected from the group consisting of CN, OH, SH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino; C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkythio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
In another specific embodiment, R1 and R2, together with the nitrogen atom they are bound to, form a mono-, bi- or polycyclic heterocyclic ring, which, apart from the compulsory nitrogen atom, may contain 1, 2 or 3 or 4 further heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO or SO2 as ring members. Very specifically, R1 and R2, together with the nitrogen atom they are bound to, form a mono- or bicyclic heterocyclic ring, specifically a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10- or 11-membered mono- or bicyclicsaturated, partially zunsaturated or maximally unsaturated heterocyclic ring, which, apart from the compulsory nitrogen atom, may contain 1 or 2 further heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO or SO2 as ring members.
The amine and the protective group precursor can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In particular, they are used in a molar ratio of from 3:1 to 1:3, more particularly 2:1 to 1:2 and specifically from 1.5:1 to 1:1.5.
If the reaction is carried out in the presence of a base, this is generally used in excess, i.e. in overstoichiometric amounts with respect to that reactant not used in excess, e.g. in an amount of from 1.1 to 5 mol per mol of the reactant not used in excess, in particular 1.1 to 4 mol per mol of the reactant not used in excess, specifically 1.1 to 3 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C. and very specifically from 20° C. to 30° C.
The reaction can be carried out by standard proceedings for introducing the respective protective group, e.g. by mixing all reagents, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Workup proceedings will be described below, as they are similar for most reactions.
Deprotection Reaction
In another particular embodiment of the invention, the organic reaction is a deprotection reaction, i.e. the removal of a protective group. The specific deprotection conditions depend on the protective group to be removed and are known in the art. They are described, for example, in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
Deprotection of Protected Primary or Secondary Amines
Suitable and preferred protective groups and suitable and preferred amines are described above. Conditions for deprotecting primary or secondary amines depend on the specific protective group and the susceptibility of the amine to undergo undesired reactions during deprotection. Generally they involve a hydrolysis or a hydrogenolysis. For instance, boc is removed via hydrolysis under acidic conditions using e.g. HCl, trifluoroacetic acid or toluenesulfonic acid. Other oxycarbonyl protective groups, such as Fmoc, can be removed via basic hydrolysis, e.g. with NaOH or an organic base, such as piperidine or pyridine. Cbz can be removed via hydrogenolysis, mostly catalyzed with Pd or Pt, or using Na/NH3, or with trimethylsilyl iodide, or via reaction with strong acids, e.g. HBr/acetic acid. Alloc is generally removed metal-catalyzed with Ni or Pt. Carbonyl protective groups, e.g. acetyl, are removed via acidic or basic hydrolysis. Generally, this requires harsher conditions, such as heating to reflux. Benzyl is generally removed via hydrogenolysis, mostly catalyzed with Pd or Pt.
In another particular embodiment of the invention, the organic reaction is a nucleophilic substitution reaction.
Nucleophilic Substitution Reactions
Nucleophilic substitution is a fundamental class of reactions in which an electron-rich nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms to replace a leaving group; the positive or partially positive atom being termed electrophile: Nu: +R-LG→R-Nu+LG:
“Nu” is the nucleophile; “:” is an electron pair; “LG” is a leaving group and “R” is a hydrocarbyl radical, e.g. an aliphatic, cycloaliphatic, aromatic, hetercyclic or heteroaromatic radical.
The electron pair (:) from the nucleophile (Nu) attacks the substrate (R-LG) forming a new bond, while the leaving group (LG) departs with an electron pair. The principal product in this case is R-Nu. The nucleophile may be electrically neutral or negatively charged, whereas the substrate is typically neutral or positively charged.
Advantageously, the leaving group forms an anion of low energy or an uncharged molecule or can be removed by an energetically advantageous process. Therefore, the leaving group is frequently a halide, a sulfonate or a diazonium group.
Nucleophilic substitution reactions form one of the largest classes of organic reactions and are therefore often treated in subclasses depending on the functional group formed, on the product formed or on the substrate used. For instance, many carbonyl reactions are nucleophilic substitutions, e.g. ester bond formations, trans esterifications, hydrolyses, amide bond formation or carbonyl halide formation; ether and thioether bond formation, amine bond formation etc. The method of the invention can be applied to all types of nucleophilic substitutions, but given the vastness of this reaction type, only some representative examples are discussed in more detail.
One subclass of nucleophilic substitution is nucleophilic aromatic substitution. Thus, in particular embodiment of the invention, the organic reaction, to be more precise the nucleophilic substitution reaction, is a nucleophilic aromatic substitution reaction.
Nucleophilic Aromatic Substitution Reactions
Nucleophilic aromatic substitution is a substitution reaction in which a nucleophile displaces a good leaving group on an aromatic or a heteroaromatic ring. Due to the system of conjugated double bonds, aromatic compounds (especially carboaromatic compounds and electron-rich heteroaromatic compounds) are Lewis bases and thus the exchange of substituents by nucleophilic reagents is distinctly more difficult than electrophilic substitutions. It is essential that the leaving group forms an anion of low energy or an uncharged molecule or can be removed by an energetically advantageous process. Therefore, the leaving group is mostly a halide, a sulfonic acid group or a diazonium group in non-activated (hetero)aromatic compounds. Nucleophilic aromatic substitution on carboaromatic rings (phenyl, naphthyl etc.) is eased if the aromatic ring is activated, i.e. contains substituents with a -M effect in ortho and/or para position to the carbon atom carrying the leaving group. Substituents with a -M effect are for example the diazonium, nitroso, nitro, cyano, formyl, or acetyl group. In this case, also less favoured leaving groups can react; e.g. even hydrogen atoms can be replaced. Electron-poor heteroaromatic rings, like the 6-membered heteroaromatic compounds (pyridine, pyridazine, pyrimidine, pyrazine, the triazines) or quinoline, also undergo readily nucleophilic substitution, even with poor leaving groups, like the hydrogen atom.
Suitable nucleophiles are in particular Lewis bases, like water, alcohols, thiols or primary or secondary amines.
The reaction is often carried out in the presence of a base, especially if the leaving group is a halide and the nucleophile is water, an alcohol, a thiol or a primary or secondary amine.
In a particular embodiment of the present invention a mono-, bi- or polycyclic aromatic or heteroaromatic halide R1—X is reacted with an alcohol R2—OH, a thiol R2—SH, a primary amine R3NH2 or a secondary amine R3(R4)NH. R1 is a mono-, bi- or polycyclic aryl or heteroaryl group; X is a halide, especially F or Cl, and R2, R3 and R4 are independently of each other an alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl group. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups R1, R2, R3 and R4 can be substituted by one or more substituents. Suitable substituents correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups R1, R2, R3 and R4 correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups have to be less reactive than the desired reaction sites for the desired reaction (i.e. less reactive than X in R1—X towards R2—OH, R2—SH, R3NH2 or R3(R4)NH; less reactive than OH, SH, NH2 or NH in R2—OH, R2—SH, R3NH2 and R3(R4)NH, respectively, towards R1—X).
In a particular embodiment the aryl group R1 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl group R1 is in particular mono-, bi- or tricyclic and is specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl, chromanyl bound via the 5-, 6-, 7- or 8-position and other heteroaromatic bicyclic rings shown below in the “general definitions”.
The aryl and heteroaryl groups R1 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C1-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, where the alkyl groups in alkylamino and dialkylamino can in turn be substituted by one or more substituents selected from the group consisting of CN, OH, SH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino; phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl. Especially in the case of the carboaromatis, e.g. the above-listed phenyl, naphthyl, anthracenyl and phenanthrenyl groups, it is expedient for these to carry a substituent with -M effect in ortho- and/or para-position to X, e.g. a nitro group. Analogously, electron-rich heterocyclic rings, like the 5-membered heteroaromatic rings, especially pyrrole, carry advantageously a -M substituent.
Especially, the mono-, bi- or polycyclic aryl or heteroaryl groups R1 are selected from the group consisting of phenyl carrying in ortho- and/or para-position to X a substituent with -M effect, specifically a nitro group, from the 6-membered heteroaromatic groups, i.e. from pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl and 1,3,5-triazinyl, and from quinolinyl. Specifically, the mono-, bi- or polycyclic aryl or heteroaryl groups R1 are selected from the group consisting of phenyl carrying in ortho- and/or para-position to X a substituent with -M effect, specifically a nitro group; pyridyl and pyrimidyl. The 6-membered heteroaromatic groups and quinolinyl may carry one or more substituents, e.g. those described above, for example those mentioned as R15 in the Suzuki reaction.
In particular, R2, R3 and R4 are independently of each other an alkyl or aryl group, where the alkyl group may carry an aryl group, where the aryl groups may carry one or more substituents, e.g. those described above, for example those mentioned as R15 in the Suzuki reaction. Specifically, R2 is an aryl group, in particular phenyl or naphthyl, which may carry one or more substituents, e.g. those described above, for example those mentioned as R15 in the Suzuki reaction. Specifically, R4 is hydrogen and R3 is C1-C4-alkyl, where alkyl may carry one or more aryl substituents, specifically one phenyl substituent, where the aryl substituents may in turn carry one or more substituents, e.g. those described above, for example those mentioned as R15 in the Suzuki reaction, specifically CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-alkoxy.
The reaction is often carried out in the presence of a base, especially if the leaving group is a halide and the nucleophile is water, an alcohol, a thiol or a primary or secondary amine. Suitable bases are those listed above in context with the Suzuki reaction.
The reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C. and very specifically from 20° C. to 30° C.
The (hetero)aromatic compound to be substituted and the nucleophile can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. Preferably they are used in a molar ratio of from 3:1 to 1:3, in particular 2:1 to 1:2 and specifically 1.5:1 to 1:1.5.
The base is generally used in at least equimolar amount, with respect to that reactant not used in excess, e.g. in an amount of from 1 to 5 mol per mol of the reactant not used in excess, in particular 1 to 3 mol per mol of the reactant not used in excess, specifically 1 to 2 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction can be carried out by standard proceedings for nucleophilic aromatic substitutions, e.g. by mixing all reagents, inclusive base, water and the cellulose derivative, and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Workup proceedings will be described below, as they are similar for most reactions.
In another particular embodiment of the present invention a mono-, bi- or polycyclic aromatic or heteroaromatic alcohol R1—OH, thiol R1—SH, primary amine R1NH2 or a secondary amine R1(R4)NH is reacted with a halide R2—X, resulting in a ether R1—O—R2, thioether R1—S—R2, secondary amine R1—N(H)—R2 or tertiary amine R1—N(R4)—R2. R1, R2 and R4 are as defined above. The reaction conditions are also as described above in context with the reaction of an aromatic or heteroaromatic halide R1—X with an alcohol R2—OH, thiol R2—SH, primary amine R3NH2 or a secondary amine R3(R4)NH.
Another subclass of nucleophilic substitution is ether bond formation. Thus, in particular embodiment of the invention, the organic reaction, to be more precise the nucleophilic substitution reaction, is an etherification reaction.
Ether Bond Formation
In this reaction class, generally a hydroxyl compound R1—OH is reacted with a compound R2-LG, wherein LG is leaving group, such as a halide, a hydroxyl group, a sulfonate group or, especially in aromatic or heteroaromatic groups R2, a diazonium group. R1 and R2 can be any aliphatic, cycloaliphatic, heterocyclic, aromatic or heteroaromatic group. If one of R1 and R2 or both are aromatic or heteroaromatic, reference is made to the above remarks made in context with nucleophilic aromatic substitution.
R1 and R2 are preferably independently alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups can be substituted by one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups have to be less reactive than the desired reaction sites for the desired reaction.
In a particular embodiment R1 is aryl or hetaryl, where preferably, the aryl group R1 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl group R1 is in particular mono-, bi- or tricyclic and is specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl, chromanyl bound via the 5-, 6-, 7- or 8-position and other heteroaromatic bicyclic rings shown below in the “general definitions”. Specifically, R1 is chromanyl bound via the 5-, 6-, 7- or 8-position.
The aryl and heteroaryl groups R1 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, (protected) amino, (protected) C1-C4-alkylamino, di-(C1-C4-alkyl)amino, where the alkyl groups in alkylamino and dialkylamino can in turn be substituted by one or more substituents selected from the group consisting of CN, OH, SH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C1-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino;
phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, (protected) amino, (protected) C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkythio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, protected amino, (protected) C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Very specifically, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of protected amino, (protected) C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
In particular, R4 is C1-C4-alkyl, where alkyl may carry one or more aryl substituents, specifically one phenyl substituent, where the aryl substituents may in turn carry one or more substituents, e.g. those described above, for example those mentioned as R15 in the Suzuki reaction, specifically F, Cl, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-alkoxy.
Another subclass of nucleophilic substitution is ester bond formation (esterification) and the reverse reaction (ester hydrolysis). Thus, in particular embodiment of the invention, the organic reaction, to be more precise the nucleophilic substitution reaction, is an esterification reaction or an ester hydrolysis.
Esterifications and Ester Hydrolysis
For the synthesis of carboxylic esters, generally a carboxylic acid or a derivative of a carboxylic acid capable of ester bond formation, for instance an acid halide or acid anhydride, is reacted with a hydroxyl compound:
In an ester hydrolysis the inverse reaction takes place: An ester is reacted (formally) with water to the respective carboxylic acid:
R1 and R2 are independently alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl, where R1 can also be H; X is OH, OR4, O—C(O)—R1′ or a halogen atom, where R4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl and R1′ is independently defined as R1. Alternatively, X is another common leaving group, for example thiophenyl or imidazolyl.
The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups can be substituted by one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. If however these groups carry substituents which can compete in the esterification reaction, e.g. further OH groups, it is expedient to protect these groups before the esterification reaction. For example, OH groups can be protected by standard O-protective groups, such as silyl groups. Suitable protective groups are for example described in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999). Alike, when these groups carry a COY substituent, where Y is as defined as X, Y has to be converted into a group which is less reactive than X versus the hydroxy compound in the esterification reaction or versus water in the hydrolysis. For instance, if X is OH, Y has to be converted into an alkoxy group, such as methoxy or ethoxy.
Esterification can be carried out by reacting the carboxylic acid (X=OH) with the hydroxy compound under heating and removal of reaction water, but is preferably carried out by activation of the carboxylic acid with, e.g. oxalylchloride [(COCl)2] or thionylchloride (SOCl2) to the respective acid chloride (X=Cl), followed by reaction with the hydroxy compound.
Alternatively, the ester R1—COOR4 is a so-called active ester, which is obtained in a formal sense by the reaction of the acid R1—COOH with an active ester-forming alcohol, such as p-nitrophenol, N-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide or OPfp (pentafluorophenol).
The acid anhydride R1—CO—O—OC—R1′ is either a symmetric anhydride R1—CO—O—OC—R1 (R1′═R1) or an asymmetric anhydride in which —O—OC—R1′ is a group which can be displaced easily by the hydroxy compound. Suitable acid derivatives with which the carboxylic acid R1—COOH can form suitable mixed anhydrides are, for example, the esters of chloroformic acid, for example isopropyl chloroformate and isobutyl chloroformate, or of chloroacetic acid.
If X is a halogen atom, the reaction is generally carried out in the presence of a base. Suitable bases are those listed above in context with the Suzuki reaction.
In ester hydrolysis, generally a base is used and elevated temperature is applied, e.g. from 30 to 70° C. or from 40 to 60° C. or from 45 to 60° C. Suitable bases are those listed above in context with the Suzuki reaction, especially the inorganic bases, specifically alkali metal hydroxides, such as NaOH or KOH.
In a particular embodiment, R1 is heterocyclyl which may be substituted as described above. Specifically, R1 is a saturated 3-, 4-, 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from N, O, S, NO, SO and SO2 as ring members, where the heterocyclic ring may be substituted as described above. Specifically, the heterocyclic ring may carry one or more substituents selected from alkyl, cycloalkyl, polycarbocyclyl, aryl and hetaryl which may in turn be substituted. Very specifically, the heterocyclic ring may carry one or more substituents selected from C1-C4-alkyl, C3-C8-cycloalkyl and a bicyclic carbocyclic ring containing 8, 9 or 10 carbon atoms as ring members, such as indanyl, indenyl, dihydronaphthyl, terahydronaphthyl, hexahydronaphthyl, octahydronaphthyl or decalin.
In the esterification, the acid (derivative) and the hydroxy compound can be used in a molar ratio of from 10:1 to 1:10, e.g. from 7:1 to 1:7 or from 5:1 to 1:5. In particular, they are used in a molar ratio of from 3:1 to 1:3, more particularly 2:1 to 1:2 and specifically from 1.5:1 to 1:1.5.
In the hydrolysis reaction, water is generally used in excess.
The esterification reaction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C.
Hydrolysis is preferably carried at at elevated temperature, e.g. from 30 to 70° C. or in particular from 40 to 60° C. or specifically from 45 to 60° C.
The esterification reaction can be carried out by standard proceedings for ester bond formation, e.g. by mixing all reagents, water and the cellulose derivative and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
The hydrolysis reaction can be carried out by standard proceedings for ester bond hydrolysis.
Workup proceedings will be described below, as they are similar for most reactions.
Another class of nucleophilic substitution is amine bond formation in which an amine is reacted with a compound carrying a leaving group.
Amination
In this context, “amination” refers only to nucleophilic substitution of a leaving group by an amino group. Suitable amines are primary and secondary amines, and also ammonia can be used. Reaction conditions and suitable reactants correspond analogously to those listed above in context with etherification reactions. Thus, generally an amino compound NHR3R4 is reacted with a compound R2-LG, wherein LG is leaving group, such as a halide, a hydroxyl group or a sulfonate group. R3 and R4, independently of each other, can be H or any aliphatic, cycloaliphatic, heterocyclic, aromatic or heteroaromatic group. If one of R3, R4 and R2 or two thereof or all three are aromatic or heteroaromatic, reference is made to the above remarks made in context with nucleophilic aromatic substitution.
Preferably, R3 is H and R4 and R2 are preferably independently alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups can be substituted by one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In these substituents, however, all functional groups have to be less reactive than the desired reaction sites for the desired reaction, unless a second reaction site is desired, like in the below-described ring formation (ammonia or a primary amine reacts at two reaction sites of R2, thus giving a ring).
Specifically, R3 is H and R4 is polycarbocyclyl which may be substituted as described above. More specifically, R1 is a 9- to 10-membered condensed saturated or partially unsaturated carbocyclic ring system, in particular selected from indanyl, tetrahydronaphthyl, hexahydronaphthyl, octahydronaphthyl and decahydronaphthyl which may carry one or more substituents as defined above. In indanyl and tetrahydronaphthyl the attachment point to N is on the nonaromatic ring moiety. Suitable substituents are e.g. selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C1-C4-alkyl substituted by a radical selected from the group consisting of CN, OH, SH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino;
C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
R2 is specifically alkyl, in particular C1-C10-alkyl which, apart from one or more groups LG, may carry other substituents. Suitable substituents are those listed above as in context with substituents on the alkyl groups R1 and R2 in the Suzuki coupling. In particular, the substituents are selected from the group consisting of halogen, cyano, nitro, OH, SH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents are selected from the group consisting of C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl, and very specifically from C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl.
The reaction product of the amination depends on the substituents R3 and R4 and on the molar ratio of the reactants. Thus, if neither R3 nor R4 is H, the reaction product will generally be a tertiary amine R2—N(R3)R4. If R3 is H and R4 is not H and R2-LG is used in excess, the reaction product might be a secondary amine R2—N(H)R4 or a tertiary amine (R2)2NR4 or a mixture thereof. If ammonia is used and R2-LG is used in excess, the reaction product might be a primary amine NH2R2, a secondary amine NH(R2)2 or a tertiary amine (R2)3N or a mixture thereof.
The reaction product of the amination depends moreover on the nature of R2: R2 may carry more than one leaving group LG, e.g. two. If ammonia or a primary amine is used, this may result in the formation of a heterocyclic ring containing the nitrogen atom deriving from ammonia or the primary amine as heteroatom ring member, especially if ammonia or the amine is not used in excess. This ring formation is favoured if the two leaving groups are bound at such a distance from each other that a 4-, 5-, 6- or 7-membered ring can form. Ring formation is also favoured by a higher dilution of the reactants in the reaction medium.
Amination is generally carried out in the presence of a base. Suitable bases are those listed above in context with the Suzuki reaction, where especially inorganic bases, specifically alkali metal hydroxides, such as NaOH or KOH, are used. In case an organic base is used, this is of course not a primary or secondary amine. The base is generally used in at least equimolar amounts, with respect to that reactant not used in excess, e.g. in an amount of from 1 to 10 mol per mol of the reactant not used in excess, in particular 1.5 to 8 mol per mol of the reactant not used in excess, specifically 2 to 7 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
Amination is preferably carried out at from 10° C. to 70° C., more preferably from 20° C. to 70° C., in particular from 30 to 70° C., more particularly from 40 to 60° C. and specifically from 45 to 60° C.
The reaction can be carried out by standard proceedings for amination reactions via nucleophilic substitution, e.g. by mixing all reagents, inclusive base, water and the cellulose derivative, and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Workup proceedings will be described below, as they are similar for most reactions.
The organic reaction can also take another form of amination than an amination via nucleophilic substitution. For instance, the amination may be a Michael addition of an N nucleophile.
Michael Addition, Especially of N Nucleophiles
In another particular embodiment of the invention, the organic reaction is a Michael addition, especially of N nucleophiles. In general terms, Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an α,β-unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. In case of N nucleophiles, the reaction can be depicted as follows:
R3 and R4 are as defined above in context with aminations as nucleophilic substitution. Ra, Rb and Rc are independently of each other selected from the group consisting of hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, or are one of the substituents listed in context with the Suzuki reaction as suitable radicals on alkyl, alkenyl, alkapoyenyl, alkynyl, alkapolyynyl or mixed alkenyl/alkynyl groups (however except for oxo (═O), ═S, and ═NR12a). More precisely, Ra, Rb and Rc are independently of each other selected from the group consisting of hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13 or —Si(R14)3; where R11, R12a, R12b, R13, R14 and R15 are independently as defined above in context with the Suzuki reaction. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups can be substituted by one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In particular at least two of Ra, Rb and Rc is hydrogen and the other is alkyl, in particular C1-C4-alkyl, which may be substituted. In particular, the alkyl substituents are selected from the group consisting of halogen, cyano, nitro, OH, SH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents are selected from the group consisting of OH, C1-C6-alkoxy and C1-C6-haloalkoxy.
Rd is selected from the group consisting of hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, OR11, SR11 or NR12aR12b; where R11, R12a and R12b are independently as defined above in context with the Suzuki reaction. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups can be substituted by one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In particular, Rd is selected from the group consisting of OH, C1-C6-alkoxy and C1-C6-haloalkoxy.
The amine and the α,β-unsaturated carbonyl compound can be used in a molar ratio of from 10:1 to 1:10, e.g. from 5:1 to 1:5 or from 3:1 to 1:3 or, preferably, from 2:1 to 1:2.
The reaction is generally carried out in the presence of a base. Suitable bases are those listed above in context with the Suzuki reaction. In case an organic base is used, this is of course not a primary or secondary amine. The base is generally used in at least equimolar amounts, with respect to that reactant not used in excess, e.g. in an amount of from 1 to 10 mol per mol of the reactant not used in excess, in particular 1.5 to 8 mol per mol of the reactant not used in excess, specifically 2 to 7 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction is preferably carried out at from 10° C. to 60° C., more preferably from 20° C. to 50° C., in particular from 20 to 40° C., more particularly from 20 to 30° C.
The reaction can be carried out by standard proceedings for Michael additions, e.g. by mixing all reagents, inclusive base, water and the cellulose derivative, and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Workup proceedings will be described below, as they are similar for most reactions.
Reductions and Oxidations
In another particular embodiment of the invention, the organic reaction is a reduction or an oxidation reaction, preferably a reduction reaction.
Reduction is the gain of electrons or a decrease in oxidation state by a molecule, atom, or ion. Oxidation, inversely, is the loss of electrons or an increase in oxidation state by a molecule, atom, or ion. Reduction reactions as well as oxidation reactions are of course always redox reactions, as the reduction agent used in the former case is necessarily oxidized, and the oxidation agent in the latter case is necessarily reduced. Redox reactions are however termed “reduction reactions” when the product of value is obtained by reducing the respective starting compound and are analogously termed “oxidation reactions” when the product of value is obtained by oxidizing the respective starting compound.
Reduction Reactions
Reduction reactions are very widespread. Some interesting reduction reactions are for example the reduction of nitro to amino groups, the reduction (hydrogenation) of olefins to alkanes, the reduction of esters to ketones, aldehydes or alcohols, the reduction of ketones or aldehydes to alcohols, the reduction of carbonyl compounds to amines (reductive amination) or the reduction of nitrile groups to amino groups. The present invention relates in particular to the reduction of nitro compounds to the corresponding amino compounds, to the reduction of C—C double bonds to C—C single bonds and to reductive aminations.
Reduction of Nitro Compounds
Nitro compounds can be reduced to the corresponding amino compounds by various reducing agents, the most widely used methods being the reduction with base metals, usually in acidic solution; and catalytic hydrogenation. Also suitable are metal hydrides, such as lithium or sodium hydride, complex hydrides, such as sodium boron hydride (NaBH4), lithium triethylborohydride (superhydride; LiBH(CH2CH3)2), lithium tri-sec-butyl(hydrido)borate (L-selectride; LiBH(CH(CH3)CH2CH3)2), lithium aluminum hydride (LAH; LiAlH4) or diisobutlyaluminum hydride (DIBAL-H; ((CH3)2CHCH2)2AlH), or boranes, e.g. diborane.
Base metals which can act as reducing agents are principally all those with a suitable redox potential and a reactivity which is controllable in aqueous medium. Despite of their redox potential, alkali metals are thus not very well suited. Examples of suitable base metals are earth alkaline metals, especially magnesium or calcium, aluminum, iron, copper, cobalt, nickel, zinc, titanium or chromium.
In view of their suitable redox potential, controllable reactivity, versatility under various reaction conditions and price, zinc and iron are among the most wide-spread reducing agents. Generally they are used in an acidic reaction medium, e.g. in diluted aqueous HCl or in ammonium chloride solution.
Thus, in a particular embodiment, the present invention relates to a method for reducing nitro compounds with Zn or Fe, optionally in acidic solution, such as aqueous HCl or ammonium chloride solution. In a specific embodiment, the present invention relates to a method for reducing nitro compounds with Zn, optionally in acidic solution, such as aqueous HCl or ammonium chloride solution. HCl or ammonium chloride are generally used in such concentration/amount that the pH of the reaction medium is from 1 to 6.
The base metal is generally used in finely divided form, e.g. in form of small granules, powder or dust, and in particular of powder or dust. As a rule, the less reactive the metal, the finer divided its use form in order to achieve a sufficient conversion rate. Accordingly, Zn and Fe are preferably used in form of powder or dust.
For reduction by catalytic hydrogenation, the catalysts may generally be all prior art catalysts which catalyze the hydrogenation of nitro compounds to the corresponding amino compounds. The catalysts may be used either in heterogeneous phase or as homogeneous catalysts. The hydrogenation catalysts preferably comprise at least one metal of group VIII and also VIIa.
Suitable metals of group VIII are selected from the group consisting of ruthenium, cobalt, rhodium, nickel, palladium und platinum. A suitable metal of group VIIa is rhenium.
The metals may also be used in the form of mixtures. Metals of group VIII may also comprise small amounts of further metals, for example metals of group VIIa, in particular rhenium, or metals of group Ib, i.e. copper, silver or gold. Particularly suitable metals of group VIII are ruthenium, nickel, palladium and platinum. The catalyst especially comprises palladium as the catalytically active species.
When a heterogeneous catalyst is used, it is suitably present in finely divided form. The finely divided form is achieved, for example, as follows:
a) Black catalyst: shortly before use as a catalyst, the metal is deposited reductively from the solution of one of its salts.
b) Adams catalyst: the metal oxides, in particular the oxides of platinum and palladium, are reduced in situ by the hydrogen used for the hydrogenation.
c) Skeletal or Raney catalyst: the catalyst is prepared as a “metal sponge” from a binary alloy of the metal (in particular nickel or cobalt) with aluminum or silicon by leaching out one partner with acid or alkali. Residues of the original alloy partner often act synergistically.
d) Supported catalyst: black catalysts can also be precipitated on the surface of a support substance. Suitable supports and support materials are described below.
The support material is generally used in the form of a fine powder. The supports may consist of metallic or nonmetallic, porous or nonporous material. Suitable metallic materials are, for example, highly alloyed stainless steels. Suitable nonmetallic materials are, for example, mineral materials, for example natural and synthetic minerals, glasses or ceramics, plastics, for example synthetic or natural polymers, or a combination of the two. Preferred support materials are carbon, in particular activated carbon, silicon dioxide, in particular amorphous silicon dioxide, alumina, and also the sulfates and carbonates of the alkaline earth metals, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium sulfate, barium carbonate and barium sulfate.
The catalyst may be applied to the support by customary processes, for example by impregnating, wetting or spraying the support with a solution which comprises the catalyst or a suitable precursor thereof.
It is also possible to use homogeneous hydrogenation catalysts, such as, for example, the Wilkinson catalyst and derivatives thereof, or BINAP-ruthenium complexes, e.g. Ru(OAc)2—(S)-BINAP. However, disadvantages of use of homogeneous catalysts are their preparation costs and also the fact that they generally cannot be regenerated. Therefore, preference is given to using heterogeneous hydrogenation catalysts.
The catalytic metal is in particular used in supported form or as metal sponge. Examples of supported catalysts are palladium, nickel or ruthenium on carbon, in particular activated carbon, silicon dioxide, in particular on amorphous silicon dioxide, barium carbonate, calcium carbonate, magnesium carbonate or alumina.
The metallic catalysts may also be used in the form of their oxides, in particular palladium oxide, platinum oxide or nickel oxide, which are then reduced under the hydrogenation conditions to the corresponding metals.
A suitable metal sponge is for example Raney nickel.
The catalyst and the form in which this is used is selected in accordance with the type of nitro compound to be reduced. For instance, if the nitro compound contains further functional groups which may principally also be hydrogenated, such as C—C double bonds, aromatic rings, carbonyl, carboxyl or cyano groups, the catalyst and the reaction conditions are chosen to be as selective as possible for the nitro group. Suitable conditions and catalysts are known to those skilled in the art and can be determined by simple preliminary tests.
In a particular embodiment of the present invention, the nitro compound is an aromatic or heteroaromatic nitro compound R1—N2, where R1 is a mono-, bi- or polycyclic aryl or heteroaryl group.
In a particular embodiment the aryl group R1 is mono-, bi- or tricyclic and is specifically selected from the group consisting of phenyl and naphthyl; and the heteroaryl group R1 is in particular mono-, bi- or tricyclic and is specifically selected from the group consisting of 5- or 6-membered heteroaromatic monocyclic rings and 9- or 10-membered heteroaromatic bicyclic rings containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members. Mono- or bicyclic aryl or heteroaryl groups R1 are for example phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazoyl, isoxazoyl, thiazoyl, isothiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, [1,3,4]triazolyl, the oxadiazolyls, the thiadiazolyls, the tetrazolyls, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, quinazalinyl and the like. More particularly, they are for example phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazalinyl and other heteroaromatic bicyclic rings shown below in the “general definitions”. Specifically, R1 is phenyl.
The aryl and heteroaryl groups R1 can carry one or more substituents, e.g. 1, 2, 3 or 4, in particular 1, 2 or 3, specifically 1 or 2 substituents. Suitable substituents are listed above in context with aryl and heteroaryl groups R1 and R2 in the Suzuki reaction. In a particular embodiment, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl. C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, aminocarbonyl, C1-C4-alkylaminocarbonyl, di-(C1-C4-alkyl)aminocarbonyl, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of halogen, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. The alkyl groups in C1-C4-alkylamino, di-(C1-C4-alkyl)amino, C1-C4-alkylaminocarbonyl and di-(C1-C4-alkyl)aminocarbonyl may in turn carry one or more substituents selected from the group consisting of halogen, cyano, OH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-halocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, aminocarbonyl, C1-C4-alkylaminocarbonyl and di-(C1-C4-alkyl)aminocarbonyl, where the alkyl groups in C1-C4-alkylamino, di-(C1-C4-alkyl)amino, C1-C4-alkylaminocarbonyl and di-(C1-C4-alkyl)aminocarbonyl may in turn carry one or more substituents selected from the group consisting of amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents on the aryl and heteroaryl groups R1 are selected from the group consisting of halogen, C1-C6-alkoxy, C1-C6-haloalkoxy, aminocarbonyl, C1-C4-alkylaminocarbonyl and di-(C1-C4-alkyl)aminocarbonyl, where the alkyl groups in C1-C4-alkylaminocarbonyl and di-(C1-C4-alkyl)aminocarbonyl may in turn carry one or more substituents selected from the group consisting of amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino.
Preferably however, the aryl or heteroaryl groups do not carry any groups prone to hydrogenation under the applied reaction conditions, such as alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, cyano, C(O)R13, C(S)R13 or C(═NR12a)R13 groups.
For such aromatic or heteroaromatic nitro compounds R1—NO2, the hydrogenation catalyst is in particular palladium on carbon.
The amount of catalyst to be used depends on factors including the particular catalytically active metal and its use form, and may be determined in the individual case by those skilled in the art. When noble metal catalysts are used which comprise, for example, platinum or palladium, the amount can be smaller by a factor of 10 as compared to the amount of for example, nickel- or cobalt-containing hydrogenation catalysts. In case of Pd or Pt, for example, the catalyst is used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.2 mol per mol of nitro compound, in particular 0.005 to 0.1 mol per mol of nitro compound, specifically 0.01 to 0.1 mol per mol of nitro compound. The amount of catalyst specified relates to the amount of active metal, i.e. to the catalytically active component of the catalyst.
The reduction (with a base metal as well as via hydrogenation) is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C. and very specifically from 20° C. to 30° C.
The reaction pressure of the hydrogenation reaction is preferably in the range of from 1 to 250 bar, in particular from 1 to 50 bar and more particularly from 1 to 5 bar. In case that the nitro compound contains groups which can also be hydrogenated, especially aromatic or heteroaromatic rings, it is expedient to work at lower pressure in order to avoid hydrogenation of such groups. In this case, the reaction pressure of the hydrogenation reaction is preferably in the range from 1 to 5 bar, more preferably 1 to 2 bar and in particular 1 to 1.5 bar.
Reduction of C—C Double Bonds
C—C double bonds are generally reduced by hydrogenation. The above remarks to the hydrogenation of nitro compounds apply here analogously, except, however, for metal hydrides, complex hydrides and boranes, which are not suitable here.
Here, too, the catalyst and the form in which this is used is selected in accordance with the type of olefinically unsaturated compound to be reduced. For instance, if the olefinically unsaturated compound contains further functional groups which may principally also be hydrogenated, such as aromatic rings, carbonyl, carboxyl or cyano groups, the catalyst and the reaction conditions are chosen to be as selective as possible for the C—C double bond. Suitable conditions and catalysts are known to those skilled in the art and can be determined by simple preliminary tests.
The compound with C—C double bonds to be hydrogenated is preferably an olefinically unsaturated compound, i.e. a compound which contains at least one C—C double bond which is not part of an aromatic or heteroaromatic system. Preferably it is a compound of formula (R1)(R2)C═C(R3)(R4), where R1, R2, R3, and R4, independently of each other, are hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heterocyclyl or are one of the substituents listed in context with the Suzuki as suitable radicals on alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl or polycarbocyclyl groups (however except for oxo (═O), ═S and ═NR12a). More precisely, R1, R2, R3, and R4, independently of each other, are hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heterocyclyl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13 or —Si(R14)3; where R11, R12a, R12b, R13, R14 and R15 are independently as defined above in context with the Suzuki reaction.
The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups R1, R2, R3 and R4 can be substituted by one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Alternatively, R1 and R3, together with the carbon atoms they are bound to, form a carbocyclic or heterocyclic, non aromatic ring, where the ring may be substituted; suitable substituents corresponding to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In particular, R1, R2, R3, and R4, independently of each other, are hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or C(═O)R13, where R13 is as defined above in context with the Suzuki reaction and is in particular C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy. Specifically, R1, R2, R3, and R4, independently of each other, are hydrogen, alkyl, aryl, heteroaryl or C(═O)R13, where R13 is as defined above in context with the Suzuki reaction and is in particular C1-C4-alkyl.
If one or more of R1, R2, R3, and R4 are aryl, heteroaryl or C(═O)R13, it is expedient to carry out the hydrogenation either under low hydrogen pressure, as said above.
In a specific embodiment, the olefinically unsaturated compound is a Michael-type compound, i.e. a compound carrying an electron withdrawing group bound to the C—C double bond, especially a C(O) group, such as C(O)R3. Preferably, one of R1, R2, R3, and R4, is C(═O)R13, where R13 is as defined above in context with the Suzuki reaction and is in particular C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy; and the others, independently of each other, are hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. As said, the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups R1, R2, R3 and R4 can be substituted by one or more substituents. Suitable substituents for alkyl, cycloalkyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, cycloalkyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In a particular embodiment the reduction agent is ligated CuH. This is generally prepared in situ by reacting a Cu salt, generally a Cu(II) salt, e.g. Cu(II) acetate, with a hydride source in the presence of a suitable ligand.
Suitable ligands are those mentioned in context with the Suzuki coupling as Pd or Ni ligands. A specific ligand in this case is 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine.
Suitable hydride sources are for example silanes, such as polymethylhydrosiloxane (PMHS; a ca. 29mer), phenylsilane or diethoxymethylsilane (DEMS). Among these, PMHS is preferred.
If a non-racemic ligand is used and R1 and R2 are different from each other and are not H and/or R3 and R4 are different from each other and are not H, the reduction can proceed stereoselectively and yield essentially just one stereoisomer.
Suitable non-racemic ligands are for example [(4R)-(4,4′-bis-1,3-benzodioxole)-5,5′-diyl]bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine] ((R)-DTBM-SEGPHOS®), (R)- or (S)-3,5-Xyl-MeO-BIPHEP, (R,S)- or (S,R)-PPF-P(t-Bu)2, or the Josiphos ligands.
The metal is generally used in catalytic, i.e. substoichiometric amounts, e.g. in an amount of from 0.001 to 0.2 mol per mol of nitro compound, in particular 0.005 to 0.1 mol per mol of nitro compound, specifically 0.01 to 0.05 mol per mol of olefinically unsaturated compound.
The silane is generally used in excess with respect to the compound to be reduced. “Excess” in this case relates to the amount of hydrogen atoms present in the siloxane molecule, divided by two (as two hydrogen atoms are necessary for the hydrogenation of the double bond), and thus, in case of polymeric silanes, such as PMHS, depends on the polymerization degree. Generally it used in such an amount that it can theoretically release 3 to 100 mol of hydrogen atoms per mol of compound with C—C double bonds, in particular 3 to 50 mol of hydrogen atoms per mol of compound with C—C double bonds, more particularly 4 to 20 mol of hydrogen atoms per mol of compound with C—C double bonds, specifically 6 to 15 mol of hydrogen atoms per mol of compound with C—C double bonds.
The reduction is preferably carried out at from 10° C. to 60° C., in particular from 20° C. to 55° C., specifically from 20° C. to 50° C. and very specifically from 20° C. to 30° C.
If the catalyst ligand or any reactant is prone to oxidation by air (such as is the case, for example, for triphenylphosphine, tri(tert-butyl)phosphine, X-Phos, 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine and several others), the reaction is preferably carried out in an inert atmosphere in order to avoid the presence of oxygen, e.g. under an argon or nitrogen atmosphere. Preferably, moreover, the solvent is used in degassed form. On a laboratory scale this is e.g. obtained by freezing, applying a vacuum and unfreezing under an inert atmosphere or by bubbling a vigorous stream of argon or nitrogen through the solvent or by ultrasonification under an inert atmosphere. On an industrial scale other methods known in the art can be applied.
Workup proceedings will be described below, as they are similar for most reactions.
Reductive Amination
In reductive aminations a carbonyl group is converted into an amino group via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. Generally, the amine first reacts with the carbonyl group to form a hemiaminal species, which subsequently loses one molecule of water in a reversible manner by alkylimino-de-oxo-bisubstitution, to form the imine. This intermediate imine can then be reduced with a suitable reducing agent to give an amine:
As the reaction is often carried out as a one pot reaction without intermediate isolation of the imine, the reduction agent and the reaction conditions are in this case expediently such that the reduction agent does not react with the carbonyl compound before the imine is formed. Suitable reduction agents are complex boron hydrides, such as sodium boron hydride (NaBH4), sodium cyanoborohydride (NaBH3CN), sodium triacetoxyborohydride (NaBH(OCOCH3)3), lithium triethylborohydride (superhydride; LiBH(CH2CH3)2), or lithium tri-sec-butyl(hydrido)borate (L-selectride; LiBH(CH(CH3)CH2CH3)2), or boranes, e.g. diborane or borane complexes, such as borane-2-picoline complex. A specifically suitable reduction agent is the borane-2-picoline complex. Also suitable is formic acid. In this case, the reductive amination is a Leuckert-Wallach reaction.
R3 and R4 are as defined above in context with aminations as nucleophilic substitution. R1 and R2 are independently of each other selected from the group consisting of hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, or are one of the substituents listed in context with the Suzuki reaction as suitable radicals on alkyl, alkenyl, alkapoyenyl, alkynyl, alkapolyynyl or mixed alkenyl/alkynyl groups (however except for oxo (═O), ═S, and ═NR12a). More precisely, R1 and R2 are independently of each other selected from the group consisting of hydrogen, alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, nitro, azido, —SCN, —SF5, OR11, S(O)mR11, NR12aR12b, C(═O)R13, C(═S)R13, C(═NR12a)R13 or —Si(R14)3; where R11, R12a, R12b, R13, R14 and R15 are independently as defined above in context with the Suzuki reaction. The alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl, heteroaryl groups can be substituted by one or more substituents. Suitable substituents for alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl and heteroaryl correspond to those listed above in context with substituents on the alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling. Suitable substituents for heterocyclyl groups correspond to those listed above in context with substituents on the cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, aryl or heteroaryl groups R1 and R2 in the Suzuki coupling.
In particular, R3 is H and R4 is aryl, where aryl may be substituted as described above. Specifically, R4 is phenyl which may be substituted. In particular, the aryl or phenyl substituents are selected from the group consisting of halogen, cyano, nitro, OH, SH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino and di-(C1-C4-alkyl)amino. Specifically, the substituents are selected from the group consisting of OH, C1-C6-alkoxy and C1-C6-haloalkoxy.
In particular, R1 is H or C1-C4-alkyl and R2 is aryl, where aryl may be substituted as described above. Specifically, R2 is phenyl which may be substituted. In particular, the aryl or phenyl substituents are selected from the group consisting of halogen, cyano, nitro, OH, SH, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl, C1-C4-haloalkoxycarbonyl, amino, C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenyl, a 5- or 6-membered heteroaromatic monocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members and a 9- or 10-membered heteroaromatic bicyclic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where phenyl and the heteroaromatic rings may carry one or more substituents selected from the group consisting of fluorine, cyano, nitro, OH, SH, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-haloalkenyl, C2-C6-alkynyl, C2-C6-haloalkynyl, C3-C8-cycloalkyl, C3-C8-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkoxy-C1-C6-alkyl, C1-C6-alkylthio, C1-C6-haloalkylthio, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, formyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl.
The amine and the carbonyl compound can be used in a molar ratio of from 5:1 to 1:5, e.g. from 3:1 to 1:3, or from 2:1 to 1:2 or, preferably, from 1.5:1 to 1:1.5.
The reduction agent is generally used in at least equimolar amounts, with respect to that reactant not used in excess, e.g. in an amount of from 1 to 3 mol per mol of the reactant not used in excess, in particular 1 to 2 mol per mol of the reactant not used in excess, specifically 1.1 to 1.5 mol per mol of the reactant not used in excess. If the reactants are used in equimolar ratio, the above amounts of base apply of course to either of the reactants.
The reaction may be carried out in the presence of an acid. Suitable acids are inorganic acids, such as HCl or phosphoric acid, and organic acids, such as acetic acid, trifluoroacetic acid, toluenesulfonic acid or diphenyl phosphate. The acid is generally used in substoichiometric mounts, relative to the reactant not used in excess, such as 1 to 50 mol %, in particular 5 to 20 mol %, relative to 1 mol of that reactant not used in excess.
The reaction is preferably carried out at from 10° C. to 60° C., more preferably from 20° C. to 50° C., in particular from 20 to 40° C., more particularly from 20 to 30° C.
The reaction can be carried out by standard proceedings for reductive aminations, e.g. by mixing all reagents, inclusive the reduction agent, water and the cellulose derivative, and reacting them at the desired temperature. Alternatively the reagents can be added gradually, especially in the case of a continuous or semicontinuous process.
Workup proceedings will be described below, as they are similar for most reactions.
Although the above reactions have all been depicted as a reaction between at least two different molecules, they can of course also be carried out as intramolecular reactions if the reactant contains the suitable functional groups in a suitable position to each other. Examples are especially intramolecular cyclizations. For instance, a compound containing both an acid and an amino group in a suitable distance to each other can react in an intramolecular amidation reaction to give a lactam. Suitable dilution is however required for intramolecular reactions if these are not favoured for other reasons over the respective intermolecular reaction.
The method of the present invention is also suitable for a suit or cascade of reaction steps, which may occur either spontaneously or by addition of further reagents after completion of one step. For instance, in reactions with Michael-type reactants, like the above-described (Rh-catalyzed) 1,4-additions or the hydrogenation of such compounds, the carboxyl, ester, amide etc. group may react spontaneously in a subsequent reaction, especially if the Michael-type reactant contains functional groups in suitable position which can give a further reaction with this carboxyl, ester, amide etc. group. For instance, if the Michael-type reactant contains an ester group and also an amine group in suitable position, a lactam can form after or before or during the 1,4-addition or the hydrogenation reaction. Another example is the protection of a functional group in a compound containing more than one functional group, e.g. protection of a primary or secondary amino group, of an OH or SH group, reaction of the other functional group(s) in as desired and deprotection of the protected group and if desired further reaction of the deprotected functional group. This suit of reactions can be carried out as a one pot reaction.
The organic reactions can be carried out in the presence of a surfactant (of course different from the cellulose derivative used according to the present invention).
Suitable surfactants are surface-active compounds, such as anionic, cationic, nonionic and amphoteric surfactants, block polymers, polyelectrolytes, and mixtures thereof.
Anionic surfactants are for example alkali, alkaline earth or ammonium salts of sulfonates, sulfates, phosphates, carboxylates, and mixtures thereof. Examples of sulfonates are alkylarylsulfonates, diphenylsulfonates, alpha-olefin sulfonates, lignine sulfonates, sulfonates of fatty acids and oils, sulfonates of ethoxylated alkylphenols, sulfonates of alkoxylated arylphenols, sulfonates of condensed naphthalenes, sulfonates of dodecyl- and tridecylbenzenes, sulfonates of naphthalenes and alkylnaphthalenes, sulfosuccinates or sulfosuccinamates. Examples of sulfates are sulfates of fatty acids and oils, of ethoxylated alkylphenols, of alcohols, of ethoxylated alcohols, or of fatty acid esters. Examples of phosphates are phosphate esters. Examples of carboxylates are alkyl carboxylates, and carboxylated alcohol or alkylphenol ethoxylates.
Nonionic surfactants are for example alkoxylates, N-substituted fatty acid amides, amine oxides, esters, sugar-based surfactants, polymeric surfactants, and mixtures thereof. Examples of alkoxylates are compounds such as alcohols, alkylphenols, amines, amides, arylphenols, fatty acids or fatty acid esters which have been alkoxylated with 1 to 50 equivalents. Ethylene oxide and/or propylene oxide may be employed for the alkoxylation, preferably ethylene oxide. Examples of N-substituted fatty acid amides are fatty acid glucamides or fatty acid alkanolamides. Examples of esters are fatty acid esters, glycerol esters or monoglycerides. Examples of sugar-based surfactants are sorbitans, ethoxylated sorbitans, sucrose and glucose esters or alkylpolyglucosides. Examples of polymeric surfactants are home- or copolymers of vinylpyrrolidone, vinylalcohols, or vinylacetate.
Cationic surfactants are for example quaternary surfactants, for example quaternary ammonium compounds with one or two hydrophobic groups, or salts of long-chain primary amines. Suitable amphoteric surfactants are alkylbetains and imidazolines. Suitable block polymers are block polymers of the A-B or A-B-A type comprising blocks of polyethylene oxide and polypropylene oxide, or of the A-B-C type comprising alkanol, polyethylene oxide and polypropylene oxide. Suitable polyelectrolytes are polyacids or polybases. Examples of polyacids are alkali salts of polyacrylic acid or polyacid comb polymers. Examples of polybases are polyvinylamines or polyethyleneamines.
In a particular embodiment, the surfactant is a polyoxyethanyl-α-tocopheryl succinate derivative. Suitable surfactants of this type are for example the above-described TPGS-750-M, TPGS-1000 and PTS-600:
Among these, TPGS-750-M is particularly suitable. The polyoxyethanyl-α-tocopheryl succinate derivative surfactants are generally used in an amount of from 0.01 to 15% by weight, in particular 0.05 to 10% by weight, more particularly 0.1 to 7% by weight, specifically 0.2 to 5% by weight, more specifically 1 to 5% by weight, based on the weight of water (water being the only solvent or making up at least 90% by weight of the solvent, in particular at least 97% by weight of the solvent, the percentages being based on the total weight of the solvent).
Specifically however, no surfactant (different from the cellulose derivative used according to the invention) is used.
One advantage of the method of the present invention is the facile workup. The cellulose derivative can be removed in a very simple way: after completion of the reaction, the resulting reaction mixture can be extracted with an organic solvent which has a sufficiently low miscibility with water and a good solubility for the desired product and reactants, if the conversion was not complete. Suitable organic solvents are for instance alkyl carboxylates, such as ethylacetate, open-chained ethers, such as diethyl ether or methyl-tert-butyl ether, halogenated alkanes, such as dichloromethane, chloroform or dichloroethane, alkanes, such as pentane, hexane, heptane or technical mixtures like petroleum ether, cycloalkanes, like cyclohexane or cycloheptane, or aromatic solvents, like toluene and the xylenes. In most cases, ethylacetate or a open-chained ethers, such as diethyl ether or methyl-tert-butyl ether, is the most useful solvent for extraction.
While the desired product and any unreacted reactants move to the organic phase, the cellulose derivative remains in the aqueous phase. If desired, this aqueous phase can be reused, if necessary after a purification step.
Cellulose derivatives with a viscosity of above 10 mPa·s can be removed by salting them out, i.e. by causing their precipitation by addition of a salt. For this purpose, an inorganic salt, e.g. in form of an aqueous solution, is added to the reaction mixture after completion of the reaction, suitably together with an organic solvent as described above. Alternatively, the organic solvent is added first and then the inorganic salt (solution). Principally, the organic solvent may also be added after the inorganic salt (solution). This proceeding is however less suited, as the products might precipitate together with the cellulose derivative. The risk of co-precipitation is somewhat reduced for water-miscible products, as compared to products with low or now miscibility with water, but still existent. Suitable salts are for example sodium sulfate, potassium sulfate, magnesium sulfate, ammonium sulfate, sodium phosphate, potassium phosphate, sodium hydrogenphosphate, potassium hydrogenphosphate, sodium chloride and the like, among which preference is given to salts with large anions, such as the sulfates, phosphates and hydrogenphosphates. In particular, sodium sulfate is used. The addition of the inorganic salt causes the cellulose derivative to precipitate, which can then be removed by standard procedures, such as sedimentation, decantation, filtration or centrifugation, while the product moves to the organic phase. If desired, the aqueous phase can be extracted once or several times with an organic solvent to remove any residual organic products from the water phase.
Another method for causing precipitation of certain cellulose derivative is heating, e.g. to at least 80° C.
If desired, the precipitated cellulose derivative can be reactivated and reused in the method of the invention. Reactivation is for example achieved by cooling, if precipitation was caused by heating, or by washing with water to remove the salt with which the cellulose derivative was salted out.
Thus, in a preferred embodiment of the present invention, after completion of the organic reaction the cellulose derivative is precipitated by heating or by adding an inorganic salt, preferably by adding an inorganic salt, where the inorganic salt is selected from the group consisting of sodium sulfate, potassium sulfate, magnesium sulfate, ammonium sulfate, sodium phosphate, potassium phosphate, sodium hydrogenphosphate, potassium hydrogenphosphate and sodium chloride, and is in particular sodium sulfate; where precipitation of the cellulose derivative can be carried out before or after removing the reaction product and, if present, unreacted starting compounds, and where the precipitated cellulose derivative, after a reactivation step, can be reused in the method as claimed in any of the preceding claims.
If the organic reaction was carried out in the presence of a heterogenous catalyst, the isolated precipitate (of the precipitated cellulose derivative) often contains the catalyst in essentially quantitative amounts. Thus, not only the cellulose derivative can be recycled, but also the heterogenous catalyst.
If the product is initially obtained as a salt, e.g. because it is a Lewis base, e.g. an amine, and the reaction medium is acidic, the reaction mixture is expediently first neutralized or made alkaline before the organic solvent is added for extraction, as otherwise the product would remain in the aqueous phase. Inversely, if the product is a salt because it is an acid and the reaction medium is basic, the reaction mixture is expediently first neutralized or made acidic before the organic solvent is added for extraction, as otherwise the product would remain in the aqueous phase.
If a silyl compound is used in the reaction, as is the case, for example, in the CuH reduction of olefinic double bonds with silanes as hydride source, it is expedient to quench this silyl compound, e.g. by addition of NH4F.
After separation from the cellulose derivative, the reaction product can be isolated and, if required, purified by standard procedures, such as chromatographic methods, distillation, sublimation, crystallization etc.
The method of the invention allows carrying out virtually all organic reactions so far carried out in organic solvents. This is surprising in cases in which one or more of the reagents or products are not or only scarcely water soluble/miscible. This is even more surprising in cases in which one or more of the reagents or products are hydrolytically labile or in which water is produced, such as in esterifications or in the above-described cyclodehydratizations, as one would expect in the latter case that the reaction would proceed extremely slowly, if at all.
Yields and purities are satisfactory to very good, and, surprisingly, in many cases better than in organic solvents. The reaction times are generally short, especially if higher reaction temperatures, e.g. around 50° C., are applied. In some cases, they are even extremely short, such as just some 15 minutes or even just 10 or 5 or 2 minutes (for a mmol scale).
The cellulose derivatives are significantly less expensive than TPGS-750-M and the other polyoxyethanyl-α-tocopheryl derivatives described above and readily available. Moreover, they can be easily separated from the reaction mixtures. If desired, they can be reused in the method of the invention, if necessary after a reactivation step.
General Definitions
The organic moieties mentioned in the above definitions of the variables are—like the term halogen—collective terms for individual listings of the individual group members. The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group.
The term halogen denotes in each case fluorine, bromine, chlorine or iodine.
Pseudohalogens are polyatomic analogues of halogens, whose chemistry, resembling that of the true halogens, allows them to substitute for halogens in several classes of chemical compounds. Examples for pseudohalogen groups, in terms of the present invention also named pseudohalogenide groups, pseudohalogenides, pseudohalide groups or or pseudohalides, are —CN, —N3, —OCN, —NCO, —CNO, —SCN, —NCS or —SeCN.
If the term “alkyl” as used herein and in the alkyl moieties of alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl and the like is used without prefix (Cn-Cm), it indicates saturated straight-chain or branched aliphatic hydrocarbon radicals having in general 1 to 30 (“C1-C30-alkyl”) carbon atoms, preferably 1 to 20 (“C1-C20-alkyl”) carbon atoms, in particular 1 to 10 (“C1-C30-alkyl”) carbon atoms, specifically 1 to 6 (“C1-C6-alkyl”) or 1 to 4 (“C1-C4-alkyl”) carbon atoms. “C1-C2-Alkyl” is a saturated aliphatic hydrocarbon radical having 1 or 2 carbon atoms. “C1-C3-alkyl” is a saturated straight-chain or branched aliphatic hydrocarbon radical having 1 to 3 carbon atoms. “C1-C4-Alkyl” is a saturated straight-chain or branched aliphatic hydrocarbon radical having 1 to 4 carbon atoms. “C1-C6-Alkyl” is a saturated straight-chain or branched aliphatic hydrocarbon radical having 1 to 6 carbon atoms. “C1-C8-Alkyl” is a saturated straight-chain or branched aliphatic hydrocarbon radical having 1 to 8 carbon atoms; etc. C1-C2-Alkyl is methyl or ethyl. Examples for C1-C3-alkyl are, in addition to those mentioned for C1-C2-alkyl, propyl and isopropyl. Examples for C1-C4-alkyl are, in addition to those mentioned for C1-C3-alkyl, butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) or 1,1-dimethylethyl (tert-butyl). Examples for C1-C6-alkyl are, in addition to those mentioned for C1-C4-alkyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl. Examples for C1-C8-alkyl are, in addition to those mentioned for C1-C6-alkyl, heptyl, octyl, 2-ethylhexyl and positional isomers thereof. Examples for C1-C10-alkyl are, in addition to those mentioned for C1-C6-alkyl, nonyl, decyl and positional isomers thereof. Examples for C1-C20-alkyl are, in addition to those mentioned for C1-C10-alkyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosyl and position isomers thereof. Examples for C1-C30-alkyl are, in addition to those mentioned for C1-C20-alkyl, n-henicosyl, n-docosyl, n-tricosyl, n-tetracosyl, n-pentacosyl, n-hexacosyl, n-octacosyl, n-nonacosyl, n-triacontyl and position isomers thereof.
If the term “haloalkyl” as used herein, which is also expressed as “alkyl which is partially or fully halogenated”, and in the alkyl moieties of haloalkoxy, haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, haloalkylcarbonyl and the like is used without prefix (Cn-Cm), it indicates saturated straight-chain or branched aliphatic hydrocarbon radicals having in general 1 to 30 (“C1-C30-haloalkyl”) carbon atoms, preferably 1 to 20 (“C1-C20-haloalkyl”) carbon atoms, in particular 1 to 10 (“C1-C10-haloalkyl”) carbon atoms, specifically 1 to 6 (“C1-C6-haloalkyl”) or 1 to 4 (“C1-C4-haloalkyl”) carbon atoms, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine.
“Halomethyl” or “halogenated methyl” or “C1-haloalkyl” is methyl in which 1, 2 or 3 of the hydrogen atoms are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine. “C1-C2-Haloalkyl” refers to alkyl groups having 1 or 2 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine. “C1-C3-Haloalkyl” refers to straight-chain or branched alkyl groups having 1 to 3 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine. “C1-C4-Haloalkyl” refers to straight-chain or branched alkyl groups having 1 to 4 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine. “C1-C6-Haloalkyl” refers to straight-chain or branched alkyl groups having 1 to 6 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine. “C1-C8-Haloalkyl” refers to straight-chain or branched alkyl groups having 1 to 8 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine. “C1-C10-Haloalkyl” refers to straight-chain or branched alkyl groups having 1 to 10 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine; etc. Examples for halomethyl are bromomethyl, chloromethyl, fluoromethyl, dichloromethyl, trichloromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl and the like. Examples for C1-C2-haloalkyl are chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl. Examples for C1-C3-haloalkyl are, in addition to those mentioned for C1-C2-haloalkyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 1,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 1,1,1-trifluoroprop-2-yl, 3-chloropropyl and the like. Examples for C1-C4-haloalkyl are, in addition to those mentioned for C1-C3-haloalkyl, 4-chlorobutyl and the like.
If the term “fluorinated alkyl” is used without prefix (Cn-Cm), it indicates saturated straight-chain or branched aliphatic hydrocarbon radicals having in general 1 to 30 (“fluorinated C1-C30-alkyl”) carbon atoms, preferably 1 to 20 (“fluorinated C1-C20-alkyl”) carbon atoms, in particular 1 to 10 (“fluorinated C1-C10-alkyl”) carbon atoms, specifically 1 to 6 (“fluorinated C1-C6-alkyl”) or 1 to 4 (“fluorinated C1-C4-alkyl”) carbon atoms, where some or all of the hydrogen atoms in these groups are replaced by fluorine atoms. “Fluorinated methyl” is methyl in which 1, 2 or 3 of the hydrogen atoms are replaced by fluorine atoms. “Fluorinated C1-C2-alkyl” refers to alkyl groups having 1 or 2 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by fluorine atoms. “Fluorinated C1-C3-alkyl” refers to straight-chain or branched alkyl groups having 1 to 3 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by fluorine atoms. “Fluorinated C1-C4-alkyl” refers to straight-chain or branched alkyl groups having 1 to 4 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by fluorine atoms. “Fluorinated C1-C6-alkyl” refers to straight-chain or branched alkyl groups having 1 to 6 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by fluorine atoms. “Fluorinated C1-C8-alkyl” refers to straight-chain or branched alkyl groups having 1 to 8 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by fluorine atoms. “Fluorinated C1-C10-alkyl” refers to straight-chain or branched alkyl groups having 1 to 10 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by fluorine atoms; etc. Examples for fluorinated methyl are fluoromethyl, difluoromethyl and trifluoromethyl. Examples for fluorinated C1-C2-alkyl are fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl. Examples for fluorinated C1-C3-alkyl are, in addition to those mentioned for fluorinated C1-C2-alkyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 1,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 1,1,1-trifluoroprop-2-yl, heptafluoropropyl, and the like. Examples for fluorinated C1-C4-alkyl are, in addition to those mentioned for fluorinated C1-C3-alkyl, 4-fluorobutyl, the nonafluorobutyls, the heptadecafluorooctyls and the like.
In perfluorinated alkyl, all hydrogen atoms are replaced by fluorine atoms. Examples are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, the nonafluorobutyls, the heptadecafluorooctyls and the like.
If the term “hydroxyalkyl” is used without prefix (Cn-Cm), it indicates saturated straight-chain or branched aliphatic hydrocarbon radicals having in general 1 to 30 (“C1-C30-hydroxyalkyl”) carbon atoms, preferably 1 to 20 (“C1-C20-hydroxyalkyl”) carbon atoms, in particular 1 to 10 (“C1-C10-hydroxyalkyl”) carbon atoms, specifically 2 to 6 (“C2-C6-hydroxyalkyl”) or 2 to 4 (“C2-C4-hydroxyalkyl”) or 2 to 3 (“C2-C3-hydroxyalkyl”) carbon atoms, where one hydrogen atom in these groups is replaced by a hydroxyl group. C2-C3-Hydroxyalkyl is for example 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxyprop-1-yl, 1-hydroxyprop-2-yl, 2-hydroxyprop-1-yl, 2-hydroxyprop-2-yl or 3-hydroxyprop-1-yl, and in particular 2-hydroxyethyl or 2-hydroxyprop-1-yl. Examples for C2-C4-hydroxyalkyl are, in addition to those listed for C2-C3-hydroxyalkyl, 1-hydroxybut-1-yl, 1-hydroxybut-2-yl, 1-hydroxybut-3-yl, 2-hydroxybut-1-yl, 2-hydroxybut-2-yl, 2-hydroxybut-3-yl, 3-hydroxybut-1-yl, 4-hydroxybut-1-yl, 1-hydroxy-2-methyl-propy-1-yl, 2-hydroxy-2-methyl-propy-1-yl, 3-hydroxy-2-methyl-propy-1-yl and 2-(hydroxymethyl)-2-methyl-eth-1-yl, and in particular 2-hydroxyethyl, 2-hydroxyprop-1-yl or 4-hydroxybut-1-yl.
If the term “alkenyl” as used herein and in the alkyl moieties of alkenyloxy, alkenylthio, alkenylsulfinyl, alkenylsulfonyl, alkenylcarbonyl and the like is used without prefix (Cn-Cm), it indicates monounsaturated (i.e. containing one C—C double bond) straight-chain or branched aliphatic hydrocarbon radicals having in general 2 to 30 (“C2-C30-alkenyl”) carbon atoms, preferably 2 to 20 (“C2-C20-alkenyl”) carbon atoms, in particular 2 to 10 (“C2-C10-alkenyl”) carbon atoms, specifically 2 to 6 (“C2-C6-alkenyl”) or 2 to 4 (“C2-C4-alkenyl”) carbon atoms, where the C—C double bond can be in any position. “C2-C3-alkenyl” refers to monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having 2 to 3 carbon atoms and a C—C double bond in any position. “C2-C4-alkenyl” refers to monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having 2 to 4 carbon atoms and a C—C double bond in any position. “C2-C6-alkenyl” refers to monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having 2 to 6 carbon atoms and a C—C double bond in any position. “C2-C8-alkenyl” refers to monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having 2 to 8 carbon atoms and a C—C double bond in any position. “C2-C10-alkenyl” refers to monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having 2 to 10 carbon atoms and a C—C double bond in any position. Examples for C2-C3-alkenyl are ethenyl, 1-propenyl, 2-propenyl or 1-methylethenyl. Examples for C2-C4-alkenyl are ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl. Examples for C2-C6-alkenyl are ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl and the like. Examples for C2-C10-alkenyl are, in addition to the examples mentioned for C2-C6-alkenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl and the positional isomers thereof.
If the terminal C—C double bond is in a terminal position, i.e. if the radical contains a C═CH2 group, the alkenyl group is also termed a vinyl group.
If the term “haloalkenyl” as used herein, which is also expressed as “alkenyl which is partially or fully halogenated”, and in the alkenyl moieties of haloalkenyloxy, haloalkenylthio, haloalkenylsulfinyl, haloalkenylsulfonyl, haloalkenylcarbonyl and the like is used without prefix (Cn-Cm), it indicates monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having in general 2 to 30 (“C2-C30-haloalkenyl”) carbon atoms, preferably 2 to 20 (“C2-C20-haloalkenyl”) carbon atoms, in particular 2 to 10 (“C2-C10-haloalkenyl”) carbon atoms, specifically 2 to 6 (“C2-C6-haloalkenyl”) or 2 to 4 (“C2-C4-haloalkenyl”) carbon atoms, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine, and where the C—C double bond can be in any position. “C2-C3-Haloalkenyl” refers to monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having 2 to 3 carbon atoms and a C—C double bond in any position (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine. “C2-C4-Haloalkenyl” refers to monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having 2 to 4 carbon atoms and a C—C double bond in any position (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine. “C2-C6-Haloalkenyl” refers to monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having 2 to 6 carbon atoms and a double bond in any position (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine. “C2-C8-Haloalkenyl” refers to monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having 2 to 8 carbon atoms and a double bond in any position (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine. “C2-C10-Haloalkenyl” refers to monounsaturated straight-chain or branched aliphatic hydrocarbon radicals having 2 to 10 carbon atoms and a double bond in any position (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and/or bromine; etc. Examples are chlorovinyl, chloroallyl and the like.
If the term “alkapolyenyl” is used without prefix (Cn-Cm), it indicates straight-chain or branched aliphatic hydrocarbon radicals having in general 4 to 30 (“C4-C30-alkapolyenyl”) carbon atoms, preferably 4 to 20 (“C4-C20-alkapolyenyl”) carbon atoms, in particular 4 to 10 (“C4-C10-alkapolyenyl”) carbon atoms, and two or more conjugated or isolated, but non-cumulated C—C double bonds. Examples are buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, penta-1,3-dien-1-yl, penta-1,3-dien-2-yl, penta-1,3-dien-3-yl, penta-1,3-dien-4-yl, penta-1,3-dien-5-yl, penta-1,4-dien-1-yl, penta-1,4-dien-2-yl, penta-1,4-dien-3-yl, and the like.
If the term “haloalkapolyenyl” is used without prefix (Cn-Cm), it indicates straight-chain or branched aliphatic hydrocarbon radicals having in general 4 to 30 (“C4-C30-haloalkapolyenyl”) carbon atoms, preferably 4 to 20 (“C4-C20-haloalkapolyenyl”) carbon atoms, in particular 4 to 10 (“C4-C10-haloalkapolyenyl”) carbon atoms, and two or more conjugated or isolated, but non-cumulated C—C double bonds, as defined above, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine.
If the term “alkynyl” as used herein and in the alkynyl moieties of alkynyloxy, alkynylthio, alkynylsulfinyl, alkynylsulfonyl, alkynylcarbonyl and the like is used without prefix (Cn-Cm), it indicates straight-chain or branched aliphatic hydrocarbon radicals having in general 2 to 30 (“C2-C30-alkynyl”) carbon atoms, preferably 2 to 20 (“C2-C20-alkynyl”) carbon atoms, in particular 2 to 10 (“C2-C10-alkynyl”) carbon atoms, specifically 2 to 6 (“C2-C6-alkynyl”) or 2 to 4 (“C2-C4-alkynyl”) carbon atoms, and one triple bond in any position. “C2-C3-Alkynyl” indicates straight-chain or branched hydrocarbon radicals having 2 to 3 carbon atoms and one triple bond in any position. “C2-C4-Alkynyl” indicates straight-chain or branched hydrocarbon radicals having 2 to 4 carbon atoms and one triple bond in any position. “C2-C6-Alkynyl” indicates straight-chain or branched hydrocarbon radicals having 2 to 6 carbon atoms and one triple bond in any position. “C2-C8-Alkynyl” indicates straight-chain or branched hydrocarbon radicals having 2 to 8 carbon atoms and one triple bond in any position. “C2-C10-Alkynyl” indicates straight-chain or branched hydrocarbon radicals having 2 to 10 carbon atoms and one triple bond in any position; etc. Examples for C2-C3-alkynyl are ethynyl, 1-propynyl or 2-propynyl. Examples for C2-C4-alkynyl are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and the like. Examples for C2-C6-alkynyl are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.
If the term “alkyne” as used herein is used without prefix (Cn-Cm), it indicates a straight-chain or branched aliphatic hydrocarbon having in general 2 to 30 (“C2-C30-alkyne”) carbon atoms, preferably 2 to 20 (“C2-C20-alkyne”) carbon atoms, in particular 2 to 10 (“C2-C10-alkyne”) carbon atoms, specifically 2 to 6 (“C2-C6-alkyne”) or 2 to 4 (“C2-C4-alkyne”) carbon atoms, and one triple bond in any position. “C2-C3-Alkyne” indicates a straight-chain or branched hydrocarbon having 2 or 3 carbon atoms and one triple bond. “C2-C4-Alkyne” indicates a straight-chain or branched hydrocarbon having 2 to 4 carbon atoms and one triple bond in any position. “C2-C6-Alkyne” indicates a straight-chain or branched hydrocarbon having 2 to 6 carbon atoms and one triple bond in any position. “C2-C8-Alkyne” indicates a straight-chain or branched hydrocarbon having 2 to 8 carbon atoms and one triple bond in any position. “C2-C10-Alkyne” indicates a straight-chain or branched hydrocarbon having 2 to 10 carbon atoms and one triple bond in any position; etc. Examples for C2-C3-alkyne are ethyne and propyne. Examples for C2-C4-alkyne are ethyne, propyne, but-1-yne and but-2-yne. Examples for C2-C6-alkynyl are ethyne, propyne, but-1-yne, but-2-yne, pent-1-yne, pent-2-yne, 3-methyl-but-1-yne, hex-1-yne, hex-2-yne, hex-3-yne, 4-methyl-pent-1-yne, 4-methyl-pent-2-yne, 3-methyl-pent-1-yne, 3,3-dimethyl-but-1-yne, and the like.
In a terminal alkyne the C—C triple bond is in a terminal position; i.e. the alkyne contains a C≡CH group.
If the term “haloalkynyl” as used herein, which is also expressed as “alkynyl which is partially or fully halogenated”, and in the alkynyl moieties of haloalkynyloxy, haloalkynylthio, haloalkynylsulfinyl, haloalkynylsulfonyl, haloalkynylcarbonyl and the like is used without prefix (Cn-Cm), it indicates straight-chain or branched aliphatic hydrocarbon radicals having in general 2 to 30 (“C2-C30-haloalkynyl”) carbon atoms, preferably 2 to 20 (“C2-C20-haloalkynyl”) carbon atoms, in particular 2 to 10 (“C2-C10-haloalkynyl”) carbon atoms, specifically 2 to 6 (“C2-C6-haloalkynyl”) or 2 to 4 (“C2-C4-haloalkynyl”) carbon atoms, and one triple bond in any position, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine. “C2-C3-Haloalkynyl” indicates straight-chain or branched hydrocarbon radicals having 2 to 3 carbon atoms and one triple bond in any position, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine. “C2-C4-Haloalkynyl” indicates straight-chain or branched hydrocarbon radicals having 2 to 4 carbon atoms and one triple bond in any position, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine. “C2-C6-Haloalkynyl” indicates straight-chain or branched hydrocarbon radicals having 2 to 6 carbon atoms and one triple bond in any position, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine. “C2-C8-Haloalkynyl” indicates straight-chain or branched hydrocarbon radicals having 2 to 8 carbon atoms and one triple bond in any position, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine. “C2-C10-Haloalkynyl” indicates straight-chain or branched hydrocarbon radicals having 2 to 10 carbon atoms and one triple bond in any position, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine; etc.
If the term “alkapolyynyl” is used without prefix (Cn-Cm), it indicates straight-chain or branched aliphatic hydrocarbon radicals having in general 4 to 30 (“C4-C30-alkapolyynyl”) carbon atoms, preferably 4 to 20 (“C4-C20-alkapolyynyl”) carbon atoms, in particular 4 to 10 (“C4-C10-alkypolyenyl”) carbon atoms, and two or more C—C triple bonds. Examples are buta-1,3-diyn-1-yl, penta-1,3-diyn-1-yl, penta-2,4-diyn-1-yl, penta-1,4-diyn-1-yl, penta-1,4-diyn-3-yl, and the like.
If the term “haloalkapolyynyl” is used without prefix (Cn-Cm), it indicates straight-chain or branched aliphatic hydrocarbon radicals having in general 4 to 30 (“C4-C30-haloalkapolyynyl”) carbon atoms, preferably 4 to 20 (“C4-C2-haloalkapolyynyl”) carbon atoms, in particular 4 to 10 (“C4-C10-haloalkapolyynyl”) carbon atoms, and two or C—C double triple, as defined above, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine.
“Mixed alkenyl/alkynyl” indicates straight-chain or branched aliphatic hydrocarbon radicals having at least one C—C double bond and at least one C—C triple bond. If the term “mixed alkenyl/alkynyl” is used without prefix (Cn-Cm), it indicates straight-chain or branched hydrocarbon radicals having in general 4 to 30 (“C4-C30-mixed alkenyl/alkynyl”) carbon atoms, preferably 4 to 20 (“C4-C20-mixed alkenyl/alkynyl”) carbon atoms, in particular 4 to 10 (“C4-C10-mixed alkenyl/alkynyl”) carbon atoms, and at least one C—C double bond and at least one C—C triple bond.
If the term “mixed haloalkenyl/alkynyl” is used without prefix (Cn-Cm), it indicates straight-chain or branched aliphatic hydrocarbon radicals having in general 4 to 30 (“C4-C30-mixed haloalkenyl/alkynyl”) carbon atoms, preferably 4 to 20 (“C4-C20-mixed haloalkenyl/alkynyl”) carbon atoms, in particular 4 to 10 (“C4-C10-mixed haloalkenyl/alkynyl”) carbon atoms, and at least one C—C double bond and at least one C—C triple bond, where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine.
If the term “cycloalkyl” is used without prefix (Cn-Cm), it indicates monocyclic saturated hydrocarbon radicals having in general 3 to 20 (“C3-C20-cycloalkyl”), in particular 3 to 10 (“C3-C10-cycloalkyl”), specifically 3 to 8 (“C3-C8-cycloalkyl”) or more specifically 3 to 6 (“C3-C6-cycloalkyl”) carbon atoms (and of course no heteroatoms) as ring members; i.e. all ring members are carbon atoms. Examples of cycloalkyl having 3 to 4 carbon atoms comprise cyclopropyl and cyclobutyl. Examples of cycloalkyl having 3 to 5 carbon atoms comprise cyclopropyl, cyclobutyl and cyclopentyl. Examples of cycloalkyl having 3 to 6 carbon atoms comprise cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of cycloalkyl having 3 to 8 carbon atoms comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of cycloalkyl having 3 to 10 carbon atoms comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.
If the term “halocycloalkyl”, which is also expressed as “cycloalkyl which is partially or fully halogenated”, is used without prefix (Cn-Cm), it indicates monocyclic saturated hydrocarbon radicals having in general 3 to 20 (“C3-C20-halocycloalkyl”), in particular 3 to 10 (“C3-C10-halocycloalkyl”), specifically 3 to 8 (“C3-C8-halocycloalkyl”) or more specifically 3 to 6 (“C3-C6-halocycloalkyl”) carbon atoms (as mentioned above), in which some or all of the hydrogen atoms are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine.
If the term “polycarbocyclyl” is used without prefix (Cn-Cm), it indicates bi- or polycyclic saturated or unsaturated hydrocarbon radicals having in general 4 to 20 (“C4-C20-polycarbocyclyl”), in particular 6 to 20 (“C6-C20-polycarbocyclyl”) carbon atoms (and of course no heteroatoms) as ring members; i.e. all ring members are carbon atoms. The bi- and polycyclic radicals can be condensed, bridged or spiro-bound rings. Unsaturated polycarbocyclyl contains one or more C—C double and/or triple bonds in the ring and are not throughout aromatic. Examples of bicyclic condensed saturated radicals having 6 to 10 carbon atoms comprise bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl (1,2,3,3a,4,5,6,6a-octahydropentalenyl), bicyclo[4.2.0]octyl, bicyclo[4.3.0]nonyl (2,3,3a,4,5,6,7,7a-octahydro-1H-indene), bicyclo[4.4.0]decyl (decalinyl) and the like. Examples of bridged bicyclic condensed saturated radicals having 7 to 10 carbon atoms comprise bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and the like. Examples of bicyclic spiro-bound saturated radicals are spiro[2.2]pentyl, spiro[2.4]heptyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[5.5]undecyl and the like. Examples for saturated polycyclic radicals comprise 2,3,4,4a,4b,5,6,7,8,8a,9,9a-dodecahydro-1H-fluorenyl, 1,2,3,4,4a,5,6,7,8,8a,9,9a,10,10a-tetradecahydroanthracenyl, 1,2,3,4,4a,4b,5,6,7,8,8a,9,10,10a-tetradecahydrophenanthrenyl, 2,3,3a,4,5,6,6a,7,8,9,9a,9b-dodecahydro-1H-phenalenyl, adamantly and the like. Examples for bicyclic condensed unsaturated radicals are 1,2,3,4,4a,5,8,8a-octahydronaphthalenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthalenyl, 1,2,3,4,4a,5,6,7-octahydronaphthalenyl, 1,2,3,4,5,6,7,8-octahydronaphthalenyl, 1,2,3,4,5,8-hexahydronaphthalenyl, 1,4,4a,5,8,8a-hexahydronaphthalenyl, indanyl, indenyl, the hexahydroindenyls, such as 2,3,3a,4,7,7a-hexahydro-1H-indenyl or 2,3,3a,4,5,7a-hexahydro-1H-indenyl, the tetrahydroindenyls, such as 2,3,3a,7a-tetrahydro-1H-indenyl or 2,3,4,7-tetrahydro-1H-indenyl, and the like. Examples for tricyclic condensed unsaturated radicals are fluorenyl, the dihydrofluorenyl, the tetrahydrofluorenyl, the hexahydrofluorenyls and the decahydrofluorenyls.
Some partially unsaturated polycarbocyclyl rings may be considered as aryl groups in the terms of the present invention if the moiety taking part in the reaction in question is aromatic. Examples are indanyl, indenyl and fluorenyl: If the reaction takes place on the 6-membered aromatic moiety of these fused systems or on a functional group bound to the 6-membered aromatic moiety of these fused systems, the indanyl, indenyl or fluorenyl radical is considered as an aryl ring (see also below definition of aryl). If the reaction is to take place on the 5-membered non-aromatic moiety or on a functional group bound to the 5-membered non-aromatic moiety, indanyl, indenyl and fluorenyl are considered as a polycarbocyclyl ring. Another example is 1,2,3,4-tetrahydronaphthyl: If the reaction takes place on the aromatic moiety of this fused system or on a functional group bound to the 6-membered aromatic moiety, the radical is considered as an aryl ring. If it takes place on the non-aromatic moiety or on a functional group bound thereto, this radical is considered as a polycarbocyclyl ring.
If the term “halopolycarbocyclyl” is used without prefix (Cn-Cm), it indicates bi- or polycyclic saturated or unsaturated hydrocarbon radicals having in general 4 to 20 (“C4-C20-halopolycarbocyclyl”), in particular 6 to 20 (“C6-C20-halopolycarbocyclyl”) carbon atoms, as defined above, in which some or all of the hydrogen atoms are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine. The bi- and polycyclic radicals can be condensed, bridged or spiro-bound rings.
If the term “cycloalkenyl” is used without prefix (Cn-Cm), it indicates monocyclic partially unsaturated, non-aromatic hydrocarbon radicals having in general 3 to 20 (“C3-C20-cycloalkenyl”), in particular 3 to 10 (“C3-C10-cycloalkenyl”), specifically 3 to 8 (“C3-C8-cycloalkenyl”) or more specifically 5 to 7 (“C5-C7-cycloalkenyl”) carbon atoms (and of course no heteroatoms) as ring members; i.e. all ring members are carbon atoms; and one or more non-cumulative, preferably one, C—C double bonds in the ring. Examples for C5-C6-cycloalkenyl are cyclopent-1-en-1-yl, cyclopent-1-en-3-yl, cyclopent-1-en-4-yl, cyclopenta-1,3-dien-1-yl, cyclopenta-1,3-dien-2-yl, cyclopenta-1,3-dien-5-yl, cyclohex-1-en-1-yl, cyclohex-1-en-3-yl, cyclohex-1-en-4-yl, cyclohexa-1,3-dien-1-yl, cyclohexa-1,3-dien-2-yl, cyclohexa-1,3-dien-5-yl, cyclohexa-1,4-dien-1-yl and cyclohexa-1,4-dien-3-yl. Examples of C5-C7-cycloalkenyl are, in addition to those mentioned above for C5-C6-cycloalkenyl, cyclohept-1-en-1-yl, cyclohept-1-en-3-yl, cyclohept-1-en-4-yl, cyclohept-1-en-5-yl, cyclohepta-1,3-dien-1-yl, cyclohepta-1,3-dien-2-yl, cyclohepta-1,3-dien-5-yl, cyclohepta-1,3-dien-6-yl, cyclohepta-1,4-dien-1-yl, cyclohepta-1,4-dien-2-yl, cyclohepta-1,4-dien-3-yl and cyclohepta-1,4-dien-6-yl. Examples of C3-C8-cycloalkenyl are, in addition to those mentioned above for C5-C7-cycloalkenyl, cycloprop-1-en-1-yl, cycloprop-1-en-3-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclooct-1-en-1-yl, cyclooct-1-en-3-yl, cyclooct-1-en-4-yl, cyclooct-1-en-5-yl, cycloocta-1,3-dien-1-yl, cycloocta-1,3-dien-2-yl, cycloocta-1,3-dien-5-yl, cycloocta-1,3-dien-6-yl, cycloocta-1,4-dien-1-yl, cycloocta-1,4-dien-2-yl, cycloocta-1,4-dien-3-yl, cycloocta-1,4-dien-6-yl, cycloocta-1,4-dien-7-yl, cycloocta-1,5-dien-1-yl, and cycloocta-1,5-dien-3-yl.
If the term “halocycloalkenyl”, which is also expressed as “cycloalkenyl which is partially or fully halogenated”, is used without prefix (Cn-Cm), it indicates monocyclic partially unsaturated, non-aromatic hydrocarbon hydrocarbon radicals having in general 3 to 20 (“C3-C20-halocycloalkenyl”), in particular 3 to 10 (“C3-C10-halocycloalkenyl”), specifically 3 to 8 (“C3-C8-halocycloalkenyl”) or more specifically 3 to 6 (“C3-C6-halocycloalkenyl”) carbon atoms (as mentioned above) and one or more non-cumulative, preferably one, C—C double bonds in the ring, where some or all of the hydrogen atoms are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine.
If the term “cycloalkynyl” is used without prefix (Cn-Cm), it indicates monocyclic hydrocarbon radicals having in general 8 to 20 (“C8-C20-cycloalkynyl”), in particular 8 to 16 (“C8-C16-cycloalkynyl”), specifically 8 to 14 (“C8-C14-cycloalkynyl”) carbon atoms (and of course no heteroatoms) as ring members; i.e. all ring members are carbon atoms; and one or more, preferably one, C—C triple bonds in the ring. Examples are cyclooctynyl, cyclodecynyl, cyclododecynyl, cyclotetradecynyl, cyclohexadecynyl and the like.
If the term “halocycloalkynyl”, which is also expressed as “cycloalkynyl which is partially or fully halogenated”, is used without prefix (Cn-Cm), it indicates monocyclic hydrocarbon radicals having in general 8 to 20 (“C8-C20-cycloalkynyl”), in particular 8 to 10 (“C8-C16-cycloalkynyl”), specifically 8 to 14 (“C8-C14-cycloalkynyl”) carbon atoms and one or more, preferably one, C—C triple bonds in the ring, where some or all of the hydrogen atoms are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine.
“Mixed cycloalkenyl/cycloalkynyl” relates to monocyclic hydrocarbon radicals comprising at least one C—C double bond and at least one C—C triple bond in the ring. If used without prefix prefix (Cn-Cm), it indicates monocyclic hydrocarbon radicals having in general 8 to 20 (“C8-C20-mixed cycloalkenyl/cycloalkynyl”), in particular 8 to 16 (“C8-C16-mixed cycloalkenyl/cycloalkynyl”), specifically 8 to 14 (“C8-C14-mixed cycloalkenyl/cycloalkynyl”) carbon atoms (and of course no heteroatoms) as ring members; i.e. all ring members are carbon atoms.
If used without prefix prefix (Cn-Cm), the term “mixed haloycloalkenyl/cycloalkynyl” indicates monocyclic hydrocarbon radicals having in general 8 to 20 (“C8-C20-mixed cycloalkenyl/cycloalkynyl”), in particular 8 to 16 (“C8-C16-mixed cycloalkenyl/cycloalkynyl”), specifically 8 to 14 (“C8-C14-mixed cycloalkenyl/cycloalkynyl”) carbon atoms and at least one C—C double bond and at least one C—C triple bond in the ring, as defined above, where some or all of the hydrogen atoms are replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine.
If the term “cycloalkyl-alkyl” is used without prefix (Cn-Cm), it indicates a cycloalkyl group as defined above, in particular a C3-C8-cycloalkyl group, specifically a C3-C6-cycloalkyl group as defined above which is bound to the remainder of the molecule via an alkyl group as defined above, in particular a C1-C4-alkyl group. The term “cycloalkyl-C1-C4-alkyl” refers to a cycloalkyl group as defined above, in particular a C3-C8-cycloalkyl group (“C3-C8-cycloalkyl-C1-C4-alkyl”), specifically a C3-C6-cycloalkyl group (“C3-C8-cycloalkyl-C1-C4-alkyl”) as defined above, which is bound to the remainder of the molecule via a C1-C4-alkyl group, as defined above. Examples for C3-C4-cycloalkyl-C1-C4-alkyl are cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl and cyclobutylpropyl, Examples for C3-C6-cycloalkyl-C1-C4-alkyl are, in addition to those mentioned for C3-C4-cycloalkyl-C1-C4-alkyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl and cyclohexylpropyl. Examples for C3-C8-cycloalkyl-C1-C4-alkyl are, in addition to those mentioned for C3-C6-cycloalkyl-C1-C4-alkyl, cycloheptylmethyl, cycloheptylethyl, cyclooctylmethyl and the like.
If the term “halocycloalkyl-alkyl” is used without prefix (Cn-Cm), it indicates a halocycloalkyl group as defined above, in particular a C3-C8-halocycloalkyl group, specifically a C3-C6-halocycloalkyl group as defined above, which is bound to the remainder of the molecule via an alkyl group as defined above, in particular a C1-C4-alkyl group. The term “halocycloalkyl-C1-C4-alkyl” refers to halocycloalkyl group as defined above, in particular a C3-C8-halocycloalkyl group as defined above, which is bound to the remainder of the molecule via a C1-C4-alkyl group, as defined above.
“Alkoxy” is an alkyl group, as defined above, attached via an oxygen atom to the remainder of the molecule; generally a C1-C30-alkyl group (“C1-C30-alkoxy”), preferably a C1-C2-alkyl group (“C1-C20-alkoxy”), in particular a C1-C10-alkyl group (“C1-C10-alkoxy”), specifically a C1-C6-alkyl group (“C1-C6-alkoxy”) or a C1-C4-alkyl group (“C1-C4-aloxy”) attached via an oxygen atom to the remainder of the molecule. “C1-C2-Alkoxy” is a C1-C2-alkyl group, as defined above, attached via an oxygen atom. “C1-C3-Alkoxy” is a C1-C3-alkyl group, as defined above, attached via an oxygen atom. C1-C2-Alkoxy is methoxy or ethoxy. C1-C3-Alkoxy is additionally, for example, n-propoxy and 1-methylethoxy (isopropoxy). C1-C4-Alkoxy is additionally, for example, butoxy, 1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or 1,1-dimethylethoxy (tert-butoxy). C1-C6-Alkoxy is additionally, for example, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy. C5-C8-Alkoxy is additionally, for example, heptyloxy, octyloxy, 2-ethylhexyloxy and positional isomers thereof. C1-C10-Alkoxy is additionally, for example, nonyloxy, decyloxy and positional isomers thereof.
“Haloalkoxy” is a haloalkyl group, as defined above, attached via an oxygen atom to the remainder of the molecule; generally a C1-C30-haloalkyl group (“C1-C30-haloalkoxy”), preferably a C1-C20-haloalkyl group (“C1-C20-haloalkoxy”), in particular a C1-C10-haloalkyl group (“C1-C10-haloalkoxy”), specifically a C1-C6-haloalkyl group (“C1-C6-haloalkoxy”) or a C1-C4-haloalkyl group (“C1-C4-haloaloxy”) attached via an oxygen atom to the remainder of the molecule. The term “C1-C2-haloalkoxy” is a C1-C2-haloalkyl group, as defined above, attached via an oxygen atom. The term “C1-C3-haloalkoxy” is a C1-C3-haloalkyl group, as defined above, attached via an oxygen atom. C1-C2-Haloalkoxy is, for example, OCH2F, OCHF2, OCF3, OCH2Cl, OCHCl2, OCCl3, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy or OC2F5. C1-C3-Haloalkoxy is additionally, for example, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, OCH2—C2F5, OCF2—C2F5, 1-(CH2F)-2-fluoroethoxy, 1-(CH2Cl)-2-chloroethoxy or 1-(CH2Br)-2-bromoethoxy. C1-C4-Haloalkoxy is additionally, for example, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy. C1-C6-Haloalkoxy is additionally, for example, 5-fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy, undecafluoropentoxy, 6-fluorohexoxy, 6-chlorohexoxy, 6-bromohexoxy, 6-iodohexoxy or dodecafluorohexoxy.
The term “alkoxy-alkyl” as used herein, refers to a straight-chain or branched alkyl group, as defined above, where one hydrogen atom is replaced by an alkoxy group, as defined above, generally to a C1-C30-alkyl group where one hydrogen atom is replaced by a C1-C30-alkoxy group (“C1-C30-alkoxy-C1-C30-alkyl”), preferably to a C1-C20-alkyl group where one hydrogen atom is replaced by a C1-C20-alkoxy group (“C1-C20-alkoxy-C1-C20-alkyl”), in particular to a C1-C10-alkyl group where one hydrogen atom is replaced by a C1-C10-alkoxy group (“C1-C10-alkoxy-C1-C10-alkyl”), specifically to a C1-C6-alkyl group where one hydrogen atom is replaced by a C1-C6-alkoxy group (“C1-C6-alkoxy-C1-C6-alkyl”), more specifically to a C1-C4-alkyl group where one hydrogen atom is replaced by a C1-C4-alkoxy group (“C1-C4-alkoxy-C1-C4-alkyl”). The term “C1-C3-alkoxy-C1-C3-alkyl” as used herein, refers to a straight-chain or branched alkyl group having 1 to 3 carbon atoms, as defined above, where one hydrogen atom is replaced by a C1-C3-alkoxy group, as defined above. Examples are methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butoxymethyl, sec-butoxymethyl, isobutoxymethyl, tert-butoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-n-butoxyethyl, 1-sec-butoxyethyl, 1-isobutoxyethyl, 1-tert-butoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, 2-sec-butoxyethyl, 2-isobutoxyethyl, 2-tert-butoxyethyl, 1-methoxypropyl, 1-ethoxypropyl, 1-propoxypropyl, 1-isopropoxypropyl, 1-n-butoxypropyl, 1-sec-butoxypropyl, 1-isobutoxypropyl, 1-tert-butoxypropyl, 2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl, 2-isopropoxypropyl, 2-n-butoxypropyl, 2-sec-butoxypropyl, 2-isobutoxypropyl, 2-tert-butoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 3-isopropoxypropyl, 3-n-butoxypropyl, 3-sec-butoxypropyl, 3-isobutoxypropyl, 3-tert-butoxypropyl and the like.
The term “haloalkoxy-alkyl” as used herein, refers to a straight-chain or branched alkyl group, as defined above, where one hydrogen atom is replaced by an alkoxy group, as defined above, and wherein at least one, e.g. 1, 2, 3, 4 or all of the remaining hydrogen atoms (either in the alkoxy moiety or in the alkyl moiety or in both) are replaced by halogen atoms, in particular by fluorine, chlorine or bromine; generally to a C1-C30-alkyl group where one hydrogen atom is replaced by a C1-C30-alkoxy group (“C1-C30-alkoxy-C1-C30-alkyl”), preferably to a C1-C20-alkyl group where one hydrogen atom is replaced by a C1-C20-alkoxy group (“C1-C20-alkoxy-C1-C20-alkyl”), in particular to a C1-C10-alkyl group where one hydrogen atom is replaced by a C1-C10-alkoxy group (“C1-C10-alkoxy-C1-C10-alkyl”), specifically to a C1-C6-alkyl group where one hydrogen atom is replaced by a C1-C6-alkoxy group (“C1-C6-alkoxy-C1-C6-alkyl”), more specifically to a C1-C4-alkyl group where one hydrogen atom is replaced by a C1-C4-alkoxy group (“C1-C4-alkoxy-C1-C4-alkyl”), and wherein at least one, e.g. 1, 2, 3, 4 or all of the remaining hydrogen atoms (either in the alkoxy moiety or in the alkyl moiety or in both) are replaced by halogen atoms, in particular by fluorine, chlorine or bromine. Examples are difluoromethoxymethyl (CHF2OCH2), trifluoromethoxymethyl, 1-difluoromethoxyethyl, 1-trifluoromethoxyethyl, 2-difluoromethoxyethyl, 2-trifluoromethoxyethyl, difluoro-methoxy-methyl (CH3OCF2), 1,1-difluoro-2-methoxyethyl, 2,2-difluoro-2-methoxyethyl and the like.
“Alkylthio” is an alkyl group, as defined above, attached via a sulfur atom to the remainder of the molecule; generally a C1-C30-alkyl group (“C1-C30-alkylthio”), preferably a C1-C20-alkyl group (“C1-C20-alkylthio”), in particular a C1-C10-alkyl group (“C1-C10-alkylthio”), specifically a C1-C6-alkyl group (“C1-C6-alkylthio”) or a C1-C4-alkyl group (“C1-C4-alkylthio”) attached via a sulfur atom to the remainder of the molecule. The term “C1-C2-alkylthio” is a C1-C2-alkyl group, as defined above, attached via a sulfur atom. The term “C1-C3-alkylthio” is a C1-C3-alkyl group, as defined above, attached via a sulfur atom. C1-C2-Alkylthio is methylthio or ethylthio. C1-C3-Alkylthio is additionally, for example, n-propylthio or 1-methylethylthio (isopropylthio). C1-C4-Alkylthio is additionally, for example, butylthio, 1-methylpropylthio (sec-butylthio), 2-methylpropylthio (isobutylthio) or 1,1-dimethylethylthio (tert-butylthio). C1-C6-Alkylthio is additionally, for example, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio or 1-ethyl-2-methylpropylthio. C1-C8-Alkylthio is additionally, for example, heptylthio, octylthio, 2-ethylhexylthio and positional isomers thereof. C1-C10-Alkylthio is additionally, for example, nonylthio, decylthio and positional isomers thereof.
“Haloalkylthio” is a haloalkyl group, as defined above, attached via a sulfur atom to the remainder of the molecule; generally a C1-C30-haloalkyl group (“C1-C30-haloalkylthio”), preferably a C1-C20-haloalkyl group (“C1-C20-haloalkylthio”), in particular a C1-C10-haloalkyl group (“C1-C10-haloalkylthio”), specifically a C1-C6-haloalkyl group (“C1-C6-haloalkylthio”) or a C1-C4-haloalkyl group (“C1-C4-haloalkylthio”) attached via a sulfur atom to the remainder of the molecule. The term “C1-C2-haloalkylthio” is a C1-C2-haloalkyl group, as defined above, attached via a sulfur atom. The term “C1-C3-haloalkylthio” is a C1-C3-haloalkyl group, as defined above, attached via a sulfur atom. C1-C2-Haloalkylthio is, for example, SCH2F, SCHF2, SCF3, SCH2Cl, SCHCl2, SCCl3, chlorofluoromethylthio, dichlorofluoromethylthio, chlorodifluoromethylthio, 2-fluoroethylthio, 2-chloroethylthio, 2-bromoethylthio, 2-iodoethylthio, 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, 2-chloro-2-fluoroethylthio, 2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio, 2,2,2-trichloroethylthio or SC2F5. C1-C3-Haloalkylthio is additionally, for example, 2-fluoropropylthio, 3-fluoropropylthio, 2,2-difluoropropylthio, 2,3-difluoropropylthio, 2-chloropropylthio, 3-chloropropylthio, 2,3-dichloropropylthio, 2-bromopropylthio, 3-bromopropylthio, 3,3,3-trifluoropropylthio, 3,3,3-trichloropropylthio, SCH2—C2F5, SCF2—C2F5, 1-(CH2F)-2-fluoroethylthio, 1-(CH2Cl)-2-chloroethylthio or 1-(CH2Br)-2-bromoethylthio. C1-C4-Haloalkylthio is additionally, for example, 4-fluorobutylthio, 4-chlorobutylthio, 4-bromobutylthio or nonafluorobutylthio. C1-C6-Haloalkylthio is additionally, for example, 5-fluoropentylthio, 5-chloropentylthio, 5-brompentylthio, 5-iodopentylthio, undecafluoropentylthio, 6-fluorohexylthio, 6-chlorohexylthio, 6-bromohexylthio, 6-iodohexylthio or dodecafluorohexylthio.
“Alkylsulfinyl” is an alkyl group, as defined above, attached via a sulfinyl [S(O)] group to the remainder of the molecule; generally a C1-C30-alkyl group (“C1-C30-alkylsulfinyl”), preferably a C1-C20-alkyl group (“C1-C20-alkylsulfinyl”), in particular a C1-C10-alkyl group (“C1-C10-alkylsulfinyl”), specifically a C1-C6-alkyl group (“C1-C6-alkylsulfinyl”) or a C1-C4-alkyl group (“C1-C4-alkylsulfinyl”) attached via a sulfinyl [S(O)] group to the remainder of the molecule. The term “C1-C2-alkylsulfinyl” is a C1-C2-alkyl group, as defined above, attached via a sulfinyl [S(O)] group. The term “C1-C3-alkylsulfinyl” is a C1-C3-alkyl group, as defined above, attached via a sulfinyl [S(O)] group. C1-C2-Alkylsulfinyl is methylsulfinyl or ethylsulfinyl. C1-C4-Alkylsulfinyl is additionally, for example, n-propylsulfinyl, 1-methylethylsulfinyl (isopropylsulfinyl), butylsulfinyl, 1-methylpropylsulfinyl (sec-butylsulfinyl), 2-methylpropylsulfinyl (isobutylsulfinyl) or 1,1-dimethylethylsulfinyl (tert-butylsulfinyl). C1-C6-Alkylsulfinyl is additionally, for example, pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl. C1-C8-Alkylsulfinyl is additionally, for example, heptylsulfinyl, octylsulfinyl, 2-ethylhexylsulfinyl and positional isomers thereof. C1-C10-Alkylsulfinyl is additionally, for example, nonylsulfinyl, decylsulfinyl and positional isomers thereof.
“Haloalkylsulfinyl” is a haloalkyl group, as defined above, attached via a sulfinyl [S(O)] group to the remainder of the molecule; generally a C1-C30-haloalkyl group (“C1-C30-haloalkylsulfinyl”), preferably a C1-C20-haloalkyl group (“C1-C20-haloalkylsulfinyl”), in particular a C1-C10-haloalkyl group (“C1-C10-haloalkylsulfinyl”), specifically a C1-C6-haloalkyl group (“C1-C6-haloalkylsulfinyl”) or a C1-C4-haloalkyl group (“C1-C4-haloalkylsulfinyl”) attached via a sulfinyl [S(O)] group to the remainder of the molecule. The term “C1-C2-haloalkylsulfinyl” is a C1-C2-haloalkyl group, as defined above, attached via a sulfinyl [S(O)] group. The term “C1-C3-haloalkylsulfinyl” is a C1-C3-haloalkyl group, as defined above, attached via a sulfinyl [S(O)] group. C1-C2-Haloalkylsulfinyl is, for example, S(O)CH2F, S(O)CHF2, S(O)CF3, S(O)CH2Cl, S(O)CHCl2, S(O)CCl3, chlorofluoromethylsulfinyl, dichlorofluoromethylsulfinyl, chlorodifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 2-chloroethylsulfinyl, 2-bromoethylsulfinyl, 2-iodoethylsulfinyl, 2,2-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, 2-chloro-2-fluoroethylsulfinyl, 2-chloro-2,2-difluoroethylsulfinyl, 2,2-dichloro-2-fluoroethylsulfinyl, 2,2,2-trichloroethylsulfinyl or S(O)C2F5. C1-C4-Haloalkylsulfinyl is additionally, for example, 2-fluoropropylsulfinyl, 3-fluoropropylsulfinyl, 2,2-difluoropropylsulfinyl, 2,3-difluoropropylsulfinyl, 2-chloropropylsulfinyl, 3-chloropropylsulfinyl, 2,3-dichloropropylsulfinyl, 2-bromopropylsulfinyl, 3-bromopropylsulfinyl, 3,3,3-trifluoropropylsulfinyl, 3,3,3-trichloropropylsulfinyl, S(O)CH2—C2F5, S(O)CF2—C2F5, 1-(CH2F)-2-fluoroethylsulfinyl, 1-(CH2Cl)-2-chloroethylsulfinyl, 1-(CH2Br)-2-bromoethylsulfinyl, 4-fluorobutylsulfinyl, 4-chlorobutylsulfinyl, 4-bromobutylsulfinyl or nonafluorobutylsulfinyl. C1-C6-Haloalkylsulfinyl is additionally, for example, 5-fluoropentylsulfinyl, 5-chloropentylsulfinyl, 5-brompentylsulfinyl, 5-iodopentylsulfinyl, undecafluoropentylsulfinyl, 6-fluorohexylsulfinyl, 6-chlorohexylsulfinyl, 6-bromohexylsulfinyl, 6-iodohexylsulfinyl or dodecafluorohexylsulfinyl.
“Alkylsulfonyl” is an alkyl group, as defined above, attached via a sulfonyl [S(O)2] group to the remainder of the molecule; generally a C1-C30-alkyl group (“C1-C30-alkylsulfonyl”), preferably a C1-C20-alkyl group (“C1-C20-alkylsulfonyl”), in particular a C1-C10-alkyl group (“C1-C10-alkylsulfonyl”), specifically a C1-C6-alkyl group (“C1-C6-alkylsulfonyl”) or a C1-C4-alkyl group (“C1-C4-alkylsulfonyl”) attached via a sulfonyl [S(O)2] group to the remainder of the molecule. The term “C1-C2-alkylsulfonyl” is a C1-C2-alkyl group, as defined above, attached via a sulfonyl [S(O)2] group. The term “C1-C3-alkylsulfonyl” is a C1-C3-alkyl group, as defined above, attached via a sulfonyl [S(O)2] group. C1-C2-Alkylsulfonyl is methylsulfonyl or ethylsulfonyl. C1-C3-Alkylsulfonyl is additionally, for example, n-propylsulfonyl or 1-methylethylsulfonyl (isopropylsulfonyl). C1-C4-Alkylsulfonyl is additionally, for example, butylsulfonyl, 1-methylpropylsulfonyl (sec-butylsulfonyl), 2-methylpropylsulfonyl (isobutylsulfonyl) or 1,1-dimethylethylsulfonyl (tert-butylsulfonyl). C1-C6-Alkylsulfonyl is additionally, for example, pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl. C1-C8-Alkylsulfonyl is additionally, for example, heptylsulfonyl, octylsulfonyl, 2-ethylhexylsulfonyl and positional isomers thereof. C1-C10-Alkylsulfonyl is additionally, for example, nonylsulfonyl, decylsulfonyl and positional isomers thereof.
“Haloalkylsulfonyl” is a haloalkyl group, as defined above, attached via a sulfonyl [S(O)2] group to the remainder of the molecule; generally a C1-C30-haloalkyl group (“C1-C30-haloalkylsulfonyl”), preferably a C1-C20-haloalkyl group (“C1-C20-haloalkylsulfonyl”), in particular a C1-C10-haloalkyl group (“C1-C10-haloalkylsulfonyl”), specifically a C1-C6-haloalkyl group (“C1-C6-haloalkylsulfonyl”) or a C1-C4-haloalkyl group (“C1-C4-haloalkylsulfonyl”) attached via a sulfonyl [S(O)2] group to the remainder of the molecule. The term “C1-C2-haloalkylsulfonyl” is a C1-C2-haloalkyl group, as defined above, attached via a sulfonyl [S(O)2] group. The term “C1-C3-haloalkylsulfonyl” is a C1-C3-haloalkyl group, as defined above, attached via a sulfonyl [S(O)2] group. C1-C2-Haloalkylsulfonyl is, for example, S(O)CH2F, S(O)2CHF2, S(OCF3, S(O)2CH2Cl, S(O)2CHCl2, S(O)2CCl3, chlorofluoromethylsulfonyl, dichlorofluoromethylsulfonyl, chlorodifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 2-chloroethylsulfonyl, 2-bromoethylsulfonyl, 2-iodoethylsulfonyl, 2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, 2-chloro-2-fluoroethylsulfonyl, 2-chloro-2,2-difluoroethylsulfonyl, 2,2-dichloro-2-fluoroethylsulfonyl, 2,2,2-trichloroethylsulfonyl or S(O)2C2F5. C1-C3-Haloalkylsulfonyl is additionally, for example, 2-fluoropropylsulfonyl, 3-fluoropropylsulfonyl, 2,2-difluoropropylsulfonyl, 2,3-difluoropropylsulfonyl, 2-chloropropylsulfonyl, 3-chloropropylsulfonyl, 2,3-dichloropropylsulfonyl, 2-bromopropylsulfonyl, 3-bromopropylsulfonyl, 3,3,3-trifluoropropylsulfonyl, 3,3,3-trichloropropylsulfonyl, S(O)2CH2—C2F5, S(O)2CF2—C2F5, 1-(CH2F)-2-fluoroethylsulfonyl, 1-(CH2Cl)-2-chloroethylsulfonyl or 1-(CH2Br)-2-bromoethylsulfonyl. C1-C4-Haloalkylsulfonyl is additionally, for example, 4-fluorobutylsulfonyl, 4-chlorobutylsulfonyl, 4-bromobutylsulfonyl or nonafluorobutylsulfonyl. C1-C4-Haloalkylsulfonyl is additionally, for example, 5-fluoropentylsulfonyl, 5-chloropentylsulfonyl, 5-brompentylsulfonyl, 5-iodopentylsulfonyl, undecafluoropentylsulfonyl, 6-fluorohexylsulfonyl, 6-chlorohexylsulfonyl, 6-bromohexylsulfonyl, 6-iodohexylsulfonyl or dodecafluorohexylsulfonyl.
The substituent “oxo” replaces a CH2 group by a C(═O) group.
Alike, the substituent “═S” replaces a CH2 group by a C(═S) group.
Alike, the substituent “═NR12a” replaces a CH2 group by a C(═NR12a) group.
“Alkylcarbonyl” is an alkyl group, as defined above, attached via a carbonyl [C(═O)] group to the remainder of the molecule; generally a C1-C30-alkyl group (“C1-C30-alkylcarbonyl”), preferably a C1-C20-alkyl group (“C1-C20-alkylcarbonyl”), in particular a C1-C10-alkyl group (“C1-C10-alkylcarbonyl”), specifically a C1-C6-alkyl group (“C1-C6-alkylcarbonyl”) or a C1-C4-alkyl group (“C1-C4-alkylcarbonyl”) attached via a carbonyl [C(═O)] group to the remainder of the molecule. Examples are acetyl (methylcarbonyl), propionyl (ethylcarbonyl), propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl and the like.
“Haloalkylcarbonyl” is a haloalkyl group, as defined above, attached via a carbonyl [C(═O)] group to the remainder of the molecule; generally a C1-C30-haloalkyl group (“C1-C30-haloalkylcarbonyl”), preferably a C1-C20-haloalkyl group (“C1-C20-haloalkylcarbonyl”), in particular a C1-C10-haloalkyl group (“C1-C10-haloalkylcarbonyl”), specifically a C1-C6-haloalkyl group (“C1-C6-haloalkylcarbonyl”) or a C1-C4-haloalkyl group (“C1-C4-haloalkylcarbonyl”) attached via a carbonyl [C(═O)] group to the remainder of the molecule. Examples are trifluoromethylcarbonyl, 2,2,2-trifluoroethylcarbonyl and the like.
“Alkoxycarbonyl” is an alkoxy group, as defined above, attached via a carbonyl [C(═O)] group to the remainder of the molecule; generally a C1-C3-alkoxy group (“C1-C30-alkoxycarbonyl”), preferably a C1-C20-alkoxy group (“C1-C20-alkoxycarbonyl”), in particular a C1-C10-alkoxy group (“C1-C10-alkoxycarbonyl”), specifically a C1-C6-alkoxy group (“C1-C6-alkoxycarbonyl”) or a C1-C4-alkoxy group (“C1-C4-alkoxycarbonyl”) attached via a carbonyl [C(═O)] group to the remainder of the molecule. Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and the like.
“Haloalkoxycarbonyl” is a haloalkoxy group, as defined above, attached via a carbonyl [C(═O)] group to the remainder of the molecule; generally a C1-C30-haloalkoxy group (“C1-C30-haloalkoxycarbonyl”), preferably a C1-C20-haloalkoxy group (“C1-C20-haloalkoxycarbonyl”), in particular a C1-C10-haloalkoxy group (“C1-C10-haloalkoxycarbonyl”), specifically a C1-C6-haloalkoxy group (“C1-C6-haloalkoxycarbonyl”) or a C1-C4-haloalkoxy group (“C1-C4-haloalkoxycarbonyl”) attached via a carbonyl [C(═O)] group to the remainder of the molecule. Examples are trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl and the like.
The term “aminocarbonyl” is a group —C(═O)—NH2.
The term “alkylaminocarbonyl” is a group —C(═O)—N(H)-alkyl, where alkyl is as defined above and is in general a C1-C30-alkyl group (“C1-C30-alkylaminocarbonyl”), preferably a C1-C20-alkyl group (“C1-C20-alkylaminocarbonyl”), in particular a C1-C10-alkyl group (“C1-C10-alkylaminocarbonyl”), specifically a C1-C6-alkyl group (“C1-C6-alkylaminocarbonyl”) or a C1-C4-alkyl group (“C1-C4-alkylaminocarbonyl”). Examples are methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl and the like.
The term “di(alkyl)aminocarbonyl” is a group —C(═O)—N(alkyl)2, where each alkyl is independently as defined above and is independently in general a C1-C6-alkyl group (“di-(C1-C30-alkyl)aminocarbonyl”), preferably a C1-C20-alkyl group (“di-(C1-C20-alkyl)aminocarbonyl”), in particular a C1-C10-alkyl group (“di-(C1-C10-alkyl)aminocarbonyl”), specifically a C1-C6-alkyl group (“di-(C1-C6-alkyl)aminocarbonyl”), or a C1-C4-alkyl group (“di-(C1-C4-alkyl)aminocarbonyl”). Examples are dimethylaminocarbonyl, diethylaminocarbonyl, ethylmethylaminocarbonyl, dipropylaminocarbonyl, diisopropylaminocarbonyl, methylpropylaminocarbonyl, methylisopropylaminocarbonyl, ethylpropylaminocarbonyl, ethylisopropylaminocarbonyl, dibutylaminocarbonyl and the like.
Aryl is a mono-, bi- or polycyclic carbocyclic (i.e. without heteroatoms as ring members) aromatic radical. One example for a monocyclic aromatic radical is phenyl. In bicyclic aryl rings two aromatic rings are condensed, i.e. they share two vicinal C atoms as ring members. One example for a bicyclic aromatic radical is naphthyl. In polycyclic aryl rings, three or more rings are condensed. Examples for polycyclic aryl radicals are phenanthrenyl, anthracenyl, tetracenyl, 1H-benzo[a]phenalenyl, pyrenyl and the like. In the terms of the present invention “aryl” encompasses however also bi- or polycyclic radicals in which not all rings are aromatic, as long as at least one ring is; especially if the reactive site is on the aromatic ring (or on a functional group bound thereto). Examples are indanyl, indenyl, tetralinyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, fluorenyl, 9,10-dihydroanthracenyl, 9,10-dihydrophenanthrenyl, 1H-benzo[a]phenalenyl and the like, and also ring systems in which not all rings are condensed, but for example spiro-bound or bridged, such as benzonorbornyl. In particular, the aryl group has 6 to 30, more particularly 6 to 20, specifically 6 to 10 carbon atoms as ring members.
Rings termed as heterocyclic rings or heterocyclyl or heteroaromatic rings or heteroaryl or hetaryl contain one or more heteroatoms as ring members, i.e. atoms different from carbon. In the terms of the present invention, these heteroatoms are N, O and S, where N and S can also be present as heteroatom groups, namely as NO, SO or SO2. Thus, in the terms of the present invention, rings termed as heterocyclic rings or heterocyclyl or heteroaromatic rings or heteroaryl or hetaryl contain one or more heteroatoms and/or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2 as ring members.
In the terms of the present invention a heterocyclic ring or heterocyclyl is a saturated, partially unsaturated or maximally unsaturated, but not aromatic heteromono-, bi- or polycyclic ring (if the ring is aromatic, it is termed heteroaromatic ring or heteroaryl or hetaryl) containing one ore more, in particular 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from the group consisting of N, O, S, NO, SO and SO2 as ring members.
Unsaturated rings contain at least one C—C and/or C—N and/or N—N double bond(s). Maximally unsaturated rings contain as many conjugated C—C and/or C—N and/or N—N double bonds as allowed by the ring size. Maximally unsaturated 5- or 6-membered heteromonocyclic rings are generally aromatic (and thus not enclosed in the present term “heterocyclic ring” or “heterocyclyl”. Exceptions are maximally unsaturated 6-membered rings containing O, S, SO and/or SO2 as ring members, such as pyran and thiopyran, which are not aromatic). Partially unsaturated rings contain less than the maximum number of C—C and/or C—N and/or N—N double bond(s) allowed by the ring size.
Although they do not contain as many conjugated double bonds as principally allowed by the ring size, some partially unsaturated heterobi- or polycyclic rings may be considered as heteroaromatic in the terms of the present invention if the moiety taking part in the reaction in question is aromatic. One example is indoline: If the reaction takes place on the 6-membered aromatic moiety of this fused system, the indoline is considered as a heteroaromatic ring. See also below examples for partially unsaturated heterobicyclic rings. If the reaction is to take place on the 5-membered non-aromatic moiety, indoline is considered as a heterocyclyl ring.
The heterocyclic and heteroaromatic ring may be attached to the remainder of the molecule via a carbon ring member or via a nitrogen ring member. As a matter of course, the heterocyclic and heteroaromatic ring contains at least one carbon ring atom. If the ring contains more than one O ring atom, these are not adjacent.
Heterocyclic rings are in particular 3 to 30-membered, more particularly 3 to 20-membered, specifically 3- to 12-membered or 3- to 11-membered.
Heteromonocyclic rings are in particular 3- to 8-membered. The term “3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from the group consisting of N, O, S, NO, SO and SO2 groups as ring members” denotes a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximum unsaturated (but not aromatic) heteromonocyclic ring containing 1, 2, 3 or 4 (preferably 1, 2 or 3) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, SO and SO2 as ring members.
Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered saturated heteromonocyclic ring include: Oxiran-2-yl, thiiran-2-yl, aziridin-1-yl, aziridin-2-yl, oxetan-2-yl, oxetan-3-yl, thietan-2-yl, thietan-3-yl, 1-oxothietan-2-yl, 1-oxothietan-3-yl, 1,1-dioxothietan-2-yl, 1,1-dioxothietan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-oxotetrahydrothien-2-yl, 1,1-dioxotetrahydrothien-2-yl, 1-oxotetrahydrothien-3-yl, 1,1-dioxotetrahydrothien-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl, isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl, isothiazolidin-5-yl, 1,2,4-oxadiazolidin-2-yl, 1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-4-yl, 1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-2-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-4-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-1-yl, 1,2,4-triazolidin-3-yl, 1,2,4-triazolidin-4-yl, 1,3,4-oxadiazolidin-2-yl, 1,3,4-oxadiazolidin-3-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-thiadiazolidin-3-yl, 1,3,4-triazolidin-1-yl, 1,3,4-triazolidin-2-yl, 1,3,4-triazolidin-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, hexahydropyridazin-1-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, hexahydropyrimidin-1-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, piperazin-1-yl, piperazin-2-yl, 1,3,5-hexahydrotriazin-1-yl, 1,3,5-hexahydrotriazin-2-yl, 1,2,4-hexahydrotriazin-1-yl, 1,2,4-hexahydrotriazin-2-yl, 1,2,4-hexahydrotriazin-3-yl, 1,2,4-hexahydrotriazin-4-yl, 1,2,4-hexahydrotriazin-5-yl, 1,2,4-hexahydrotriazin-6-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl, 1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-2-yl, 1,1-dioxothiomorpholin-3-yl, 1,1-dioxothiomorpholin-4-yl, azepan-1-, -2-, -3- or -4-yl, oxepan-2-, -3-, -4- or -5-yl, hexahydro-1,3-diazepinyl, hexahydro-1,4-diazepinyl, hexahydro-1,3-oxazepinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,3-dioxepinyl, hexahydro-1,4-dioxepinyl,
oxocane, thiocane, azocanyl, [1,3]diazocanyl, [1,4]diazocanyl, [1,5]diazocanyl, [1,5]oxazocanyl and the like.
Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturated heteromonocyclic ring include: 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,4-dihydrofuran-2-yl, 2,4-dihydrofuran-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- or tetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- or tetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl, 5-di- or tetrahydropyrimidinyl, di- or tetrahydropyrazinyl, 1,3,5-di- or tetrahydrotriazin-2-yl, 1,2,4-di- or tetrahydrotriazin-3-yl, 2,3,4,5-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 3,4,5,6-tetrahydro[2H]azepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, tetrahydrooxepinyl, such as 2,3,4,5-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl, tetrahydro-1,3-oxazepinyl, tetrahydro-1,4-oxazepinyl, tetrahydro-1,3-dioxepinyl, tetrahydro-1,4-dioxepinyl, 1,2,3,4,5,6-hexahydroazocine, 2,3,4,5,6,7-hexahydroazocine, 1,2,3,4,5,8-hexahydroazocine, 1,2,3,4,7,8-hexahydroazocine, 1,2,3,4,5,6-hexahydro-[1,5]diazocine, 1,2,3,4,7,8-hexahydro-[1,5]diazocine and the like.
Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered maximally unsaturated (but not aromatic) heteromonocyclic ring are pyran-2-yl, pyran-3-yl, pyran-4-yl, thiopryran-2-yl, thiopryran-3-yl, thiopryran-4-yl, 1-oxothiopryran-2-yl, 1-oxothiopryran-3-yl, 1-oxothiopryran-4-yl, 1,1-dioxothiopryran-2-yl, 1,1-dioxothiopryran-3-yl, 1,1-dioxothiopryran-4-yl, 2H-oxazin-2-yl, 2H-oxazin-3-yl, 2H-oxazin-4-yl, 2H-oxazin-5-yl, 2H-oxazin-6-yl, 4H-oxazin-3-yl, 4H-oxazin-4-yl, 4H-oxazin-5-yl, 4H-oxazin-6-yl, 6H-oxazin-3-yl, 6H-oxazin-4-yl, 7H-oxazin-5-yl, 8H-oxazin-6-yl, 2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl, 2H-1,3-oxazin-6-yl, 4H-1,3-oxazin-2-yl, 4H-1,3-oxazin-4-yl, 4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl, 6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-oxazin-6-yl, 2H-1,4-oxazin-2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl, 2H-1,4-oxazin-6-yl, 4H-1,4-oxazin-2-yl, 4H-1,4-oxazin-3-yl, 4H-1,4-oxazin-4-yl, 4H-1,4-oxazin-5-yl, 4H-1,4-oxazin-6-yl, 6H-1,4-oxazin-2-yl, 6H-1,4-oxazin-3-yl, 6H-1,4-oxazin-5-yl, 6H-1,4-oxazin-6-yl, 1,4-dioxine-2-yl, 1,4-oxathiin-2-yl, 1H-azepine, 1H-[1,3]-diazepine, 1H-[1,4]-diazepine, [1,3]diazocine, [1,5]diazocine, [1,5]diazocine and the like.
Heteroaromatic monocyclic rings are in particular 5- or 6-membered.
Examples for 5- or 6-membered monocyclic heteroaromatic rings are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,5-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,3,4-tetrazin-1-yl, 1,2,3,4-tetrazin-2-yl, 1,2,3,4-tetrazin-5-yl and the like.
In the present invention, the “heterobicyclic rings” or “heterobicyclyl” contain two rings which have at least one ring atom in common. At least one of the two rings contains a heteroatom or heteroatom group selected from the group consisting of N, O, S, NO, SO and SO2 as ring member. The term comprises condensed (fused) ring systems, in which the two rings have two neighboring ring atoms in common, as well as spiro systems, in which the rings have only one ring atom in common, and bridged systems with at least three ring atoms in common. In terms of the present invention, the heterobicyclic rings do not include throughout aromatic bicyclic ring systems; these are termed heteroaromatic bicyclic rings or bicycyclic het(ero)aryl or heterobiaryl. If in a condensed system one ring is aromatic and the other is not and if the reaction in question is to take place on the aromatic moiety of the bicyclic system, these rings are considered to belong to heteroaromatic rings (het(ero)aryl), although the system is not completely aromatic. The heterobicyclic rings are preferably 7-, 8-, 9-, 10- or 11-membered. The heteroaromatic bicyclic rings are preferably 9-, 10- or 11-membered. Throughout heteroaromatic heterobicyclic rings are 9- or 10-membered.
Examples for fused systems:
Examples for a 7-, 8-, 9-, 10- or 11-membered saturated heterobicyclic ring containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members are:
Examples for a 7-, 8-, 9-, 10- or 11-membered saturated heterobicyclic ring containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members are:
In the above examples, one ring is aromatic. If the reaction in question is to take place on the aromatic moiety of the bicyclic system (or on a functional group bound thereto), these rings are considered to belong to heteroaromatic rings (het(ero)aryl), although the system is not completely heteroaromatic.
Examples for a 7-, 8-, 9-, 10- or 11-membered maximally unsaturated (but not throughout heteroaromatic) heterobicyclic ring containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members are:
In the above examples, one ring is (hetero)aromatic. If the reaction in question is to take place on the (hetero)aromatic moiety of the bicyclic system (or on a functional group bound thereto), these rings are considered to belong to heteroaromatic rings (het(ero)aryl), although the system is not completely heteroaromatic.
Examples for a 9- or 10-membered maximally unsaturated, throughout heteroaromatic heterobicyclic ring containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members are:
Examples for spiro-bound 7-, 8-, 9-, 10- or 11-membered heterobicyclic rings containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members are
Examples for bridged 7-, 8-, 9-, 10- or 1-membered heterobicyclic rings containing 1, 2 or 3 (or 4) heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO and SO2, as ring members are
and the like.
In the above structures # denotes the attachment point to the remainder of the molecule. The attachment point is not restricted to the ring on which this is shown, but can be on either of the two rings, and may be on a carbon or on a nitrogen ring atom. If the rings carry one or more substituents, these may be bound to carbon and/or to nitrogen ring atoms.
Polycyclic heterocyclic rings (polyheterocyclyl) contain three or more rings, each of which having at least one ring atom in common with at least one of the other rings of the polycyclic system. The rings can be condensed, spiro-bound or bridged; mixed systems (e.g. one ring is spiro-bound to a condensed system, or a bridged system is condensed with another ring) are also possible. Throughout aromatic rings are not encompassed in the polycyclic heterocyclic ring (polyheterocyclyl); these are termed polycyclic heteroaromatic rings or heteropolyaryls.
If in a polycyclic system one ring is aromatic and (one of) the other(s) is/are not and if the reaction in question is to take place on the aromatic moiety of the polycyclic system (or on a functional group bound thereto), these rings are considered to belong to heteroaromatic rings (het(ero)aryl), although the system is not completely aromatic.
Aryloxy, heterocyclyloxy and heteroaryloxy (also expressed as O-aryl, O-heterocyclyl and O-heteroaryl) are aryl, heterocyclyl and heteroaryl, respectively, as defined above, bound via an oxygen atom to the remainder of the molecule. Examples are phenoxy or pyridyloxy.
If two radicals bound on the same nitrogen and, together with this nitrogen atom, form a mono-, bi- or polycyclic heterocyclic ring (e.g.: in the Buchwald Hartwig reaction: R1 and R3, together with the nitrogen atom they are bound to, may form a mono-, bi- or polycyclic heterocyclic ring, or R4 and R5, together with the nitrogen atom they are bound to, may form a mono-, bi- or polycyclic heterocyclic ring; or in the carboxamide or sulfonamide bond formation not requiring transition metal catalysis R2 and R3, together with the nitrogen atom they are bound to, may form a mono-, bi- or polycyclic heterocyclic ring; or in the protection of primary or secondary amino groups R1 and R2, together with the nitrogen atom they are bound to, may form a mono-, bi- or polycyclic heterocyclic ring) this ring, apart from the compulsory nitrogen atom, may contain 1, 2 or 3 or 4 further heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO or SO2 as ring members. The ring may be saturated, partially unsaturated or maximally unsaturated, including heteroaromatic. Monocyclic rings are in particular 3- to 8-membered. Bicyclic rings are in particular 7- to 20-membered, specifically 7- to 11-membered.
Examples of such monocyclic saturated heterocyclic rings are aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrazolidin-1-yl, imidazolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, 1,2,4-oxadiazolidin-2-yl, 1,2,4-oxadiazolidin-4-yl, 1,2,4-thiadiazolidin-2-yl, 1,2,4-thiadiazolidin-4-yl, 1,2,4-triazolidin-1-yl, 1,2,4-triazolidin-4-yl, 1,3,4-oxadiazolidin-3-yl, 1,3,4-thiadiazolidin-3-yl, 1,3,4-triazolidin-1-yl, 1,3,4-triazolidin-3-yl, piperidin-1-yl, hexahydropyridazin-1-yl, hexahydropyrimidin-1-yl, 1 piperazin-1-yl, 1 1,3,5-hexahydrotriazin-1-yl, 1 1,2,4-hexahydrotriazin-1-yl, 1,2,4-hexahydrotriazin-2-yl, 1,2,4-hexahydrotriazin-4-yl, morpholin-4-ylthiomorpholin-4-yl, 1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, azepan-1-yl, hexahydro-1,3-diazepin-1-yl, hexahydro-1,4-diazepin-1-yl, hexahydro-1,3-oxazepin-3-yl, hexahydro-1,4-oxazepin-4-yl, azocan-1-yl, [1,3]diazocan-1-yl, [1,4]diazocan-1-yl, [1,5]diazocan-1-yl, [1,5]oxazocan-1-yl and the like.
Examples of such monocyclic partially unsaturated heterocyclic rings include: 2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, 2,3-dihydro-1H-pyrazol-1-yl, 4,5-dihydro-1H-pyrazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl, 2,5-dihydro-1H-imidazol-1-yl, 4,5-dihydro-1H-imidazol-1-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydroisoxazol-2-yl, 2,5-dihydroisoxazol-2-yl, 2,3-dihydrothiazol-3-yl, 2,3-dihydroisothiazol-2-yl, 2,5-dihydroisothiazol-2-yl, 1,2-dihydropyridin-1-yl, 1,4-dihydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridazin-1-yl, 1,2,3,4-tetrahydropyridazin-2-yl, 1,2,3,6-tetrahydropyridazin-1-yl, 1,2-dihydropyridazin-1-yl, 1,4-dihydropyridazin-1-yl, 1,6-dihydropyridazin-1-yl, 1,2-dihydropyrimidin-1-yl, 1,4-dihydropyrimidin-1-yl, 1,2,3,4-tetrahydropyrimidin-1-yl, 1,2,3,4-tetrahydropyrimidin-3-yl, 1,2,5,6-tetrahydropyrimidin-1-yl, 1,4,5,6-tetrahydropyrimidin-1-yl, 1,2-dihydropyrazin-1-yl, 1,4-dihydropyrazin-1-yl, 1,2,3,4-tetrahydropyrazin-1-yl, 1,2,3,6-tetrahydropyrazin-1-yl, 1,2-dihydro-1,3,5-triazin-1-yl, 1,4-dihydro-1,3,5-triazin-1-yl, 1,2,3,4-tetrahydro-1,3,5-triazin-1-yl, 1,2,3,4-tetrahydro-1,3,5-triazin-3-yl, 2,3,4,5-tetrahydro-1H-azepin-1-yl, 2,3,4,7-tetrahydro-1H-azepin-1-yl, 2,3,6,7-tetrahydro-1H-azepin-1-yl, 2,3-dihydro-1H-azepin-1-yl, 2,5-dihydro-1H-azepin-1-yl, 4,5-dihydro-1H-azepin-1-yl,
Examples of such monocyclic maximally unsaturated heterocyclic, inclusive heteroaromatic, rings include 1-pyrrolyl, 1-pyrazolyl, 1-imidazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1H-azepin-1-yl and the like.
Examples of such bicyclic heterocyclic rings are the above-depicted 7-, 8-, 9-, 10- or 11-membered saturated, partially unsaturated or maximally unsaturated fused, spiro-bound or bridged heterobicyclic rings which contain at least one secondary nitrogen atom (NH) as ring member and in which the attachment point to the remainder of the molecule (#) is on this secondary nitrogen ring atom.
In the Baylis-Hillman reaction, R1 and R2 may form together with the carbon atom they are bound to a carbocyclic or heterocyclic ring. This ring may be saturated or partially unsaturated, monocyclic, bicyclic or polycyclic. If this ring is heterocyclic, it contains 1, 2 or 3 or 4 heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, SO or SO2 as ring members.
For instance, R1 and R2 may form together —(CH2)3—, —(CH2)4—, —(CH2)5—, —(CH2)6—, —CH═CH—, —CH═CH—CH2—, —CH═CH—CH═CH—, —CH2—CH═CH—CH2—, —CH═CH—CH2—CH═CH—, —CH2—O—CH2—CH2—, —CH2—N(R)—CH2—CH2—, —CH2—CH2—O—CH2—CH2—, —CH2—CH2—N(R)—CH2—CH2—, and the like.
Sulfonates as leaving groups (as used, for example, in most of the above-described transition-metal catalyzed C—C coupling reactions, like the Suzuki, Sonogashira, Heck reactions etc.) are in general fluorinated alkyl sulfonates, in particular fluorinated C1-C10-alkylsulfonates, more particularly perfluorinated C1-C10-alkylsulfonates, or aryl sulfonates, such as tosylate (p-toluene sulfonate). In particular they are triflate (trifluoromethane sulfonate), nonaflate (nonafluorobutyl sulfonate), heptadecafluorooctyl sulfonate or tosylate.
A metal equivalent M (as present for example in the boron compound R1—BF3M) is a metal cation equivalent of formula (Mn+)1/n, where M is a metal, in particular an alkali metal, such as Li, Na or K, an earth alkaline metal, such as Mg or Ca, Al or a transition metal, such as Fe, Ni, Cu etc.
An acyl group in a group R—C(═O)—, where R is alkyl, alkenyl, alkapolyenyl, alkynyl, alkapolyynyl, mixed alkenyl/alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, mixed cycloalkenyl/cycloalkynyl, polycarbocyclyl, heterocyclyl, aryl or heteroaryl group, as defined above, where this group may carry one or more substituents, as defined above.
The invention will be further illustrated by the following, non-limiting examples.
EXAMPLES
Abbreviations
r.t. room temperature (20 to 25° C.)
TLC thin layer chromatography
LCMS liquid chromatography mass spectrometry
t-Bu, tBu tert-butyl
O-t-Bu, OtBu tert-butanolate
KO-t-Bu, KOtBu potassium tert-butanolate
NaO-t-Bu, NaOtBu sodium tert-butanolate
OAc acetate
KOAc potassium acetate
EtOAc ethylacetate
OTf triflate
dtbpf 1,1′-bis(di-tert-butylphosphino)ferrocene
mida, MIDA N-methyliminodiacetic acid (see above)
Fmoc fluorenylmethoxycarbonyl
Val-OH L-valine
Fmoc-Val-OH N-(9-fluorenylmethoxycarbonyl)-L-valine
B2pin2 bis(pinacolato)diboron
In order to have reproducible conditions and exclude any (positive or negative) influence from the water used (e.g. from traces of metal or metal ions which may be present in common distilled water), Milli-Q® water was used. This Millipore Corporation trademark relates to ‘ultrapure’ water of “Type 1”, as defined by various authorities (e.g. ISO 3696). The purification processes involve successive steps of filtration and deionization to achieve a purity expediently characterised in terms of resistivity (typically 18 MΩ·cm at 25° C.). In the present case it was obtained with an EMD Millipore Milli-Q™ Advantage A10 water purification system from EMD Millipore Z00Q0V0US. This water is termed in the following “Millipore water”. But the reactions of the present invention can of course also be carried out with “normal” distilled water as used in any laboratory or industry or also just with tap water.
Preliminary Remarks
The viscosities of the cellulose derivatives given in the below examples are the values given by the respective suppliers of a 2% by weight solution at 20° C. They coincide well with the values obtained with the methods described above (for 1-70 mPa·s: Malvern Instruments Viscosizer 200 and an uncoated glass capillary; 25° C.; for >70-4000 mPa·s: falling-sphere viscosimeter; 25° C.; for >4000 mPa·s: single-cylinder type spindle viscosimeter; 20° C.
Following cellulosic products were used:
Viscosity
given by
Determined
supplier
viscosity
Commercial
[mPa · s
[mPa · s
Product
product name
Supplier
or cps]
or cps]
HPMC
Mantrocel E5 2910
Parmentier
4-6
3.9
HPMC
Hydroxypropyl
Sigma-
40-60
methyl cellulose
Aldrich
40-60
HPMC
Hydroxypropyl
Alfa Aesar
40-60
42.8
methyl cellulose
40-60
HPMC
Hydroxypropyl
Sigma-
80-120
77.3
methyl cellulose
Aldrich
80-120
HPMC
Hydroxypropyl
Sigma-
2600-5600
methyl cellulose
Aldrich
2600-5600
HPMC
Methocel E4M
Colorcon
3000-5600
Premium EP
GmbH
HPMC
Mantrocel K4M
Parmentier
4100
3263
GmbH
MC
Methyl cellulose
Sigma-
25
M6385
Aldrich
MC
Methyl cellulose
Sigma-
15
M7140
Aldrich
MC
Methyl cellulose
ABCR
1600
AB211131
HEC
Hydroxyethylcellulose
Sigma-
80-125
Aldrich
HEC
Hydroxyethylcellulose
Sigma-
145
Aldrich
HPC
Hydroxypropylcellulose
ABCR
3-5
AB137066
HPC
Hydroxypropylcellulose
Sigma-
75-150*
191884
Aldrich
HECE
Polyquatemium 10
Sigma-
400
Aldrich
MH
Tylose MH300
Sigma-
150-450
Aldrich
*determined at 25° C.; 5% in H2O
HPMC hydroxypropylmethylcellulose
MC methylcellulose
HEC hydroxyethylcellulose
HPC hydroxypropylcellulose
HECE Polyquaternium-10; hydroxyethylcellulose ethoxylate (quaternized hydroxyethyl cellulose)
Tylose MH300 methyl-2-hydroxyethylcellulose
I. General Procedure for the Preparation of the Aqueous Oligosaccharide Solutions (Per 100 ml)
66 ml of Millipore water was heated to 70° C. under stirring in a reaction flask. The appropriate amount of an oligosaccharide was added. Subsequently 34 ml of Millipore water was added and the reaction mixture was allowed to cool to room temperature under stirring. The solution was purged with Argon for 30 minutes.
A. Procedure for the Preparation of 2% HPMC (40-60 cps=mPa·s) in Water (Per 100 ml):
66 ml of Millipore water was heated to 70° C. under stirring in a reaction flask. 2 g of HPMC (40-60 cps) were added. The reaction mixture formed a cloudy solution. Subsequently 34 ml of Millipore water was added and the reaction mixture was allowed to cool to room temperature under stirring to form a clear solution. The solution was purged with Argon for 30 minutes.
B. Procedure for the Preparation of 5% HPMC (40-60 cps) in Water (Per 100 ml):
66 ml of Millipore water was heated to 70° C. under stirring in a reaction flask. 5 g of HPMC (40-60 cps) were added. The reaction mixture formed a cloudy solution. Subsequently 34 ml of Millipore water was added and the reaction mixture was allowed to cool to room temperature under stirring to form a clear solution. The solution was purged with Argon for 30 minutes.
C. Procedure for the Preparation of 3% HPMC (40-60 cps) in Water (Per 100 ml):
66 ml of Millipore water was heated to 70° C. under stirring in a reaction flask. 3 g of HPMC (40-60 cps) were added. The reaction mixture formed a cloudy solution. Subsequently 34 ml of Millipore water was added and the reaction mixture was allowed to cool to room temperature under stirring to form a clear solution. The solution was purged with Argon for 30 minutes.
D. Procedure for the Preparation of 1% HPMC (40-60 cps) in Water (Per 100 ml):
66 ml of Millipore water was heated to 70° C. under stirring in a reaction flask. 1 g of HPMC (40-60 cps) were added. The reaction mixture formed a cloudy solution. Subsequently 34 ml of Millipore water was added and the reaction mixture was allowed to cool to room temperature under stirring to form a clear solution. The solution was purged with Argon for 30 minutes.
E. Procedure for the Preparation of 0.5% HPMC (40-60 cps) in Water (Per 100 ml):
66 ml of Millipore water was heated to 70° C. under stirring in a reaction flask. 500 mg of HPMC (40-60 cps) were added. The reaction mixture formed a cloudy solution. Subsequently 34 ml of Millipore water was added and the reaction mixture was allowed to cool to room temperature under stirring to form a clear solution. The solution was purged with Argon for 30 minutes.
Other oligosaccharides were prepared analogously.
II. Preparation Examples
1H-NMR: The signals are characterized by chemical shift (ppm) vs. tetramethylsilane, by their multiplicity and by their integral (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of the signals: m=multiplett, q=quartett, t=triplett, d=doublet, s=singlett, dd=doublet of doublets, dt=doublet of tripletts, dq=doublet of quartetts, ddd=doublet of doublets of doublets, td=triplett of doublets, tdd=triplett of doublets of doublets; tt=triplett of tripletts, br or=broad (e.g. sbr or bs=broad singlett).
1. Buchwald-Hartwig Reactions
General Procedure for Buchwald-Hartwig Aminations I
[(π-allyl)PdCl]2 catalyst (0.005 eq), a phosphine ligand (0.020 eq) and a base (1.50 eq) were added under an Argon atmosphere into a 5.0 mL microwave vial containing a magnetic stir bar and Teflon-lined septum. HPMC in water solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water) was added under a positive flow of argon, followed by the addition of the amine (1.20 eq) and subsequently of the aryl bromide (1.0 eq) (however, any liquid components were always added after the solvent). The reaction mixture was stirred at 1200 rpm for the indicated time at the indicated temperature. To the reaction mixture were added ethyl acetate and saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel.
General Procedure for Buchwald-Hartwig Aminations II
An amine (1.2 eq), an aryl bromide (1.0 eq), [(π-allyl)PdCl]2 catalyst (0.005 eq), a phosphine ligand (0.020 eq) and a base (1.50 eq) were added under an Argon atmosphere into a 5.0 mL microwave vial containing a magnetic stir bar and Teflon-lined septum. HPMC in water solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water) was added under a positive flow of argon (however, any liquid components were always added after the solvent). The reaction mixture was stirred at 1200 rpm for the indicated time at the indicated temperature. To the reaction mixture were added ethyl acetate and saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-30% ethyl acetate/heptane).
1.1 Preparation of N-(p-tolyl)naphthalen-2-amine According to the General Procedure I
Following the general procedure I using [(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand (7.0 mg, 0.020 mmol), KO-t-Bu (168 mg, 1.50 mmol), a HPMC-solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water), p-toluidine (129 mg, 1.20 mmol) and naphthyl bromide (211 mg, 1.0 mmol). The reaction mixture was stirred at 1200 rpm for 4 h at room temperature LC-MS indicated however that the reaction was already completed after 2 h. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-30% ethyl acetate/heptane). The desired product was obtained as an off-white solid (211 mg, 88% yield).
ESI-MS: m/z (%): 234.20 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.70 (m, 2H), 7.60 (m, 1H), 7.40 (m, 2H), 7.30 (m, 1H), 7.20 (m, 1H), 7.15 (m, 2H), 7.10 (m, 2H), 5.80 (sbr, 1H), 2.30 (s, 3H).
1.2 Preparation of N-(p-tolyl)naphthalen-2-amine According to the General Procedure II
Following the general procedure II using p-toluidine (129 mg, 1.20 mmol), naphthyl bromide (211 mg, 1.0 mmol), [(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand (7.0 mg, 0.020 mmol), KO-t-Bu (168 mg, 1.50 mmol) and a HPMC-solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 15 min. at 50° C. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-30% ethyl acetate/heptane). The desired product was obtained as an off-white solid (224 mg, 90% yield, 94% purity).
ESI-MS: m/z (%): 234.20 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.70 (m, 2H), 7.60 (m, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 7.20 (m, 1H), 7.15 (m, 2H), 7.10 (m, 2H), 5.85 (sbr, 1H), 2.35 (s, 3H).
1.3 Preparation of 4-methoxy-N-(p-tolyl)aniline According to General Procedure II
1.3.1) According to the general procedure II, p-toluidine (129 mg, 1.20 mmol), 1-bromo-4-methoxybenzene (189 mg, 1.0 mmol), [(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand (7.0 mg, 0.020 mmol), KO-t-Bu (168 mg, 1.50 mmol) and a HPMC-solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm overnight at room temperature. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (213 mg, 100% yield).
1.3.2) According to the general procedure II, p-toluidine (129 mg, 1.20 mmol), 1-bromo-4-methoxybenzene (189 mg, 1.0 mmol), [(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand (7.0 mg, 0.020 mmol, KO-t-Bu (168 mg, 1.50 mmol) and HPMC-solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 1 h at 50° C. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (209 mg, 98% yield).
1.3.3) According to the general procedure II, p-toluidine (129 mg, 1.20 mmol), 1-bromo-4-methoxybenzene (189 mg, 1.0 mmol), [(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand (7.0 mg, 0.020 mmol), KO-t-Bu (168 mg, 1.50 mmol) and a HPMC-solution (4-6 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 40 min at 50° C. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (204 mg, 96% yield).
1.3.4) According to the general procedure II, p-toluidine (129 mg, 1.20 mmol), 1-bromo-4-methoxybenzene (189 mg, 1.0 mmol), [(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand (7.0 mg, 0.020 mmol), KO-t-Bu (168 mg, 1.50 mmol) and a HPMC-solution (4-6 cps, 0.35 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 9 min at 50° C. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (183 mg, 86% yield).
ESI-MS: m/z (%): 214.20 (100, [M+H]+).
1H NMR (600 MHz, d6-DMSO): δ [ppm]: 7.68 (s, 1H), 7.01-6.95 (m, 4H), 6.87-6.80 (m, 4H), 3.70 (s, 3H), 2.19 (s, 3H).
1.4 Preparation of 4-methoxy-N-(m-tolyl)benzamide
1.4.1) According to the general procedure II, 4-methoxybenzamide (181 mg, 1.20 mmol), 3-bromo-toluene (171 mg, 0.98 mmol), [(π-allyl)PdCl]2 catalyst (5.6 mg, 0.011 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (tBuXPhos) ligand (18.3 mg, 0.043 mmol), NaO-t-Bu (141 mg, 1.50 mmol) and a HPMC-solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 5 h at room temperature. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (209 mg, 89% yield).
1.4.2) According to the general procedure II, 4-methoxybenzamide (181 mg, 1.20 mmol), 3-bromo-toluene (171 mg, 0.98 mmol), [(π-allyl)PdCl]2 catalyst (5.6 mg, 0.011 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (tBuXPhos) ligand (18.3 mg, 0.043 mmol), NaO-t-Bu (141 mg, 1.50 mmol) and a HPMC-solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 30 min at 50° C. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (230 mg, 97% yield).
1.4.3) According to the general procedure II, 4-methoxybenzamide (181 mg, 1.20 mmol), 3-bromo-toluene (171 mg, 0.98 mmol), [(π-allyl)PdCl]2 catalyst (5.6 mg, 0.011 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (tBuXPhos) ligand (18.3 mg, 0.043 mmol), NaO-t-Bu (141 mg, 1.50 mmol) and a HPMC-solution (4-6 cps, 2 wt % in 0.35 ml degassed Millipore water) were stirred at 1200 rpm for 30 min at 50° C. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (221 mg, 89% yield, 95% purity).
ESI-MS: m/z (%): 242.20 (100, [M+H]+).
1H NMR (600 MHz, d6-DMSO): δ [ppm]: 10.01 (s, 1H), 7.99-7.92 (m, 2H), 7.61 (d, J=1.8 Hz, 1H), 7.59-7.53 (m, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.09-7.03 (m, 2H), 6.90 (d, J=7.5 Hz, 1H), 3.84 (s, 3H), 2.30 (s, 3H).
1.5 Preparation of ethyl-4-((tert-butoxycarbonyl)amino)benzoate
1.5.1) According to the general procedure I, tert-butyl carbamate (176 mg, 1.50 mmol), ethyl 4-bromobenzoate (229 mg, 1.00 mmol), [(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand (7.1 mg, 0.020 mmol), NaO-t-Bu (144 mg, 1.50 mmol) and a HPMC-solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 1 h at room temperature. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (220 mg, 79% yield).
1.5.2) According to the general procedure I, tert-butyl carbamate (176 mg, 1.50 mmol), ethyl 4-bromobenzoate (229 mg, 1.00 mmol), [(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand (7.1 mg, 0.020 mmol), NaO-t-Bu (144 mg, 1.50 mmol) and a HPMC-solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 15 min at 50° C. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (225 mg, 85% yield).
1.5.3) According to the general procedure I, tert-butyl carbamate (176 mg, 1.50 mmol), ethyl 4-bromobenzoate (229 mg, 1.00 mmol), [(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand (7.1 mg, 0.020 mmol), NaO-t-Bu (144 mg, 1.50 mmol) and a HPMC-solution (4-6 cps, 0.35 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 4 min at 50° C. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (275 mg, 98% yield).
ESI-MS: m/z (%): 210.20 (100, [M+H-t-Bu]+), 266.25 (75, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 8.00 (m, 2H), 7.45 (m, 2H), 6.65 (sbr, 1H), 4.35 (m, 2H), 1.50 (s, 9H), 1.40 (m, 3H).
1.6 Preparation of tert-butyl pyrimidin-5-ylcarbamate
According to the general procedure I, tert-butyl carbamate (176 mg, 1.50 mmol), 5-bromopyrimidine (164 mg, 1.00 mmol), [Pd(1-phenylallyl)Cl]2 catalyst (10.4 mg, 0.02 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (tBuXPhos) ligand (17.0 mg, 0.04 mmol), potassium hydroxide (84 mg, 1.50 mmol), triisopropylsilanol (267 mg, 1.50 mmol) and a HPMC-solution (4-6 cps, 0.333 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 45 min at 50° C. To the reaction mixture was added bulk sorbents (diatomaceous earth; mean particle size: 150-850 μm; pore size/porosity; 60 A; Telos® NM from Kinesis Bulk Media). The solid was then added on top of a silica gel chromatography cartridge and was further purified by flash chromatography on silica gel (0-40% ethyl dichloromethane/methanol). The desired product was obtained as an off-white solid (191 mg, 83% yield, 85% purity).
APCI-MS: m/z (%): 196.20 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 8.95 (s, 1H), 8.85 (s, 2H), 6.50 (sbr, 1H), 1.55 (s, 9H).
1.7 Preparation of 6-methyl-N-(3-phenylpropyl)pyridine-2-amine
1.7.1) According to the general procedure II, 3-phenylpropylamine (162 mg, 1.20 mmol), 2-chloro-6-methylpyridine (128 mg, 1.00 mmol), [(π-allyl)PdCl]2 catalyst (5.7 mg, 0.011 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (t-BuXPhos) ligand (18.8 mg, 0.044 mmol) NaO-t-Bu (145 mg, 1.50 mmol) and a HPMC-solution (40-60 cps, 1 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 5 h at room temperature. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (150 mg, 66% yield).
1.7.2) According to the general procedure II, 3-phenylpropylamine (162 mg, 1.20 mmol), 2-chloro-6-methylpyridine (128 mg, 1.00 mmol), [(π-allyl)PdCl]2 catalyst (5.7 mg, 0.011 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (t-BuXPhos) ligand (18.8 mg, 0.044 mmol), NaO-t-Bu (145 mg, 1.50 mmol) and a HPMC-solution (40-60 cps, 1 ml of 2 wt % in degassed Millipore water) were stirred at 1200 rpm for 3 h at 50° C. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off-white solid (183 mg, 81% yield).
ESI-MS: m/z (%): 227.20 (100, [M+H]+).
1H NMR (600 MHz, d6-DMSO): δ [ppm]: 7.31-7.24 (m, 2H), 7.27-7.19 (m, 3H), 7.21-7.14 (m, 1H), 6.38 (t, J=5.5 Hz, 1H), 6.30 (d, J=7.1 Hz, 1H), 6.22 (d, J=8.3 Hz, 1H), 3.23-3.16 (m, 2H), 2.68-2.61 (m, 2H), 2.23 (s, 3H), 1.81 (tt, J=7.5, 6.4 Hz, 2H).
General Procedure for Buchwald-Hartwig Reactions Using Sulfonamides
To allylpalladium chloride dimer (0.02 equiv.), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (0.04 equiv.), NaOtBu (1.5 equiv.) and the sulfonamide (1.2 equiv.) under an argon atmosphere was added 2 wt % solution of HPMC (40-60 cps) in Millipore water and the arylbromide (1.0 equiv.). The reaction was stirred under an argon atmosphere for the indicated time at the indicated temperature. The mixture was diluted with EtOAc (3 mL) and then with a sat. solution of Na2SO4 (3 mL). After Extraction with EtOAc (1×15 mL), the mixture was brought to pH 3 by using a 5% solution of citric acid in water (3 mL) and extracted again using EtOAc (2×15 mL). The clean product was obtained after flash chromatography on silica gel.
1.8 Preparation of ethyl 4-(methylsulfonamido)benzoate
1.8.1) Following the general procedure using ethyl 4-bromobenzoate (229 mg, 1.00 mmol, 1.0 equiv.), methanesulfonamide (114 mg, 1.20 mmol, 1.2 equiv.), allylpalladium chloride dimer (7.3 mg, 0.02 mmol, 0.02 equiv.), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (14 mg, 0.04 mmol, 0.04 equiv.), NaOtBu (144 mg, 1.50 mmol, 1.5 equiv.) and a HPMC solution (40-60 cps, 1 ml of 2 wt % in degassed Millipore water) the reaction was allowed to stir vigorously under an argon atmosphere for 6 h at 50° C., 20 h at room temperature, 6 h at 50° C. and again for 20 h at room temperature. After column chromatography (0-50% EtOAc/heptane), the product was obtained (158 mg, 0.65 mmol, 65%).
1.8.2) Following the general procedure using ethyl 4-bromobenzoate (229 mg, 1.00 mmol, 1.0 equiv.), methanesulfonamide (114 mg, 1.20 mmol, 1.2 equiv.), allylpalladium chloride dimer (7.3 mg, 0.02 mmol, 0.02 equiv.), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (14 mg, 0.04 mmol, 0.04 equiv.), NaOtBu (144 mg, 1.50 mmol, 1.5 equiv.) and a HPMC-solution (40-60 cps, 0.333 ml of 2 wt % in degassed Millipore water) the reaction was allowed to stir vigorously under an argon atmosphere for 6 h at 50° C., 20 h at room temperature, 6 h at 50° C. and again for 20 h at room temperature. After column chromatography (0-50% EtOAc/heptane), the product was obtained (158 mg, 0.65 mmol, 65%).
ESI-MS: m/z (%): 244.0 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 8.10-7.97 (m, 2H), 7.25-7.21 (m, 2H), 6.61 (sbr, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.09 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).
General Procedure for Buchwald-Hartwig Reactions Using Urea Derivatives
To allylpalladium chloride dimer (0.02 equiv.), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (0.04 equiv.), KOH (1.5 equiv.) and the urea derivative (1.2 equiv.) under an argon atmosphere was added a 2 wt % solution of HPMC in Millipore water, the arylbromide (1.0 equiv.) and finally TIPS-OH (1.2 equiv.). The reaction was stirred under an argon atmosphere for the indicated time at the indicated temperature. The mixture was diluted with EtOAc (3 mL) and then with a sat. solution of Na2SO4 (3 mL). After Extraction with EtOAc (up to 9×5 mL), the crude product was purified by flash chromatography on silica gel.
1.9 Preparation of ethyl 4-(piperidine-1-carboxamido)benzoate
1.9.1) Following the general procedure using ethyl 4-bromobenzoate (229 mg, 1.00 mmol, 1.0 equiv.), piperidine-1-carboxamide (159 mg, 1.20 mmol, 1.2 equiv.), allylpalladium chloride dimer (7.2 mg, 0.02 mmol, 0.02 equiv.), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (14 mg, 0.04 mmol, 0.04 equiv.), KOH (82 mg, 1.50 mmol, 1.5 equiv.), triisopropylsilanol (261 mg, 1.50 mmol, 1.5 equiv.) and a 2 wt % solution of HPMC (40-60 cps) in Millipore water (2.0 mL) the reaction was allowed to stir vigorously under an argon atmosphere for 2.5 h at 50° C. After column chromatography (0-50% EtOAc/heptane), the product was obtained (249 mg, 0.88 mmol, 89%).
1.9.2) Following the general procedure using ethyl 4-bromobenzoate (229 mg, 1.00 mmol, 1.0 equiv.), piperidine-1-carboxamide (159 mg, 1.20 mmol, 1.2 equiv.), allylpalladium chloride dimer (7.2 mg, 0.02 mmol, 0.02 equiv.), di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (14 mg, 0.04 mmol, 0.04 equiv.), KOH (82 mg, 1.50 mmol, 1.5 equiv.), triisopropylsilanol (261 mg, 1.50 mmol, 1.5 equiv.) and a 2 wt % solution of HPMC (4-6 cps) in Millipore water (0.33 mL) the reaction was allowed to stir vigorously under an argon atmosphere for 40 min at 50° C. After column chromatography (0-50% EtOAc/heptane), the product was obtained (276 mg, 0.95 mmol, 97%).
ESI-MS: m/z (%): 277.1 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 8.00-7.94 (m, 2H), 7.47-7.42 (m, 2H), 6.53 (sbr, 1H), 4.35 (q, J=7.1 Hz, 2H), 3.50-3.44 (m, 4H), 1.70-1.60 (m, 6H), 1.38 (t, J=7.1 Hz, 3H).
1.10 Preparation of N-(p-tolyl)naphthalen-2-amine Using HPMC in Various Concentrations
[(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(1-methyl-2,2-diphenyl-cyclopropyl)phosphine (cBRIDP) ligand (7.0 mg, 0.020 mmol) and KO-t-Bu as base (168 mg, 1.50 mmol) were added under an Argon atmosphere into a 5.0 mL microwave vial containing a magnetic stir bar and Teflon-lined septum. As solvent an HPMC (40-60 cps)-water solution (specifications & volume see table below) was added under a positive flow of Argon, followed by the addition of p-toluidine (129 mg, 1.20 mmol) and subsequently naphthyl bromide (211 mg, 1.0 mmol). The reaction mixture was stirred at 1200 rpm for the indicated time (see table below) at 50° C. To the reaction mixture were added ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was extracted three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-30% ethyl acetate/heptane). The desired product was obtained as an off-white solid.
Amount
Viscosity
Volume
Molarity
Reaction
Ex. No.
HPMC
solvent
solvent
reaction1
time
Yield2
1.10.1
0.2 wt %
1.02
cps
3.00 mL
0.33M
30 min
87%
1.10.2
0.2 wt %
1.02
cps
0.35 mL
2.86M
90 sec
92%
1.10.3
2.0 wt %
42.88
cps
3.00 mL
0.33M
15 min
90%
1.10.4
2.0 wt %
42.88
cps
0.35 mL
2.86M
90 sec
98%
1mol naphthyl bromide per 11 of solvent
2realtive to naphthyl bromide
The same reaction as in 1.10.3 and 1.10.4 was carried out at room temperature. The results are compiled in the following table:
Amount
Viscosity
Volume
Molarity
Reaction
Ex. No.
HPMC
solvent
solvent
reaction1
time
Yield2
1.10.5
2.0 wt %
42.88 cps
3.00 mL
0.33M
3
h
91%
1.10.6
2.0 wt %
42.88 cps
0.35 mL
2.86M
5
min
97%
1mol naphthyl bromide per 11 of solvent
2realtive to naphthyl bromide
1.11 Preparation of N-(p-tolyl)naphthalen-2-amine Using HPMCs of Various Viscosities and Other Cellulose Derivatives
[(π-allyl)PdCl]2 catalyst (1.8 mg, 0.005 mmol), di-tert-butyl(I-methyl-2,2-diphenylcyclopropyl)phosphine (cBRIDP) ligand (7.0 mg, 0.020 mmol) and KO-t-Bu as base (168 mg, 1.50 mmol) were added under an argon atmosphere into a 5.0 mL microwave vial containing a magnetic stir bar and Teflon-lined septum. A 2 wt % solution of cellulose derivative in Millipore water (molarity of the reaction: 0.3 M, specifications of the cellulose derivative: see table below) was added under a positive flow of Argon, followed by the addition of p-toluidine (129 mg, 1.20 mmol) and subsequently naphthyl bromide (211 mg, 1.0 mmol). The reaction mixture was stirred at 1200 rpm until full conversion (followed by LCMS, see table below) at 50° C. To the reaction mixture were added ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-30% ethyl acetate/heptane). The desired product was obtained as an off-white solid.
Reaction
Ex. No.
Cellulose derivative
Temperature
time
Yield
1.11.1
HPMC (4.8-7.2 cps)
RT
3
h
90%
1.11.2
HPMC (80-120 cps)
RT
72
h
89%
1.11.3
HPMC (2600-5600 cps)
RT
6.5
h
92%
1.11.4
HPMC (3000-5600 cps)
RT
3
h
93%
1.11.5
HPMC (4100 cps)
RT
1
h
89%
1.11.6
MC (25 cps)
RT
4
h
94%
1.11.7
HPMC (4-6 cps)
50° C.
15
min
89%
1.11.8
HPMC (40-60 cps)
50° C.
15
min
90%
1.11.9
MC (15 cps)
50° C.
15
min
92%
1.11.10
MC (1600 cps)
50° C.
5
min
88%
1.11.11
HEC (80-125 cps)
50° C.
20
min
89%
1.11.12
HEC (145 cps)
50° C.
6
min
95%
1.11.13
HECE (Polyquat. 10)
50° C.
12
min
94%
1.11.14
HPC (3-5 cps)
50° C.
15
min
92%
1.11.15
HPC (75-150 cps)
50° C.
20
min
84%
1.11.16
Tylose MH300
50° C.
25
min
94%
HPMC hydroxypropylmethylcellulose
MC methylcellulose
HEC hydroxyethylcellulose
HPC hydroxypropylcellulose
HECE Polyquaternium-10; hydroxyethylcellulose ethoxylate (quaternized hydroxyethyl cellulose)
Tylose MH300 methyl-2-hydroxyethylcellulose
The same reaction as in 1.11.7 was carried out, using however only 0.35 ml of the 2 wt % solution of HPMC (4-6) in Millipore water (molarity of the reaction: 2.86 M). The result is compiled below:
Reaction
Ex. No.
Cellulose derivative
Temperature
time
Yield
1.11.17
HPMC (4-6 cps)
50° C.
90 sec
90%
2. Suzuki Reactions
General Procedure for Suzuki Reactions Using Boronic Acids
A 5 mL microwave vial was charged with the aryl halide (1.0 equiv.), the boronic acid (1.0-2.10 equiv.) and PdCl2(dtbpf) (0.02 equiv.). After the addition of HPMC-solution (40-60 cps, 2 wt % in Millipore water, 3.0 mL) and triethylamine (3.0 equiv.) the reaction mixture was vigorously stirred (1200 rpm) at the defined temperature until LCMS or TLC showed full conversion of the aryl halide. The mixture was diluted with EtOAc (5 mL) followed by the addition of a saturated aqueous solution of sodium sulfate (4 mL). After 5 min of stirring (200 rpm) the precipitated solids were filtered off and washed with EtOAc (3×15 mL)). After extraction, the organic layer was dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel.
2.1 Preparation of 3-(thiophen-3-yl)quinoline
2.1.1) Following the general procedure using 3-bromoquinoline (208 mg, 1.00 mmol, 1.0 equiv.), thiophene-3-boronic acid (256 mg, 2.00 mmol, 2.00 equiv.), PdCl2(dtbpf) (13.0 mg, 0.02 mmol, 0.02 equiv.) and triethylamine (304 mg, 3.00 mmol, 3.0 equiv.) the reaction was allowed to stir for 1 h at room temperature. After column chromatography on silica gel (0-30% ethyl acetate-cyclohexane) the product was obtained as a white solid (199 mg, 0.94 mmol, 94%).
2.1.2) Following the general procedure using 3-bromoquinoline (219 mg, 1.05 mmol, 1.0 equiv.), thiophene-3-boronic acid (269 mg, 2.11 mmol, 2.00 equiv.), PdCl2(dtbpf) (13.7 mg, 0.02 mmol, 0.021 equiv.) and triethylamine (320 mg, 3.16 mmol, 3.0 equiv.) the reaction was allowed to stir for 10 min at 50° C. After column chromatography on silica gel (0-30% ethyl acetate-cyclohexane) the product was obtained as a white solid (209 mg, 0.99 mmol, 94%).
ESI-MS: m/z (%): 212.1 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 9.20 (d, J=2.3 Hz, 1H), 8.28 (d, J=2.3, 1H), 8.19-8.04 (m, 1H), 7.90-7.77 (m, 1H), 7.73-7.68 (m, 1H), 7.67-7.64 (m, 1H), 7.59-7.54 (m, 1H), 7.54-7.51 (m, 1H), 7.50-7.47 (m, 1H).
2.2 Preparation of 4,6-bis(4-(trifluoromethyl)phenyl)pyrimidine
Following the general procedure using 4,6-dichloropyrimidine (149 mg, 1.00 mmol, 1.0 equiv.), 4-(trifluoromethyl)phenylboronic acid (399 mg, 2.10 mmol, 2.10 equiv.), PdCl2(dtbpf) (13.0 mg, 0.02 mmol, 0.02 equiv.) and triethylamine (304 mg, 3.00 mmol, 3.0 equiv.) the reaction was allowed to stir for 1 h at 50° C. After column chromatography on silica gel (0-30% ethyl acetate-cyclohexane) the product was obtained as a white solid (345 mg, 0.94 mmol, 94%).
ESI-MS: m/z (%): 369.2 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 9.36 (s, 1H), 8.26 (d, J=8.2 Hz, 4H), 8.13 (s, 1H), 7.79 (d, J=8.4 Hz, 4H).
General Procedure for Suzuki Reactions Using Boronic Acid Mida Esters
A 5 mL microwave vial was charged with the boronic acid mida ester (1.0 equiv.), the aryl halide (1.0 equiv.) and PdCl2(dtbpf) (0.02 equiv.). After the addition of HPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.5 mL) and triethylamine (152 mg, 1.50 mmol, 3.0 equiv.) the reaction mixture was vigorously stirred (1200 rpm) at room temperature until LCMS or TLC showed full conversion of the aryl halide. The mixture was diluted with EtOAc (3 mL) followed by the addition of a saturated aqueous solution of sodium sulfate (4 mL). After 5-15 min of stirring (200 rpm) the mixture was filtered through a plug of silica which was then washed with EtOAc (3×15 mL). After extraction, the organic layer was dried over sodium sulfate. The solvent was removed to obtain the product.
2.3 Preparation of 5-(benzofuran-2-yl)pyrimidine
Following the general procedure using 2-benzofuranylboronic acid mida ester (137 mg, 0.50 mmol, 1.0 equiv.), 5-bromopyrimidine (79 mg, 0.50 mmol, 1.0 equiv.), PdCl2(dtbpf) (6.5 mg, 0.01 mmol, 0.02 equiv.) and triethylamine (152 mg, 1.50 mmol, 3.0 equiv.) the reaction was allowed to stir for 6 h at room temperature. The product was obtained as a white solid (88 mg, 0.45 mmol, 90%).
ESI-MS: m/z (%): 197.3 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 9.25-9.12 (m, 3H), 7.67-7.63 (m, 1H), 7.60-7.56 (m, 1H), 7.40-7.35 (m, 1H), 7.32-7.28 (m, 1H), 7.22 (s, 1H).
2.4 Preparation of 4-(benzofuran-3-yl)aniline
Following the general procedure using 2-benzofuranylboronic acid mida ester (137 mg, 0.50 mmol, 1.0 equiv.), 4-bromoaniline (86 mg, 0.50 mmol, 1.0 equiv.), PdCl2(dtbpf) (6.5 mg, 0.01 mmol, 0.02 equiv.) and triethylamine (152 mg, 1.50 mmol, 3.0 equiv.) the reaction was allowed to stir for 14 h at room temperature. The product was obtained as a yellow solid (101 mg, 0.48 mmol, 96%).
ESI-MS: m/z (%): 210.2 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.72-7.64 (m, 2H), 7.57-7.45 (m, 2H), 7.25-7.14 (m, 2H), 6.87-6.79 (m, 1H), 6.79-6.71 (m, 2H), 3.84 (s, 2H).
3. Sonogashira Reactions
General Procedure for Sonogashira Reactions
Under an argon atmosphere, an aryl halide (1.00 mmol), bis(acetonitrile)palladium(II) dichloride (0.01 mmol) and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′biphenyl]-2-yl)phosphine (0.013 mmol) were weighed into a 5 mL microwave vial containing a magnetic stir bar and Teflon-lined septum. Aqueous oligosaccharide solution (3 ml of 2 wt % HPMC, 40-60 cps, in degassed Millipore water) and subsequently an alkyne (1.00 mmol) and a base (2.00 mmol) were added. The mixture was stirred vigorously at room temperature for the indicated time. To the reaction mixture was added ethyl acetate and saturated aqueous sodium sulfate solution. The solids were filtered off and the aqueous phase was extracted 4× with ethyl acetate. The combined organic extracts were combined and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.
3.1 Preparation of 2-methoxy-4-(phenylethynyl)benzonitrile
3.1.1) Following the general procedure using 4-bromo-2-methoxybenzonitrile (212 mg, 1.00 mmol), triethylamine (0.28 ml, 2.00 mmol) and phenylacetylene (110 μg, 1.00 mmol) the reaction was allowed to stir overnight at room temperature. After column chromatography (0-35% ethyl acetate-cyclohexane), the product was obtained as a clear oil (186 mg, 80%; 91% purity).
3.1.2) Following the general procedure using 4-bromo-2-methoxybenzonitrile (212 mg, 1.00 mmol), cesium carbonate (652 mg, 2.00 mmol) and phenylacetylene (110 μg, 1.00 mmol) the reaction was allowed to stir overnight at room temperature. After column chromatography (0-35% ethyl acetate-cyclohexane), the product was obtained as a clear oil (210 mg, 90%, 79% purity).
ESI-MS: m/z (%): 234.10 (100, [M+H]+).
1H NMR (600 MHz, d6-DMSO): δ [ppm]: 7.79 (d, J=7.9 Hz, 1H), 7.65-7.58 (m, 2H), 7.52-7.44 (m, 3H), 7.43 (d, J=1.3 Hz, 1H), 7.27 (dd, J=7.9, 1.4 Hz, 1H), 3.97 (s, 3H).
4. Heck Couplings
General Procedure for Heck Couplings
Under an argon atmosphere, Pd(t-Bu3)P2 (5.1 mg, 0.010 mmol) and an aryl halide (0.50 mmol) were weighed into a 5 mL microwave vial containing a magnetic stir bar and Teflon-lined septum. An acrylate (1.00 mmol) followed by the aqueous oligosaccharide solution (1.5 ml of 2 wt % HPMC, 40-60 cps, in degassed Millipore water) were added. Triethylamine (0.21 ml, 1.50 mmol) was then added via syringe. The mixture was stirred vigorously for the indicated time at the indicated temperature. To the reaction mixture was added ethyl acetate (4 ml) and subsequently a saturated aqueous sodium sulfate solution (1.5 ml). The solids were filtered off and the solid was washed 3× with ethyl acetate. The aqueous phase was extracted once with ethyl acetate. The organic extracts were combined and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.
4.1 Preparation of (E)-t-butyl 3-(4-methoxyphenyl)acrylate
4.1.1) Following the general procedure using 1-iodo-4-methoxybenzene (117 mg, 0.50 mmol) and t-butyl acrylate (128 mg, 1.00 mmol) the reaction was allowed to stir for 4 h at room temperature. After column chromatography (0-30% ethyl acetate-heptane), the product was obtained as a clear oil (80 mg, 65%).
4.1.2) Following the general procedure using 1-iodo-4-methoxybenzene (117 mg, 0.50 mmol) and t-butyl acrylate (128 mg, 1.00 mmol) the reaction was allowed to stir for 1 h at 50° C. After column chromatography (0-30% ethyl acetate-heptane), the product was obtained as a clear oil (98 mg, 81%).
ESI-MS: m/z (%): 179.10 (100, [M+H-t-Bu]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.55 (d, J=16.1 Hz, 1H), 7.45 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.25 (d, J=16.1 Hz, 1H), 3.85 (s, 3H), 1.55 (s, 9H).
4.2 Preparation of t-butyl Cinnamate
4.2.1) Following the general procedure using bromobenzene (79 mg, 0.50 mmol) and t-butyl acrylate (128 mg, 1.00 mmol) the reaction was allowed to stir for 72 h at room temperature. After column chromatography (0-30% ethyl acetate-heptane), the product was obtained as a pale oil (80 mg, 40%).
4.2.2) Following the general procedure using bromobenzene (79 mg, 0.50 mmol) and t-butyl acrylate (128 mg, 1.00 mmol) the reaction was allowed to stir for 4 h at 50° C. (the conversion was however already completed after 3 h, as indicated by LC-MS). After column chromatography (0-30% ethyl acetate-heptane), the product was obtained as a clear oil (93 mg, 88%).
ESI-MS: m/z (%): 149.10 (100, [M+H-t-Bu]+).
1H NMR (600 MHz, CDCl3): a [ppm]: 7.60 (d, J=16.1 Hz, 1H), 7.55 (m, 2H), 7.35 (m, 3H), 6.35 (d, J=16.1 Hz, 1H), 1.55 (s, 9H).
5. C—H-Activation Reactions
General Procedure for C—H-Activation Reactions
Urea (1.0 equiv.), aryl halide (2.0 equiv.), AgOAc (2.0 equiv.), and Pd(OAc)2 (0.1 equiv.) were sequentially added in air to a microwave reaction tube equipped with a stir bar and a septum. HPMC solution (4-6 cps) in Millipore water (0.25M, 2 wt %), and 48 wt % HBF4 solution (5 equiv.) were added by syringe and vigorously stirred at room temperature for 72 h (1200 rpm). EtOAc (3 mL) was added and the mixture was stirred for 15 min at room temperature. A sat. aq. sol. of Na2SO4 (3 mL) was added and the mixture was stirred for an additional 15 min. The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The organic layers were combined and washed with water and brine and then dried over Na2SO4. Concentration of the organic layer afforded the crude material. The clean product was obtained after flash chromatography on silica gel.
5.1 Preparation of 3-(4′-methoxy-[1,1′-biphenyl]-2-yl)-1,1-dimethylurea
Following the general procedure using 1,1-Dimethyl-3-phenylurea (100 mg, 0.61 mmol, 1.0 equiv.), 4-iodoanisole (285 mg, 1.22 mmol, 2.0 equiv.), AgOAc (203 mg, 1.22 mmol, 2.0 equiv.), Pd(OAc)2 (14 mg, 0.06 mmol, 0.1 equiv.), HPMC solution (2.4 mL, 2 wt %), and 48 wt % HBF4 solution (0.38 mL, 3.04 mmol, 5 equiv.) the reaction was allowed to stir for 72 h at room temperature. After chromatography on silica gel (25-50% EtOAc/Hept) the pure product was obtained as an orange solid (114 mg, 0.42 mmol, 69%, 76% brsm).
APCI-MS: m/z (%): 271.2 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 8.17 (d, J=8.3 Hz, 1H), 7.39-7.28 (m, 3H), 7.17 (dd, J=7.6, 1.6 Hz, 1H), 7.05 (td, J=7.6, 1.2 Hz, 1H), 7.04-6.93 (m, 2H), 6.52 (s, 1H), 3.86 (s, 3H), 2.82 (s, 6H).
6. Stile Couplings
General Procedure for Stille Couplings
To Pd(PtBu3)2 (0.02 equiv.), 1,4-diazabicyclo[2.2.2]octane (3.0 equiv.) and NaCl (1.0 equiv.) under an argon atmosphere was given a 2 wt % solution of HPMC (4-6 cps) in Millipore water (0.5 M), followed by the aryl halide (1.0 equiv.) and the stannyl reagent (1.1 equiv.). The mixture was stirred vigorously under an argon atmosphere at the indicated temperature for the indicated time. The reaction was quenched with trimethylamine (0.5 mL) and diluted with EtOAc (1 mL). After the addition of a saturated Na2SO4-solution (1 mL) the mixture was extracted with EtOAc (2×10 mL). The clean product was obtained after flash chromatography on silica gel.
6.1 Preparation of (Z)-2-(2-ethoxyvinyl)-1,3-dimethylbenzene
6.1.1) Following the general procedure using 2-bromo-m-xylene (92 mg, 0.5 mmol, 1.0 equiv), (Z)-1-ethoxy-2-(tributylstannyl)ethene (197 mg, 0.55 mml, 1.1 equiv), Pd(PtBu3)2 (5.0 mg, 0.01 mmol, 0.02 equiv.), 1,4-diazabicyclo[2.2.2]octane (167 mg, 1.5 mmol, 3.0 equiv.) and NaCl (29 mg, 0.5 mmol, 1.0 equiv.) the reaction was allowed to stir vigorously under an argon atmosphere for 48 h at room temperature. After column chromatography (EtOAc/hexanes), the product was obtained (68 mg, 0.38 mmol, 78%)
6.1.2) Following the general procedure using 2-bromo-m-xylene (92 mg, 0.5 mmol, 1.0 equiv), (Z)-1-ethoxy-2-(tributylstannyl)ethene (197 mg, 0.55 mmol, 1.1 equiv), Pd(PtBu3)2 (5.0 mg, 0.01 mmol, 0.02 equiv.), 1,4-diazabicyclo[2.2.2]octane (167 mg, 1.5 mmol, 3.0 equiv.) and NaCl (29 mg, 0.5 mmol, 1.0 equiv.) the reaction was allowed to stir vigorously (1200 rpm) under an argon atmosphere for 2 h at 50° C. and then for 24 h at room temperature. After column chromatography (EtOAc/hexanes), the product was obtained (45 mg, 0.26 mmol, 52%)
ESI-MS: m/z (%): 177.2 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.10-6.98 (m, 3H), 6.20 (d, J=6.9 Hz, 1H), 5.20 (d. J=6.9 Hz, 1H), 3.86 (q, J=7.1 Hz, 2H), 2.27 (s, 6H), 1.24 (t, J=7.1 Hz, 3H).
7. Cross Metathesis
General Procedure for Cross Metathesis
Under an argon atmosphere, Grubbs second-generation catalyst (3.4 mg, 0.004 mmol) was weighed into a 5 mL microwave vial containing a magnetic stir bar and Teflon-lined septum. The alkene (0.50 mmol) and acrylate (1.00 mmol) were added sequentially into the vial, followed by addition of the aqueous oligosaccharide solution (2 ml of 2 wt % HPMC, 40-60 cps, in degassed Millipore water). The mixture was stirred vigorously at room temperature for the indicated time. To the reaction mixture was added ethyl acetate and saturated aqueous sodium sulfate solution. The solids were filtered off and the aqueous phase was extracted 3× with ethyl acetate. The combined organic extracts were combined and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.
7.1 Preparation of (E)-tert-butyl 4-(4-methoxyphenyl)but-2-enoate
7.1.1) Following the general procedure using 4-allylanisole (74 mg, 0.50 mmol) and tert-butyl acrylate (128 mg, 1.00 mmol) the reaction was allowed to stir overnight at room temperature. After column chromatography (0-10% ethyl acetate-dichloromethane), the product was obtained as a clear oil (73 mg, 59%).
7.1.2) Following the general procedure using 4-allylanisole (74 mg, 0.50 mmol), tert-butyl acrylate (128 mg, 1.00 mmol) and additionally citric acid (9.6 mg, 0.005 mmol) was added and the reaction was allowed to stir overnight at room temperature. After column chromatography (0-20% ethyl acetate-dichloromethane), the product was obtained as a clear oil (96 mg, 77%).
ESI-MS: m/z (%): 193.10 (100, [M+H-tBu]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.11-7.07 (m, 2H), 7.00-6.94 (m, 1H), 6.87-6.83 (m, 2H), 5.73-5.68 (m, 1H), 3.80 (s, 3H), 3.45-3.41 (m, 2H), 1.46 (s, 9H).
8. Rh-Catalyzed 1,4-Additions
General Procedure for Rh-Catalyzed 1,4-Additions
Under an argon atmosphere, an aryl boronic acid (1.84 mmol), potassium carbonate (254 mg, 1.84 mmol) and hydroxyl(cyclootadiene)rhodium(I)dimer (21 mg, 0.046 mmol) were weighed into a 5 mL microwave vial containing a magnetic stir bar, Teflon-lined septum and the aqueous oligosaccharide solution (3 ml of 2 wt % HPMC, 40-60 cps, in degassed Millipore water). To the reaction mixture was added an α,β-unsaturated ethyl ester (0.92 mmol) and stirred vigorously at the indicated temperature for the indicated time. To the reaction mixture was added saturated aqueous sodium sulfate solution and ethyl acetate. The aqueous phase was extracted 4× with ethyl acetate. The combined organic extracts were combined and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.
8.1 Preparation of 4-methyl-3,4-dihydroquinolin-2(1H)-one
Following the general procedure using (2-aminophenyl)boronic acid (252 mg, 1.84 mmol) and (E-)ethyl but-2-enoate (105 mg, 0.92 mmol) the reaction was allowed to stir for 5 h at 50° C. After column chromatography (0-30% ethyl acetate-cyclohexane), the product was obtained (147 mg, 99%).
ESI-MS: m/z (%): 162.20 (100, [M+H]+).
1H NMR (600 MHz, d6-DMSO): δ [ppm]: 10.09 (s, 1H), 7.19 (ddd, J=7.5, 1.5, 0.8 Hz, 1H), 7.13 (td, J=7.6, 1.5 Hz, 1H), 6.94 (td, J=7.5, 1.2 Hz, 1H), 6.85 (dd, J=7.9, 1.2 Hz, 1H), 3.04 (q, J=6.9 Hz, 1H), 2.58 (dd, J=15.9, 5.9 Hz, 1H), 2.23 (dd, J=15.9, 7.0 Hz, 1H), 1.17 (d, J=7.0 Hz, 3H).
9. Gold-Catalyzed Cyclizations
General Procedure for Gold-Catalyzed Cyclizations
Under an argon atmosphere the diol (1.0 equiv.) was dissolved in a 2 wt % solution of HPMC (4-6 cps) in Millipore water (0.8 mL). After the addition of gold(III) bromide (0.025 equiv.) and silver triflate (0.025 equiv.) the mixture was stirred under an argon atmosphere at room temperature (1200 rpm) for 4 h. The mixture was diluted with EtOAc (3 mL) and filtered through a pad of silica which was washed with EtOAc (3×10 ml). The clean product was obtained after flash chromatography on silica gel.
9.1 Preparation of 2,3-dimethyl-5-phenylfuran
Following the general procedure using 3-methyl-5-phenylpent-4-yne-2,3-diol (76 mg, 0.40 mmol, 1.0 equiv.), AuBr3 (4.4 mg, 0.01 mmol, 0.025 equiv.) and AgOTf (2.6 mg, 0.01 mmol, 0.025 equiv.) the reaction was allowed to stir for 4 h at room temperature under an argon atmosphere. After column chromatography (cyclohexane), the product was obtained as a pale orange oil (49 mg, 0.29 mmol, 71%).
ESI-MS: m/z (%): 173.3 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.63-7.56 (m, 2H), 7.37-7.28 (m, 2H), 7.23-7.14 (m, 1H), 6.43 (s, 1H), 2.26 (s, 3H), 1.97 (s, 3H).
10. Miyaura Borylations
General Procedure for Miyaura Borylations
To Pd(PtBu3)2 (0.03 equiv.), B2pin2 (1.1 equiv.) and KOAc (3.0 equiv) under an argon atmosphere was given a 2 wt % solution of HPMC (4-6 cps) in Millipore water (1.0 mL). After 10 min of vigorous stirring, the aryl bromide (1.0 equiv.) was added, followed by an additional amount of a 2 wt % solution of HPMC (4-6 cps) in Millipore water (1.0 mL). The mixture was stirred vigorously under an argon atmosphere for the indicated time at the indicated temperature. The reaction was diluted with a saturated Na2SO4-solution (2 mL), stirred for 3 min and then extracted with EtOAc (3×10 mL). The clean product was obtained after flash chromatography on silica gel.
10.1 Preparation of 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Following the general procedure using 4-bromoanisole (94 mg, 0.5 mmol, 1.0 equiv.), bis(pinacolato)diboron (140 mg, 0.55 mmol, 1.1 equiv.), bis(tri-tert-butylphosphine)palladium(0) (7.7 mg, 0.015 mmol, 0.03 equiv.) and KOAc (147 mg, 1.5 mmol, 3.0 equiv.) the reaction was allowed to stir vigorously for 2 h at room temperature. After column chromatography (EtOAc/hexanes), the product was obtained (94 mg, 0.40 mmol, 80%).
ESI-MS: m/z (%): 235.1 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.77-7.73 (m, 2H), 6.91-6.87 (m, 2H), 3.82 (s, 3H), 1.33 (s, 12H).
10.2 Preparation of 2-(2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Following the general procedure using 2-bromo-m-xylene (93 mg, 0.5 mmol, 1.0 equiv.), bis(pinacolato)diboron (140 mg, 0.55 mmol, 1.1 equiv.), bis(tri-tert-butylphosphine)palladium(0) (15 mg, 0.03 mmol, 0.06 equiv.) and KOAc (147 mg, 1.5 mmol, 3.0 equiv.) the reaction was allowed to stir vigorously (1200 rpm) for 7 h at 50° C. and then for 24 h at room temperature. After column chromatography (EtOAc/hexanes), the product was obtained (85 mg, 0.37 mmol, 73%).
ESI-MS: m/z (%): 233.1 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.15-7.08 (m, 1H), 6.97-6.89 (m, 2H), 2.39 (s, 6H), 1.39 (s, 12H).
11. Wittig Reactions
General Procedure for Wittig Reactions
A 5 mL microwave vial was charged with the carbonyl compound (1.0 equiv.) and the Wittig reagent (1.5 equiv.). After the addition of HPMC-solution (40-60 cps, 2 wt % in Millipore water, 2.0 mL) the reaction mixture was vigorously stirred (1200 rpm) at the indicated temperature until LCMS or TLC showed full conversion of the carbonyl compound. The mixture was diluted with EtOAc (3 mL) followed by the addition of a saturated aqueous solution of sodium sulfate (4 mL). After 5-15 min of stirring (200 rpm) the mixture was filtered through a plug of silica which was then washed with EtOAc (3×15 mL). The combined organic layers were dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel.
11.1 Preparation of (E)-methyl 3-(4-methoxyphenyl)acrylate
Following the general procedure using 4-methoxybenzaldehyde (68 mg, 0.50 mmol, 1.0 equiv.) and methyl (triphenylphosphoranylidene)acetate (251 mg, 0.75 mmol, 1.5 equiv.) the reaction was allowed to stir for 30 min at 50° C. After column chromatography on silica gel (5-30% ethyl acetate-cyclohexane) the product was obtained as a white solid (90 mg, 0.47 mmol, 94%). (E/Z=14/1)
ESI-MS: m/z (%): 193.2 (80, [M+H]+).
1H NMR (600 MHz, CDCl3) (of the E configurated product): δ [ppm]: 7.66 (d, J=16.0 Hz, 1H), 7.54-7.42 (m, 2H), 6.97-6.86 (m, 2H), 6.32 (d, J=16.0 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H).
12. Diels-Alder Reactions
General Procedure for Diels-Alder Reactions
A 5 mL microwave vial was charged with the dienophile (1.0 equiv.) and the diene (1.0-1.5 equiv.). After the addition of HPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.0 mL) the reaction mixture was vigorously stirred (1200 rpm) at the indicated temperature until LCMS or TLC showed full conversion of the dienophile. The mixture was diluted with EtOAc (3 mL) followed by the addition of a saturated aqueous solution of sodium sulfate (4 mL). After 5-15 min of stirring (200 rpm) the mixture was filtered through a plug of silica which was then washed with EtOAc (3×15 mL). After phase separation, the organic layer was dried over sodium sulfate. The clean product was obtained after flash chromatography on silica gel.
12.1 Preparation of (7-methyl-1,3-dioxo-2-propyl-2,3,3a,4,7,7a-hexahydro-1H-iso-indol-4-yl)methyl Acetate
Following the general procedure using 1-propyl-1H-pyrrole-2,5-dione (139 mg, 1.00 mmol, 1.0 equiv.) and (2E,4E)-hexa-2,4-dien-1-yl acetate (154 mg, 1.10 mmol, 1.1 equiv.) the reaction was allowed to stir for 4 h at 50° C. After column chromatography on silica gel (0-30% ethyl acetate-cyclohexane) the product was obtained as a colourless oil (201 mg, 0.72 mmol, 72%)
ESI-MS: m/z (%): 280.3 (80, [M+H]+), 581.3 (100, [2M+H]+).
1H NMR (600 MHz, CDCl3): 5.82-5.69 (m, 2H), 4.74-4.60 (m, 1H), 4.55-4.46 (m, 1H), 3.44-3.32 (m, 2H), 3.28-3.18 (m, 1H), 3.09-2.99 (m, 1H), 2.68-2.55 (m, 1H), 2.49-2.38 (m, 1H), 2.09 (s, 3H), 1.54-1.47 (m, 2H), 1.45 (d, J=7.4 Hz, 3H), 0.83 (t, J=7.5 Hz, 3H).
13. Baylis-Hillman Reactions
General Procedure for Baylis-Hillman Reactions
To the aldehyde (1.0 equiv.) in a 2 wt % solution of HPMC (4-6 cps) in Millipore water (0.3 M) was given the alkene (7.0 equiv.) and 1,4-diazabicyclo[2.2.2]octane (0.2 equiv.). The mixture was stirred in a spetum-closed 5 mL-microwave vial for the indicated time at room temperature. The mixture was diluted with EtOAc (3 mL) and then with a sat. solution of Na2SO4 (3 mL). After stirring for 3 min the mixture was filtered through a pad of silica which was washed with EtOAc (3×15 mL). The clean product was obtained after flash chromatography on silica gel.
13.1 Preparation of 2-((4-chlorophenyl)(hydroxy)methyl)acrylonitrile
Following the general procedure using 4-chlorobenzaldehyde (141 mg, 1.0 mmol, 1.0 equiv.), acrylonitrile (371 mg, 7.0 mmol, 7.0 equiv.) and 1,4-diazabicyclo[2.2.2]octane (22 mg, 0.2 mmol, 0.2 equiv.) the reaction was allowed to stir for 23 h at room temperature. After column chromatography (ethyl acetate/cyclohexane), the product was obtained as a white solid (148 mg, 0.76 mmol, 76%).
APCI-MS: m/z (%): 194.0 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.38-7.32 (m, 2H), 7.32-7.27 (m, 2H), 6.13-6.04 (m, 1H), 6.04-5.96 (m, 1H), 5.24 (s, 1H), 3.07 (sbr, 1H).
14. Amide Bond Formations
General Procedure for Amide Bond Formations Using 1-hydroxybenzotriazol (HOBT) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimid Hydrochloride (EDC Hydrochloride)
Under an argon atmosphere, an acid (1.00 mmol) was weighed into a 5 mL microwave vial containing a magnetic stir bar and a Teflon-lined septum. Subsequently EDC hydrochloride (240 mg, 1.25 mmol), HOBT (184 mg, 1.20 mmol) and an aqueous oligosaccharide solution (3 ml of 2 wt % HPMC, 40-60 cps, in degassed Millipore water) were added and the reaction mixture was stirred vigorously at the indicated temperature. After 2 min an amine (1.10 mmol) was added and stirring was continued for the indicated time. The reaction mixture was adjusted to an alkaline pH by adding 1 ml of a 2N aqueous sodium hydroxide solution and extracted 4× with ethyl acetate. The combined organic extracts were dried with magnesium sulfate and after filtration concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.
14.1 Preparation of N-(2-(diethylamino)ethyl)-4-nitrobenzamide
Following the general procedure using 4-nitrobenzoic acid (167 mg, 1.00 mmol) and N,N-diethylethylenediamine (128 mg, 1.10 mmol) the reaction was allowed to stir for 20 min at room temperature (the conversion was however already completed after 2 min, as indicated by LC-MS). After column chromatography (0-10% methanol-dichloromethane), the product was obtained (220 mg, 83%).
ESI-MS: m/z (%): 266.20 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 8.31-8.24 (m, 2H), 8.02-7.97 (m, 2H), 3.63-3.57 (m, 2H), 2.83 (s, 2H), 2.73 (d, J=12.3 Hz, 4H), 1.17-1.10 (m, 6H).
General Procedure for Amide Bond Formations Using (1-cyano-2-ethoxy-2-oxoethyliden-aminooxy)dimethylamino-morpholino-carbenium-hexafluorophosphat (COMU)
Under an argon atmosphere, an acid (1.10 mmol) was weighed into a 5 mL microwave vial containing a magnetic stir bar and a Teflon-lined septum. The aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Millipore water) was added, followed by 2,6-dimethylpyridine (332 mg, 3.1 mmol), and the reaction mixture was vigorously stirred at room temperature for 5 min. An amine (1.00 mmol) followed by 1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium-hexafluorophosphat (COMU) (471 mg, 1.10 mmol) were added to the reaction mixture and stirring was continued for the indicated time at the indicated temperature. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium sulfate solution. The solids were filtered and washed 4× with ethyl acetate. The combined organic extracts were treated 3× with aqueous 1 N hydrochloride solution and subsequently 4× with saturated aqueous sodium carbonate solution. The organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.
14.2 Preparation of (R)-ethyl 2-(((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanoyl)oxy-4-methylpentanoate
Following the general procedure using Fmoc-Val-OH (373 mg, 1.10 mmol), L-Leucine ethyl ester hydrochloride (196 mg, 1.00 mmol) and 1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium-hexafluorophosphat (COMU) (471 mg, 1.10 mmol) in 1.25 ml of aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Millipore water), the reaction was allowed to stir overnight at room temperature. After column chromatography (0-10% methanol-dichloromethane), the product was obtained (430 mg, 89%).
ESI-MS: m/z (%): 481.20 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.77 (dq, J=7.7, 1.2 Hz, 2H), 7.60 (d, J=7.5 Hz, 2H), 7.40 (tdd, J=7.4, 2.2, 1.0 Hz, 2H), 7.32 (tdd, J=7.5, 2.4, 1.1 Hz, 2H), 6.06 (d, J=8.2 Hz, 1H), 5.40 (d, J=9.0 Hz, 1H), 4.64-4.57 (m, 1H), 4.42 (dd, J=10.6, 7.4 Hz, 1H), 4.36 (dd, J=10.6, 7.1 Hz, 1H), 4.26-4.15 (m, 3H), 4.00 (dd, J=8.9, 6.3 Hz, 1H), 2.13 (dt, J=13.4, 6.7 Hz, 1H), 1.65 (s, 2H), 1.55 (s, 1H), 1.28 (t, J=7.2 Hz, 3H), 1.01-0.90 (m, 12H).
14.3 Preparation of N-3,4-dimethoxyphenethyl)-2-phenylacetamide
14.3.1) Following the general procedure using phenyl acetic acid (150 mg, 1.10 mmol), 3,4-dimethoxyphenethylamine (181 mg, 1.00 mmol) and COMU (471 mg, 1.10 mmol) in 2 ml of aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Millipore water), the reaction was allowed to stir for 30 min. at room temperature. After column chromatography (50-100% ethyl acetate-heptane), the product was obtained as a clear oil (243 mg, 78%).
14.3.2) Following the general procedure using phenyl acetic acid (150 mg, 1.10 mmol), 3,4-dimethoxyphenethylamine (181 mg, 1.00 mmol) and 2 ml of aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed water), the reaction was allowed to stir for 20 min. at 50° C. After column chromatography (50-100% ethyl acetate-heptane), the product was obtained as a clear oil (258 mg, 82%).
14.3.3) Following the general procedure using phenyl acetic acid (150 mg, 1.10 mmol), 3,4-dimethoxyphenethylamine (181 mg, 1.00 mmol) and COMU (471 mg, 1.10 mmol) in 0.35 ml of aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Millipore water), the reaction was allowed to stir for 20 min. at room temperature. LC-MS and TLC indicated however that the reaction was already completed after 1 min. After column chromatography (50-100% ethyl acetate-heptane), the product was obtained as a clear oil (251 mg, 81%, 97% purity).
14.3.4) Following the general procedure using phenyl acetic acid (150 mg, 1.10 mmol), 3,4-dimethoxyphenethylamine (181 mg, 1.00 mmol) and COMU (471 mg, 1.10 mmol) in 0.35 ml of aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Millipore water), the reaction was allowed to stir for 15 min. at 50° C. LC-MS and TLC indicated however that the reaction was already completed after 1 min. After column chromatography (50-100% ethyl acetate-heptane), the product was obtained as a clear oil (255 mg, 81%, 95% purity).
ESI-MS: m/z (%): 300.10 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.35-7.25 (m, 3H), 7.15 (m, 2H), 6.70 (m, 1H), 6.60 (m, 1H), 6.55 (m, 1H), 5.35 (sbr, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.55 (s, 2H), 3.45 (m, 2H), 2.70 (t, 3H).
General Procedure for Sulfonylations
Under an argon atmosphere, a base (2.97 mmol) and the aqueous oligosaccharide solution (2 wt % HPMC, in degassed Millipore water) were weighed into a 5 mL microwave vial containing a magnetic stir bar and a Teflon-lined septum. An amine (0.99 mmol) and subsequently a sulfonyl chloride (1.98 mmol) were added to the vigorously stirred reaction mixture at room temperature. Stirring was continued for the indicated time at the indicated temperature. The reaction mixture was diluted with ethyl acetate, the solids were filtered and the aqueous phase was extracted 3× with ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.
14.4 Preparation of 1-(phenylsulfonyl)indoline
14.4.1) Following the general procedure using potassium trimethylsilanolate (380 mg, 2.97 mmol), indoline (119 mg, 0.99 mmol), benzenesulfonyl chloride (364 mg, 1.98 mmol) and 3 ml of aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Millipore water), the reaction was allowed to stir for 30 min room temperature. After column chromatography (40-100% n-heptane-dichloromethane), the product was obtained as a white crystalline material (233 mg, 89%).
14.4.2) Following the general procedure using potassium trimethylsilanolate (380 mg, 2.97 mmol), indoline (119 mg, 0.99 mmol), benzenesulfonyl chloride (220 mg, 1.20 mmol) and 3 ml of aqueous oligosaccharide solution (2 wt % HPMC, 4-6 cps, in degassed Millipore water), the reaction was allowed to stir for 30 min room temperature. LC-MS and TLC indicated that the reaction was already completed after 5 min. After column chromatography (40-100% n-heptane-dichloromethane), the product was obtained as a white crystalline material (262 mg, 97%, 96% purity).
ESI-MS: m/z (%): 260.20 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.80 (m, 2H), 7.65 (m, 1H), 7.55 (m, 1H), 7.45 (m, 2H), 7.20 (m, 1H), 7.10 (m, 1H), 7.00 (m, 1H), 3.95 (m, 2H), 2.90 (m, 2H).
14.5 Preparation of N-(4-fluorophenyl)-4-methylbenzenesulfonamide
Following the general procedure using triethylamine (209 μl, 1.50 mmol), 4-fluoroaniline (112 mg, 1.00 mmol), 4-methylbenzene-1-sulfonyl chloride (233 mg, 1.20 mmol) and 3 ml of aqueous oligosaccharide solution (2 wt % HPMC, 4-6 cps, in degassed Millipore water), the reaction was allowed to stir for 20 min room temperature. After column chromatography (0-50% n-heptane-ethyl acetate), the product was obtained as a clear oil (222 mg, 80%).
ESI-MS: m/z (%): 266.20 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.60 (m, 2H), 7.20 (m, 2H), 7.00 (m, 2H), 6.95 (m, 2H), 6.30 (sbr, 1H), 2.40 (s, 3H).
15. Nucleophilic Aromatic Substitutions
General Procedure for Nucleophilic Aromatic Substitutions
To the aryl halide (1.0 equiv.) and the nucleophile (1.0-1.1 equiv.) in a 5 mL microwave vial was added a 2 wt % solution of HPMC (40-60 cps) in Millipore water (1 mL). After the addition of sodium tert-butoxide (1.1 equiv) the mixture was vigorously stirred (1200 rpm) at room temperature until LCMS or TLC showed full conversion of the aryl halide. The mixture was diluted with EtOAc (3 mL) followed by the addition of a saturated aqueous solution of sodium sulfate (2 mL). After 5-15 min of stirring (200 rpm) the precipitated solids were filtered off and washed with EtOAc (3×15 mL.). After extraction, the organic layer was dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel.
15.1 Preparation of 2,5-dichloro-N-(3,4-dimethoxyphenethyl)pyrimidin-4-amine
Following the general procedure using 3,4-dimethoxyphenethylamine (90.0 mg, 0.50 mmol, 1.0 equiv.), 2,4,5-trichloropyrimidine (91.5 mg, 0.50 mmol, 1.0 equiv.) and sodium tert-butoxide (52.8 mg, 0.55 mmol, 1.1 equiv) the reaction was allowed to stir for 10 min at room temperature. After column chromatography (0-30% ethyl acetate-cyclohexane), the product was obtained as a white solid (140 mg, 0.43 mmol, 86%).
ESI-MS: m/z (%): 328 (100, [M]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.99 (s, 1H), 6.88-6.79 (m, 1H), 6.80-6.71 (m, 2H), 5.61 (sbr, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.79-3.73 (m, 2H), 2.88 (t, J=6.9 Hz, 2H).
15.2 Preparation of N-benzyl-2-nitroaniline
Following the general procedure using benzylamine (53.6 mg, 0.50 mmol, 1.0 equiv.), 1-fluoro-2-nitrobenzene (70.5 mg, 0.50 mmol, 1.0 equiv.) and sodium tert-butoxide (72.1 mg, 0.75 mmol, 1.5 equiv) the reaction was allowed to stir for 3 h at room temperature. After column chromatography (0-30% ethyl acetate-cyclohexane), the product was obtained as a white solid (89 mg, 0.39 mmol, 78%).
ESI-MS: m/z (%): 229.20 (100, [M]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 8.44 (s, 1H), 8.20 (dd, J=8.6, 1.6 Hz, 1H), 7.44-7.27 (m, 7H), 6.83-6.79 (m, 1H), 6.69-6.64 (m, 1H), 4.55 (d, J=5.7 Hz, 2H).
15.3 Preparation of naphthalen-2-yl(2-nitrophenyl)sulfane
Following the general procedure using 1-fluoro-2-nitrobenzene (70.5 mg, 0.50 mmol, 1.0 equiv.), 2-naphthalenethiol (88.0 mg, 0.55 mmol, 1.1 equiv.) and sodium tert-butoxide (52.8 mg, 0.55 mmol, 1.1 equiv) the reaction was allowed to stir for 3 h at room temperature. After column chromatography (0-30% ethyl acetate-cyclohexane), the product was obtained as a yellow solid (127 mg, 0.45 mmol, 90%).
ESI-MS: m/z (%): 304.1 (40, [M+Na]+), 585.2 (100, [2M+Na]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 8.28-8.21 (m, 1H), 8.20-8.14 (m, 1H), 7.95-7.88 (m, 2H), 7.89-7.83 (m, 1H), 7.64-7.54 (m, 2H), 7.54-7.50 (m, 1H), 7.32-7.26 (m, 1H), 7.23-7.17 (m, 1H), 6.89 (dd, J=8.3, 1.2 Hz, 1H).
16. Nitro Reduction
General Procedure for Nitro Reduction Using Zinc
Under an argon atmosphere, a nitro group-containing compound (0.237 mmol) was weighed into a 5 mL microwave vial containing a magnetic stir bar and a Teflon-lined septum. Subsequently zinc dust (155 mg, 2.37 mmol), ammonium chloride (25 mg, 0.475 mmol) and the aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Millipore water) were added and the reaction mixture was vigorously stirred at the indicated temperature for the indicated time. The reaction mixture was diluted with ethyl acetate, the solids were filtered and the aqueous phase was extracted 3× with ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.
16.1 Preparation of 4-amino-N-(2-(diethylamino)ethyl)benzamide
Following the general procedure using N-(2-diethylamino)ethyl)-4-nitrobenzamide (63 mg, 0.237 mmol), zinc (155 mg, 2.37 mmol), ammonium chloride (25 mg, 0.475 mmol) and 1.25 ml of aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Millipore water), the reaction was allowed to stir for 2 h at room temperature (the conversion was however already completed after 5 min, as indicated by LC-MS). After the work-up the clean product was obtained (46 mg, 82%).
ESI-MS: m/z (%): 236.10 (100, [M+H]+).
1H NMR (600 MHz, d6-DMSO): δ [ppm]: 7.91 (d, J=6.0 Hz, 1H), 7.56-7.50 (m, 2H), 6.56-6.49 (m, 2H), 5.59 (s, 2H), 3.30-3.24 (m, 2H), 2.57-2.51 (m, 6H), 0.97 (t, J=7.1 Hz, 6H).
16. Preparation of 3-fluoro-4-methoxyaniline
Following the general procedure using 2-fluoro-4-nitroanisole (171 mg, 1.00 mmol), zinc (327 mg, 5.00 mmol), ammonium chloride (64 mg, 1.20 mmol) and 2 ml of aqueous oligosaccharide solution (2 wt % HPMC, 40-60 cps, in degassed Millipore water), the reaction was allowed to stir for 5 min at room temperature. After column chromatography (0-100% ethyl acetate-dichloromethane), the product was obtained (110 mg, 78%).
ESI-MS: m/z (%): 142.10 (100, [M+H]+).
1H NMR (600 MHz, d6-DMSO): δ [ppm]: 6.85-6.81 (m, 1H), 6.41-6.37 (m, 1H), 6.31-6.28 (m, 1H), 4.91 (sbr, 2H), 3.68 (s, 3H).
General Procedure for Hydrogenations of Nitro Groups Using Pd/C
To the nitro compound (1.0 equiv.) was added a 2 wt % solution of HPMC (40-60 cps) in Millipore water (0.5 M) and palladium on carbon (10%, 0.05 equiv.). The mixture was stirred vigorously under a hydrogen atmosphere for the indicated time at room temperature. The mixture was diluted with EtOAc (3 mL) and a sat. solution of Na2SO4 (2 mL), filtered, extracted with EtOAc (3×15 mL) and dried over MgSO4. The clean product was obtained after flash chromatography on silica gel.
16.3 Preparation of 4-methoxyaniline
Following the general procedure using 4-nitroanisole (600 mg, 3.92 mmol, 1.0 equiv.) and palladium on carbon (10%, 208 mg, 0.2 mmol, 0.05 equiv) the reaction was allowed to stir under a hydrogen atmosphere for 18 h at room temperature. After column chromatography (dichloromethane/ethyl acetate), the product was obtained (430 mg, 3.49 mmol, 89%).
ESI-MS: m/z (%): 124.1 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 6.79-6.71 (m, 2H), 6.68-6.63 (m, 2H), 3.75 (s, 3H), 3.52 (sbr, 2H).
17. CuH Reductions of Double Bonds
General Procedure for CuH Reductions of Double Bonds
To Cu(OAc)2 (0.03 equiv.) and (6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethylphenyl)phosphine) (0.03 equiv.) under argon was given a 2 wt % solution of HPMC (4-6 cps) in Millipore water (0.25 M). After the addition of the alkene (1.0 equiv.) the mixture was stirred for 5 min at room temperature. Polymethylhydrosiloxane (0.31 equiv.) was slowly added and the mixture was stirred under argon for the indicated time at room temperature. The reaction was quenched with a NH4F solution and stirred for 2 h at room temperature. The mixture was filtered through a short pad of silica which was washed with methanol (3×15 ml). The clean product was obtained after flash chromatography on silica gel.
17.1 Preparation of ethyl 3-phenylbutanoate
Following the general procedure using ethyl trans-beta-methylcinnamate (95 mg, 0.5 mmol, 1.0 equiv.), (6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(bis(3,5-dimethyl-phenyl)phosphine) (10.4 mg, 0.015 mmol, 0.03 equiv.), polymethylhydrosiloxane (294 mg, 0.155 mmol, 0.31 equiv.) and Cu(OAc)2 (2.7 mg, 0.015 mmol, 0.03 equiv.) the reaction was allowed to stir under an argon atmosphere for 24 h at room temperature. After column chromatography (ethyl acetate/cyclohexane), the product was obtained (95 mg, 0.49 mmol, 99%).
APCI-MS: m/z (%): 193.2 (100, [M+H]+).
1H NMR (600 MHz, d6-DMSO): δ [ppm]: 7.33-7.22 (m, 4H), 7.23-7.13 (m, 1H), 4.03-3.91 (m, 2H), 3.21-3.09 (m, 1H), 2.63-2.54 (m, 2H), 1.21 (d, J=7.0 Hz, 3H), 1.09 (t, J=7.1 Hz, 3H).
18. Reductive Amination
General Procedure for Reductive Aminations Using Aldehydes
A 5 mL microwave vial was charged with the amine (1.0 equiv.), borane-2-picoline complex (1.2 equiv.) and diphenyl phosphate (0.1 equiv.). After the addition of HPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.25 mL) and the aldehyde (1.2 equiv.) the reaction mixture was vigorously stirred at room temperature until LCMS or TLC showed full conversion of the starting materials. The mixture was quenched with a saturated solution of sodium hydrogen carbonate in water (1 mL), diluted with EtOAc (3 mL) and stirred for 2 min. After the addition of a saturated solution of sodium sulfate (2 mL) the phases were separated and the aqueous phase was further extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel.
18.1 Preparation of N-benzyl-4-methoxyaniline
Following the general procedure using p-anisidine (62.0 mg, 0.50 mmol, 1.0 equiv.), borane-2-picoline complex (64.6 mg, 0.60 mmol, 1.2 equiv.), diphenyl phosphate (12.6 mg, 0.05 mmol, 0.1 equiv.) and freshly distilled benzaldehyde (64.1 mg, 0.60 mmol, 1.2 equiv.) the reaction was stirred for 2 h at room temperature. After column chromatography on silica gel (0-100% ethyl acetate-heptane) the product was obtained as a colorless oil (88 mg, 0.41 mmol, 82%).
ESI-MS: m/z (%): 214.1 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.37-7.21 (m, 5H), 6.79-6.71 (m, 2H), 6.61-6.51 (m, 2H), 4.23 (s, 2H), 3.75 (sbr, 1H), 3.69 (s, 3H).
General Procedure for Reductive Aminations Using Ketones
A 5 mL microwave vial was charged with the amine (1.0 equiv.), borane-2-picoline complex (1.2 equiv.) and diphenyl phosphate (0.1 equiv.). After the addition of HPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.25 mL) and the ketone (1.2 equiv.) the reaction mixture was vigorously stirred at room temperature until LCMS or TLC showed full conversion of the starting materials. The mixture was quenched with a saturated solution of sodium hydrogen carbonate in water (1 mL), diluted with EtOAc (3 mL) and stirred for 2 min. After the addition of a saturated solution of sodium sulfate (2 mL) the phases were separated and the aqueous phase was further extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel.
18.2 Preparation of 4-methoxy-N-(1-phenylethyl)aniline
Following the general procedure using p-anisidine (62.0 mg, 0.50 mmol, 1.0 equiv.), borane-2-picoline complex (64.6 mg, 0.60 mmol, 1.2 equiv.), diphenyl phosphate (12.6 mg, 0.05 mmol, 0.1 equiv.) and acetophenone (72.6 mg, 0.60 mmol, 1.2 equiv.) the reaction was stirred for 48 h at room temperature. After column chromatography on silica gel (0-100% ethyl acetate-heptane) the product was obtained as a colorless oil (88 mg, 0.39 mmol, 77%).
ESI-MS: m/z (%): 228.1 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.36-7.25 (m, 4H), 7.22-7.17 (m, 1H), 6.70-6.64 (m, 2H), 6.47-6.42 (m, 2H), 4.38 (q, J=6.7 Hz, 1H), 3.72 (sbr, 1H), 3.65 (s, 3H), 1.46 (d, J=6.8 Hz, 3H).
19. Introduction of Protective Groups
General Procedure for Boc-Protections of Primary Amines
A 5 mL microwave vial was charged with the amine (1.0 equiv.) and a HPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.5 mL). After the addition of di-tert-butyl dicarbonate (1.1 equiv.) and trimethylamine (1.1 equiv.) the reaction mixture was stirred at room temperature until LCMS or TLC showed full conversion of the starting materials. Ethyl acetate (1 mL) was added followed by a saturated solution of sodium sulfate in water (2 mL). The mixture was filtered through a plug of neutral aluminum oxide, which was washed with ethyl acetate. The organic phase was dried over sodium sulfate and the product was obtained after removal of the solvent or after column chromatography on silica gel.
19.1 Preparation of tert-butyl (1,2,3,4-tetrahydronaphthalen-2-yl)carbamate
Following the general procedure using 1,2,3,4-tetrahydronaphthalen-2-amine (74.0 mg, 0.50 mmol, 1.0 equiv.), di-tert-butyl dicarbonate (121 mg, 0.55 mmol, 1.1 equiv.) and trimethylamine (56.0 mg, 0.55 mmol, 1.1 equiv) the reaction was stirred for 30 min at room temperature. The product was obtained as a white solid (80 mg, 0.32 mmol, 64%).
ESI-MS: m/z (%): 270.4 (100, [M+Na]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.14-7.02 (m, 4H), 4.70-4.60 (m, 1H), 4.03-3.92 (m, 1H), 3.15-3.06 (m, 1H), 2.93-2.82 (m, 2H), 2.66-2.58 (m, 1H), 2.10-2.02 (m, 1H), 1.78-1.69 (m, 1H), 1.45 (s, 9H).
General Procedure for Z-Protections of Primary Amines
A 5 mL microwave vial was charged with the amine (1.0 equiv.) and a HPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.5 mL). After the addition of dibenzyl dicarbonate (1.0 equiv.) the reaction mixture was stirred at room temperature until LCMS or TLC showed full conversion of the starting materials. Ethyl acetate (1 mL) was added followed by a saturated solution of sodium sulfate in water (2 mL). The organic phase was dried over sodium sulfate and the product was obtained after column chromatography on silica gel.
19.2 Preparation of Benzyl (4-(cyanomethyl)phenyl)carbamate
Following the general procedure using 4-aminophenylacetonitrile (66.0 mg, 0.50 mmol, 1.0 equiv) and dibenzyl dicarbonate (143.0 mg, 0.50 mmol, 1.0 equiv) the reaction was stirred for 20 min at room temperature. After column chromatography on silica gel (0-1% dichloromethane-methanol) the product was obtained as a white solid (91 mg, 0.34 mmol, 68%).
ESI-MS: m/z (%): 267.1 (80, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.51-6.84 (m, 10H), 5.18 (s, 2H), 3.66 (s, 2H).
General Procedure for Acetyl Protections of Primary Amines
A 5 mL microwave vial was charged with the amine (1.0 equiv.) and a HPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.5 mL). After the addition of acetic anhydride (1.1 equiv.) and triethylamine (1.5 equiv.) the reaction mixture was stirred at room temperature until LCMS or TLC showed full conversion of the starting materials. Ethyl acetate (1 mL) was added followed by a saturated solution of sodium sulfate in water (1 mL). The mixture was filtered through a plug of silica, which was washed with ethyl acetate. The organic phase was dried over sodium sulfate and the product was obtained after removal of the solvent or after column chromatography on silica gel.
19.3 Preparation of N-(1,2,3,4-tetrahydronaphthalen-2-yl)acetamide
Following the general procedure using 1,2,3,4-tetrahydronaphthalen-2-amine (74.0 mg, 0.50 mmol, 1.0 equiv.), acetic anhydride (56.4 mg, 0.55 mmol, 1.1 equiv.) and trimethylamine (76.0 mg, 0.75 mmol, 1.5 equiv) the reaction was stirred for 10 min at room temperature. Ethyl acetate (1 mL) was added followed by a saturated solution of sodium sulfate in water (1 mL). The crude reaction mixture was filtered through a plug of silica. The organic phase was dried over sodium sulfate. After removal of the solvent the product was obtained as a white solid (61 mg, 0.32 mmol, 64%).
ESI-MS: m/z (%): 190.4 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.19-6.99 (m, 4H), 5.87 (s, 1H), 4.33-4.21 (m, 1H), 3.16-3.05 (m, 1H), 2.96-2.80 (m, 2H), 2.68-2.60 (m, 1H), 2.08-2.01 (m, 1H), 1.97 (s, 3H), 1.81-1.72 (m, 1H).
General Procedure for Acetyl Protections of Primary Amines in High Concentrations
A 5 mL microwave vial was charged with the amine (1.0 equiv.) and a HPMC-solution (40-60 cps, 2 wt % in Millipore water, 0.165 mL). After the addition of acetic anhydride (1.1 equiv.) and triethylamine (1.2 equiv.) the reaction mixture was stirred for at room temperature until LCMS or TLC showed full conversion of the starting materials.
19.4 Preparation of N-(4-(5-cyano-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-3-yl)phenylacetamide
Following the general procedure using 3-(4-aminophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (35 mg, 0.12 mmol, 1.0 equiv.), acetic anhydride (13.9 mg, 0.14 mmol, 1.1 equiv.) and triethylamine (15.0 mg, 0.15 mmol, 1.2 equiv.) the reaction was stirred for 5 min at room temperature. After the addition of brine (0.3 mL) the formed solid was filtered off, washed with water (0.5 mL) and dried. The product was obtained as an off-white solid (40 mg, 0.12 mmol, quant.).
ESI-MS: m/z (%): 326.1 (100, [M+H]+).
1H NMR (600 MHz, dmso): δ [ppm]: 10.79 (s, 1H), 9.93 (s, 1H), 7.63-7.26 (m, 4H), 6.57 (s, 1H), 2.05 (s, 3H).
19.5 Preparation of N-(4-(6-cyano-7-hydroxy-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)phenyl)acetamide
Following the general procedure using 1-(4-aminophenyl)-7-hydroxy-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile hydrochloride (32 mg, 0.11 mmol, 1.0 equiv.), acetic anhydride (11.9 mg, 0.12 mmol, 1.1 equiv.) and triethylamine (34.2 mg, 0.34 mmol, 3.2 equiv.) the reaction was stirred for 1 h at room temperature. After the addition of brine (1.0 mL) the formed solid was filtered off, washed with water (0.5 mL) and dried. The product was obtained as an off-white solid (20 mg, 0.07 mmol, 62%).
ESI-MS: m/z (%): 309.2 (100, [M+H]+).
1H NMR (500 MHz, dmso): δ [ppm]: 9.98 (s, 1H), 9.69 (s, 1H), 7.66-7.18 (m, 4H), 6.93 (d, J=2.9 Hz, 1H), 5.85 (d, J=3.0 Hz, 1H), 2.06 (s, 3H).
19.6 Preparation of ethyl 3-acetamido-1H-pyrrole-2-carboxylate (10154514-1934)
Following the general procedure using ethyl 3-amino-H-pyrrole-2-carboxylate (100 mg, 0.64 mmol, 1.0 equiv.), acetic anhydride (71.4 mg, 0.70 mmol, 1.1 equiv.) and a HPMC-solution (40-60 cps, 2 wt % in Millipore water, 0.212 mL) the reaction was stirred for 10 min at room temperature. After the addition of ethyl acetate (20.0 mL) and a saturated solution of sodium sulfate in water (0.2 mL) the phases were separated. The organic layer was dried over sodium sulfate. The product was obtained after removal of the solvent (126 mg, 0.61 mmol, 95%).
ESI-MS: m/z (%): 197.1 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 9.17 (s, 1H), 8.55 (s, 1H), 7.07-7.04 (m, 1H), 6.85-6.78 (m, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.19 (s, 3H), 1.38 (t, J=7.1 Hz, 3H).
20. One Pot Multi Step Reactions
20.1 One-Pot Two Step Reaction Including Double Nucleophilic Substitution with Ring Formation to an Azetidine and Subsequent Ester Hydrolysis
General Procedure for a One-Pot Azetidine Formation and Ester Hydrolysis
A 5 mL microwave vial was charged with the primary amine (1.0 equiv.), the bis-triflate (1.5 equiv.) and a HPMC-solution (40-60 cps, 2 wt % in Millipore water, 1.0 mL). After the addition of potassium hydroxide (6.0 equiv.) the mixture was stirred at 50° C. for the indicated time. The product was obtained reversed phase high pressure liquid chromatography of the crude reaction mixture.
20.1.1 Preparation of 3-methyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)azetidine-3-carboxylic Acid
Following the general procedure for a one-pot azetidine formation and ester hydrolysis using 1,2,3,4-tetrahydronaphthalen-2-amine (73.6 mg, 0.50 mmol, 1.0 equiv.), methyl 2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2-((((trifluoromethyl)sulfonyl)oxy)-methyl)propanoate (309 mg, 0.75 mmol, 1.5 equiv.) and potassium hydroxide (168 mg, 3.00 mmol, 6.0 equiv.) the reaction was stirred for 2 h at 50° C. After reversed phase high pressure liquid chromatography the product was obtained as a white solid (91 mg, 0.37 mmol, 74%).
ESI-MS: m/z (%): 246.4 (100, [M+H]+).
1H NMR (600 MHz, DMSO-d6): δ [ppm]: 7.21-7.06 (m, 4H), 4.48-4.38 (m, 2H), 4.14-4.05 (m, 2H), 3.71 (sbr, 1H), 3.67-3.57 (m, 1H), 3.17-3.09 (m, 1H), 2.92-2.47 (m, 4H), 2.17-2.05 (m, 1H), 1.54 (s, 3H).
13C NMR (126 MHz, DMSO-d6) δ [ppm]: 174.78, 135.25, 132.57, 129.52, 128.98, 126.82, 126.52, 60.87, 59.63, 59.61, 38.74, 29.65, 27.23, 23.46, 21.80.
20.2 One-Pot Four Step Reaction Including Boc-Protection of an Amino Group, Nucleophilic Substitution, Deprotection and Michael Addition of an N Nucleophile
20.2.2 Preparation of ethyl 3-(((S)-7-((2-ethyl-6-fluorobenzyl)oxy)chroman-3-yl)amino)-2-(hydroxymethyl)propanoate
(S)-3-Aminochroman-7-ol hydrochloride (500 mg, 2.48 mmol, 1.0 eq.) and di-tert-butyl dicarbonate (635 μl, 2.76 mmol, 1.1 eq.) were loaded into a 5.0 mL microwave vial opened in the air and containing a magnetic stir bar and Teflon-lined septum. HPMC in water solution (Matrocel E5, 8.3 ml of 2 wt % in degassed Millipore water) was added followed by trimethylamine (382 μl, 2.73 mmol, 1.1 eq.). The microwave tube was close with a septa and the reaction mixture was stirred at room temperature for 5 minutes. Completion of the reaction was confirmed by LC/MS.
To the reaction mixture was added 2-(bromomethyl)-1-ethyl-3-fluorobenzene (592 mg, 2.73 mmol, 1.1 eq.) and sodium hydroxide (129 mg, 3.22 mmol, 1.3 eq.) and the suspension was stirred at 65° C. for 15 min. As the reaction did not go to completion an extra 1.0 eq. of sodium hydroxide and 0.2 eq. of 2-(bromomethyl)-1-ethyl-3-fluorobenzene were added and the reaction mixture was stirred at 65° C. for an extra 15 min. Completion of the reaction was confirmed by LC/MS.
12N HCl was added dropwise to adjust the pH of the mixture to 4. p-Toluenesulfonic acid (1.71 g, 9.92 mmol, 4.00 eq.) was added to the mixture in two portions. The mixture was then vigorously stirred and heated at 65° C. for 15 min. As no reaction was observed after 15 min extra p-toluenesulfonic acid (850 mg, 4.96 mmol, 2.00 eq.) was added and the reaction was complete after 1 h.
The mixture was cooled to room temperature and trimethylamine (1.74 mL, 12.40 mmol, 5.00 eq.) was added in order to adjust the pH to 9. Ethyl 2-(hydroxymethyl)acrylate (323 mg, 2.48 mmol, 1.00 eq.) was then added and the mixture was stirred at room temperature for 12 h. LCMS shows some starting material left. An extra 0.50 eq. of ethyl 2-(hydroxymethyl)acrylate (162 mg, 1.24 mmol) was added and the mixture was stirred for an extra 3 h.
To the reaction mixture were added ethyl acetate and saturated aqueous sodium sulfate solution. The mixture was stirred at room temperature for 10 min and filtered through celite to remove the solid. The solid was washed three times with ethyl acetate. The organic phase was separated from the aqueous layer. The combined ethyl acetate phases were dried in vacuo to give 1.00 g of crude material. After column chromatography on silica gel (0-5% dichloromethane-methanol in presence of 1% triethylamine) the product was obtained as a colorless oil (810 mg, 1.88 mmol, 76%).
ESI-MS: m/z (%): 432.0 (100, [M+H]+)
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.33-7.29 (m, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.00-6.92 (m, 2H), 6.59 (d, J=8.3 Hz, 1H), 6.54 (s, 1H), 5.07 (s, 2H), 4.25-4.09 (m, 3H), 4.08-3.90 (m, 3H), 3.33-3.21 (m, 1H), 3.23-3.07 (m, 2H), 3.07-2.95 (m, 1H), 2.86-2.70 (m, 3H), 2.64 (dd, J=15.9, 6.6 Hz, 2H), 1.34-1.18 (m, 6H).
21. Cyclopropanation
General Procedure for Cyclopropanations with In-Situ Formation of the Diazo Compound from Glycine Ethyl Ester Hydrochloride
A 10 mL vial was charged with the alkene (1.0 equiv.), meso-tetraphenylporphyrin iron(III) chloride complex (0.01 equiv.) and glycine ethyl ester hydrochloride (2.0 equiv.). After the addition of dichloroethane (0.4 mL per mmol of alkene), a HPMC-solution (40-60 cps, 2 wt % in Millipore water, 4 mL per mmol of alkene) and acetic acid (0.15 equiv.), the mixture was heated to 40° C. Sodium nitrite (2.4 equiv) was added and the mixture was stirred for 20 h at 40° C. The mixture was diluted with ethyl acetate (2 mL/mmol) and a saturated solution of sodium sulfate (2 mL/mmol). After extraction with ethyl acetate (3×) the combined organic layers were dried over sodium sulfate. The crude product was purified by flash chromatography on silica gel.
21.1 Preparation of ethyl 2-([1,1′-biphenyl]-4-yl)cyclopropanecarboxylate
Following the general procedure using 4-vinylbiphenyl (90 mg, 0.5 mmol, 1.0 equiv.), meso-tetraphenylporphyrin iron(III) chloride complex (3.5 mg, 0.005 mmol, 0.01 equiv.), glycine ethyl ester hydrochloride (140 mg, 1.0 mmol, 2.0 equiv.), acetic acid (4.5 mg, 0.075 mmol, 0.15 mmol) and sodium nitrite (83 mg, 1.2 mmol, 2.4 equiv.) the reaction mixture was stirred for 20 h at 40° C. After column chromatography on silica gel (0-100% ethyl acetate-heptane) the product was obtained as a pale yellow solid (50 mg, 0.19 mmol, 38%). The product was a mixture of trans:cis=8:1.
Analytical data for the trans product:
ESI-MS: m/z (%): 267.2 (100, [M+H]+).
1H NMR (600 MHz, CDCl3): δ [ppm]: 7.62-7.09 (m, 9H), 4.17 (q, J=7.1 Hz, 2H), 2.60-2.51 (m, 1H), 1.98-1.90 (m, 1H), 1.70-1.58 (m, 1H), 1.38-1.31 (m, 1H), 1.28 (t, J=7.1 Hz, 3H).
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17060801
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abbvie inc.
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Apr 27th, 2022 08:36AM
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Apr 27th, 2022 08:36AM
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AbbVie
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:abbv
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AbbVie
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Aug 6th, 2013 12:00AM
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Dec 31st, 2009 12:00AM
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https://www.uspto.gov?id=US08501759-20130806
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Use of fibrates
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The present invention, which is applicable in the pharmaceutical industry, relates to the use of fibrates, in particular fenofibrate, especially in the form of a solid oral composition, for the manufacture of a drug for the treatment of sleep apnea, sleep apnea syndrome, in particular obstructive sleep apnea or obstructive sleep apnea syndrome.
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8501759
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1. A method of treating sleep apnea or sleep apnea syndrome in a subject suffering therefrom, said method comprising administering to said subject a pharmacologically effective amount of a fibrate.
2. A method as claimed in claim 1, wherein the sleep apnea is obstructive sleep apnea and the sleep apnea syndrome is obstructive sleep apnea syndrome.
3. A method as claimed in claim 1, wherein said fibrate is fenofibrate.
4. A method as claimed in claim 1, wherein said method of treating sleep apnea or sleep apnea syndrome also improves vigilance in said subject.
5. A method as claimed in claim 1, wherein said fibrate is a choline salt of fenofibric acid.
6. A method as claimed in claim 1, wherein said fibrate is administered orally to said subject.
7. A method as claimed in claim 1, wherein said fibrate is administered daily for at least 30 days.
8. A method as claimed in claim 1, wherein said fibrate is administered in a daily dose equivalent to an amount of from 45 to 235 mg of fenofibric acid.
9. A method as claimed in claim 8, wherein said fibrate is administered in a daily dose equivalent to about 135 mg of fenofibric acid.
10. A method as claimed in claim 1, wherein said fibrate is administered in conjunction with administration of a hydroxymethylglutaryl coenzyme A reductase inhibitor or statin.
11. A method as claimed in claim 10, wherein said hydroxymethylglutaryl coenzyme A reductase inhibitor or statin is selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, pitavastatin, rosuvastatin and fluvastatin.
12. A method as claimed in claim 1, wherein said fibrate is fenofibrate or a choline salt of fenofibric acid, and wherein said fibrate is administered orally daily for at least 30 days in a daily dose equivalent to an amount of from 45 to 235 mg of fenofibric acid.
13. A method as claimed in claim 12, wherein the sleep apnea is obstructive sleep apnea and the sleep apnea syndrome is obstructive sleep apnea syndrome.
14. A method as claimed in claim 12, wherein said method of treating sleep apnea or sleep apnea syndrome also improves vigilance in said subject.
15. A method as claimed in claim 12, wherein said fibrate is administered in a daily dose equivalent to about 135 mg of fenofibric acid.
16. A method as claimed in claim 12, wherein said fibrate is administered in conjunction with administration of a hydroxymethylglutaryl coenzyme A reductase inhibitor or statin.
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16
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FIELD OF THE INVENTION
The present invention generally relates to a novel therapeutical use of fibrates, in particular fenofibrate. More specifically, the present invention relates to the use of a fibrate for the preparation of a medicament useful for the treatment of sleep apnea and sleep apnea syndrome, in particular obstructive sleep apnea and obstructive sleep apnea syndrome.
BACKGROUND OF THE INVENTION
Sleep apnea is the cessation of breathing for at least 10 seconds, whereas 50% to 80% reduction in airflow for significant periods during sleep is called hypopnea. These events are accompanied with reduction in oxygen (O2) saturation, increase in arterial pressure and decrease in heart rate. Apneic and hypopneic events are combined into the apneic/hypopneic index (AHI), which is the total number of apneic/hypopneic events per hour of sleep. AHI is usually of 10 or more in sleep apnea.
There are 3 types of sleep apnea: obstructive sleep apnea (OSA), central sleep apnea (CSA) and mixed sleep apnea which has both OSA and CSA as components.
Obstructive sleep apnea (OSA) is due to the occlusion of the airways leading to ineffective respiratory efforts during sleep. OSA is often associated with obesity. Its hallmark clinical symptom is excessive snoring which abruptly ceases during the apneic episodes and the brief period of patient arousal and then resumes when the patient again falls asleep. This may cause excessive daytime sleepiness that can lead to impairment of almost any daytime activity (sleep apnea syndrome).
Central sleep apnea (CSA), which is rare, is usually due to central nervous system dysfunction and causes no respiratory effort.
The most common treatment for patients with severe sleep apnea is continuous positive airway pressure (CPAP), usually through a nasal mask, during sleep. There is no evidence, apart from major weight reduction or abstinence from alcohol, that simple, non-invasive lifestyle changes improve sleep apnea or its consequences.
On the other hand, fibrates have been reported to lower plasma triglycerides and cholesterol levels and to be beneficial in the prevention of ischemic heart disease in individuals with elevated levels of LDL cholesterol. They can also decrease to some extent elevated fibrinogen and PAI-1 levels. Fibrate compounds can also elevate the level of plasma HDL cholesterol.
In the present invention, fibrates are defined as PPARα agonists (peroxisome proliferator activated receptor alpha agonists), including fibric acid derivatives (e.g. fenofibric acid or clofibric acid) and pharmaceutically acceptable salts and esters of such fibric acid derivatives.
Fibrate compounds include, but are not limited to, gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate, and analogs, derivatives and pharmaceutically acceptable salts thereof.
According to the present invention, the preferred fibrate is fenofibrate, fenofibric acid (active metabolite of fenofibrate) and/or a salt of fenofibric acid, in particular photostable salts of fenofibric acid as described in U.S. Pat. No. 7,259,186, especially choline, ethanolamine, diethanolamine, piperazine, calcium and tromethamine salts of fenofibric acid.
Fenofibrate has been commercially available in Europe (Lipanthyl®) since 1975 and in the USA (TriCor®) since 1998.
Fenofibrate is indicated as adjunct therapy to diet for the treatment of patients with primary hypercholesterolemia (Fredrickson Type IIa) or mixed dyslipidemia (Fredrickson Type IIb). Fenofibrate is also indicated as adjunctive therapy to diet for treatment of adult patient with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia). The effects of fenofibrate observed in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein ilipase and reducing production of apolipoprotein CIII (an inhibitor of lipoprotein lipase activity).
Fenofibrate also decreased plasma fibrinogen levels in normolipidemic patients and in dyslipidemic patients. The fibrinogen-lowering effect of fenofibrate was shown to be in the range −7% to −17%. This reduction of fibrinogen was accompanied by a reduction in other acute phase proteins such as interleukin 6 and C reactive protein.
Fenofibrate is virtually insoluble in water, which limits its absorption and contributes to a significant increase in exposure when administered with food. The absorption of fenofibrate, as currently marketed in Europe (tablets 160 mg and micronized capsules 67 mg, 200 mg and 267 mg dose strengths), is subject to substantial food effects. When the 160 mg tablet is administered with food, exposure to fenofibric acid, the active metabolite of fenofibrate, is increased by 35% compared to administration under fasting conditions. In order to improve convenience for patients, a fenofibrate tablet formulation has been developed which is devoid of food effect and may be taken without regard to meals. This new tablet formulation, based on a further reduction of fenofibrate particle size using a NanoCrystal® technology also allows a lower strength tablet (145 mg) to provide fenofibric acid exposure equivalent to that from the reference 200 mg micronized fenofibrate capsules and 160 mg tablet.
SUMMARY OF THE INVENTION
The present invention is based on the unexpected discovery that fibrates, in particular fenofibrate, lead to an improvement in most sleep apnea indices, in particular a reduction in number of obstructive apneas, and an increase in oxygen saturation during sleep as well as in attention tests on the next morning.
More precisely, the beneficial effect of fibrates on symptoms and biological changes associated with the sleep apnea syndrome has been demonstrated by a 1-month, randomized, double-blind, placebo-controlled study of fenofibrate 145 mg tablet in patients with sleep apnea syndrome.
In a first aspect, the present invention is therefore directed to the use of a fibrate, in particular fenofibrate, for the preparation of a medicament useful for the treatment of sleep apnea, sleep apnea syndrome, in particular obstructive sleep apnea and obstructive sleep apnea syndrome, and for improving vigilance.
In a second aspect, the present invention provides a method for treatment of sleep apnea, sleep apnea syndrome, in particular obstructive sleep apnea and obstructive sleep apnea syndrome, comprising administering a fibrate, in particular fenofibrate, to a subject in need thereof.
A further understanding of the nature and advantages of the present invention may be realized by reference to the remaining portions of the specification and claims.
DETAILED DESCRIPTION
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention pertains.
In addition, the following definitions are provided to assist the reader in the practice of the invention.
The “subject” is preferably a mammal, more preferably a human.
The term “for the treatment” as used herein is to be understood as covering the direct use of the compound for the treatment of the specified disease.
The term “fibrate” will be used to denote both the fibric acid and the salified or esterified form of this compound.
Similarly, the term “fenofibrate” will be used to denote both the fenofibric acid and the salified or esterified form of this compound.
Within the framework of the present invention, the active substance can be therefore a fibric acid (e.g. fenofibric acid) as well as a pharmaceutically acceptable salt (e.g. salt of fenofibric acid, in particular a photostable salt such as a salt with choline or with ethanolamine, diethanolamine, piperazine, calcium, tromethamine) or ester (e.g. fenofibrate) of such fibric acid.
Any fibrate known and described in the art can be used in order to practice the use and method as described herein according to the present invention. Such fibrate compounds include, but are not limited to, fenofibrate, gemfibrozil, bezafibrate, clofibrate, ciprofibrate, and analogs, derivatives and pharmaceutically acceptable salts thereof.
Preferably, the fibrate is fenofibrate or a salt of fenofibric acid, in particular a photostable salt such as a salt with choline or with ethanolamine, diethanolamine, piperazine, calcium, tromethamine.
The fibrate according to the present invention can be directly administered under sterile conditions to the subject to be treated. The fibrate can also be administered as the active ingredient of a pharmaceutical composition or medicament.
Such pharmaceutical compositions typically comprise at least one fibrate together with one or more acceptable carriers thereof. Pharmaceutically carriers enhance or stabilize the composition, or facilitate preparation of the composition. Pharmaceutically acceptable carriers are determined in part by the particular composition being administered as well as by the particular method used to administer the composition. They should also be both pharmaceutically and physiologically acceptable in the sense of being compatible with the other ingredients and not injurious to the subject. Such carriers may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, sublingual, nasal, or parenteral.
The pharmaceutical compositions can be prepared in various forms, such as granules, tablets, pills, capsules, suspensions and the like. The concentration of therapeutically active compound in the formulation may vary from about 0.1-100% by weight. These compositions are prepared by any methods well known in the art of pharmacy. They can be included in a container, pack, or dispenser together with instructions for administration.
In general, in the treatment of sleep apnea or sleep apnea syndrome, in particular of obstructive sleep apnea or obstructive sleep apnea syndrome according to the invention, the fibrate will be administered orally, especially in the form of tablet.
Thus, according to an advantageous embodiment, the medicament to be used for the use and method of the present invention, is in a form suitable for oral administration.
Particularly valuable results in the treatment of sleep apnea syndrome have been obtained according to the invention by the administration of a 145 mg NanoCrystal® tablet.
This galenical form and the process for its manufacture have been described in the FDA (U.S. Food and Drug Administration) files corresponding to the product TriCor® tablet 145 mg and information regarding the NanoCrystal® technology can be found in U.S. Pat. Nos. 5,145,684, 7,276,249 and 6,277,405, which are incorporated here by way of reference.
The use of fenofibrate in this galenical form is particularly valuable insofar as the safety of its use has been demonstrated in a large number of patients. The use of choline salt of fenofibric acid is particularly valuable as well insofar as the safety of its use has been demonstrated in a large number of patients (see the FDA (U.S. Food and Drug Administration) files relating to the product named TriLipix®.
The medicament of the present invention can be combined with or used in association with other therapeutic agents. For example, a subject may be treated with a fibrate, in particular fenofibrate, along with other conventional drugs. Examples of such known drugs include hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor or statin.
The use according to the invention therefore provides a medicament that can be used in association with a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor or statin, such as, for example, pravastatin, lovastatin, simvastatin, atorvastatin, pitavastatin, rosuvastatin or fluvastatin.
Subjects suffering from sleep apnea or sleep apnea syndrome, in particular obstructive sleep apnea or obstructive sleep apnea syndrome are typically treated with pharmaceutical compositions of the present invention for a continued period of time (e.g., at least 30 days, 60 days, 90 days, or longer).
The pharmaceutical compositions comprise a pharmaceutically effective amount or prophylactically effective amount of a fibrate, in particular fenofibrate or a choline salt of fenofibric acid.
A suitable therapeutic dose can be determined by any of the well-known methods such as clinical studies on mammalian species to determine maximum tolerable dose and on normal human subjects to determine safe dosage.
In all use and method described herein, the medicament is preferably administered daily for at least 30 days. It can also be administered for at least 60 days, 90 days, or longer.
Preferably, when the active substance is fenofibrate, the daily dosage is of 45 to 235 mg, more preferably of 135 mg, expressed in fenofibric acid equivalent (145 mg of fenofibrate are equivalent to 135 mg of fenofibric acid). Otherwise stated, the medicament is used daily in an amount of fenofibrate that corresponds to a mass of fenofibric acid after hydrolysis of that amount of fenofibrate, of 45 to 235 mg, more preferably of 135 mg.
When the active substance is a fibrate, the medicament will be used in a daily dosage equivalent to 45 to 235 mg of fenofibric acid, preferably equivalent to 135 mg of fenofibric acid. In the following description, the following abbreviations and definitions of terms will be used:
Abbreviations
Abbreviation
Full term
AE
adverse event
ALT (SGPT)
alanine aminotransferase
ANCOVA
analysis of covariance
AHI
apnea/hypopnea index
AST (SGOT)
aspartate aminotransferase
BMI
body mass index
bpm
beats per minute
CI
confidence interval
CK
creatine kinase
CPAP
continuous positive airway pressure
CSA
central sleep apnea
DBP
diastolic blood pressure
ESS
Epworth sleepiness scale
FAS
Full Analysis Set
HDL-C
high-density lipoprotein cholesterol
ICD9
International Classification of Diseases 9th edition
LDL-C
Low-density lipoprotein cholesterol
LLN
lower limit of normal
Max
maximal value
Min
minimal value
N
total number of patients in a data set
n
number of patients in a data set for whom results
were available
NCEP-ATPIII
National cholesterol education program-Adult
treatment panel III
OSA
obstructive sleep apnea
PK
pharmacokinetics
PPARα
peroxisome proliferator activated receptor alpha
RBC
red blood cells
SAE
serious averse event
SD
standard deviation
SBP
systolic blood pressure
SpO2
Oxygen saturation of hemoglobin measured by
pulse oximetry
TC
total cholesterol
TG
triglycerides
ULN
upper limit of normal
V1, V2, V3
visit numbers
WBC
white blood cells
Demonstration of the Effects of Fibrates in the Treatment of Sleep Apnea
1. CHARACTERISTICS OF THE POPULATION STUDDED AND STUDY DESIGN
The beneficial effects of fibrates in the treatment of sleep apnea syndrome were demonstrated by a 1-month, randomized, double-blind, placebo-controlled study of fenofibrate 145 mg tablet in patients with sleep apnea syndrome.
This study comprised 2 phases:
a run-in period of 1 to 5 weeks, on usual diet,
a treatment period of at least 4 weeks (40 days maximum).
The study design can be represented diagrammatically as follows:
V1
Visit 1, inclusion visit 1 to 5 weeks before randomization
V2
Randomization visit
V3
End-of-treatment visit
Patient Selection
Patients fulfilling the following criteria have been included in the study:
both genders, from 18 to 70 years old,
having previous diagnosis of sleep apnea not treated with CPAP or presenting clinical symptoms of sleep apnea, such as:
having reported to snore at home, on most if not all nights,
or daytime sleepiness assessed through the Epworth sleepiness scale (a value>10 on this scale was to be considered as a clinical symptom of day time sleepiness),
overweight or obese, with body mass index (BMI)≧25 kg/m2 and <40 kg/m2,
known moderate hypertriglyceridemia, with fasting triglycerides (TG) level≧2.0 and <6.0 mmol/L within 3 months before the inclusion, confirmed by an inclusion laboratory test.
Thirty four (34) patients with sleep apnea syndrome were thus selected.
Run-In Period
Patients were to be on usual diet throughout the 1 to 5-week run-in period. Patients on fibrates at V1 (inclusion) and without any previous history of major hypertriglyceridemia or pancreatitis were to have stopped the treatment for 4 weeks before blood sampling.
Treatment Period
The treatment period was to last for at least 4 weeks (40 days maximum).
The patients were randomized to 1 of the 2 following treatment groups:
145 mg NanoCrystal® fenofibrate tablet,
fenofibrate-matching placebo tablet.
Selection of Doses in the Study
The selected dosage for fenofibrate in this study was the no-food effect 145-mg NanoCrystal® tablet. This tablet had been shown to be bioequivalent to the 200 mg fenofibrate capsule and to the 160 mg fenofibrate tablet.
This dosage taken once daily is the standard dose used in the treatment of dyslipidemia.
Selection and Timing of Dose for Each Patient
During the 4 weeks of the treatment period, the patients were to take orally 1 tablet of 145 mg NanoCrystal® fenofibrate (active or placebo) in the morning with or without the meal.
Prior and Concomitant Therapy
The usual medications taken by the patients were not to be changed during the study. Treatment with statins were allowed provided that the dosage remained unchanged throughout the study.
Health Advice
The patients were asked not to change their usual diet throughout the study.
The efficacy of the treatment has been evaluated using the following variables:
Primary variables: number of obstructive apneas, of central apneas, of mixed apneas, total number of apneas, index of apnea per sleep hour, total number of hypopneas, index of hypopnea per sleep hour, index of apnea/hypopnea per sleep hour, total number of desaturations per sleep hour (with a variation of at least 3-4%), and percentage of time spent with SpO2<90%.
Variables assessed as complementary analyses: cumulated duration of apnea, mean duration of apnea, duration of the longest apnea, number of non cortical micro-awakening indicators related to respiratory events/hour, number of non cortical micro-awakening indicators related to respiratory events, oxygen saturation in blood measured by pulse oximetry (SpO2) in wake state, mean SpO2 on sleep recording, minimum value of SpO2, percentage of time spent with SpO2<80%, percentage of time spent with SpO2<85%, number of tachycardia, mean duration of tachycardia, number of bradycardia, mean duration of bradycardia, mean pulse rate, standard deviation pulse rate, minimum pulse rate, maximum pulse rate, decrease in daytime sleepiness assessed by the ESS, vigilance tests (reflexive visually guided saccades, antisaccades and sustained attention test).
Secondary variables: % change from baseline (V2) in fasting and post-prandial TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG), fibrinogen and insulin.
Plasma Study Drug Concentration:
Blood was collected for measurement of fenofibric acid at V2, pre-dose in the morning after the first sleep study, and at V3, pre-dose (24 h after last study drug intake) and 4 h after study drug intake, with breakfast, after the second sleep study.
Safety:
Analysis of safety included change in alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), creatinine, white blood cell (WBC) and differential count, red blood cells (RBC), hemoglobin, hematocrit and platelets. Incidence of adverse events (AEs), serious or not, related to study drug or not, experienced during the treatment period.
The following procedures have been used for evaluating the above mentioned variables:
Determination of Apnea/Hypopnea Index (AHI)
Throughout the night, respiration was monitored by a sound pressure transducer placed on the suprasternal notch facing the trachea or thoracic strain gauges (model CID 102) (Van Surell C, Lemaigre D, Leroy M, Foucher A, Hagenmuller M P, Raffestin B. Evaluation of an ambulatory device, CID 102, in the diagnosis of obstructive sleep apnea syndrome. Eur Respir J. 1995; 8(5):795-800).
Apnea is defined as an absence of inspiratory flow for at least 10 seconds.
Hypopnea is defined as a 50% to 80% reduction in airflow combined with 3-4% oxygen desaturations.
Sleep apneas are classified as obstructive or central.
Central apneas are defined as total absence of inspiratory flow and chest/abdominal movement during the period of absence of inspiration flow.
Obstructive sleep apneas are defined by a decrease in airflow of more than 80% in the presence of paradoxical movements of the ribcage and abdomen. Similar to AHI, the obstructive and central apneas were based on definitions that require events to be associated with 3-4% desaturations.
Percent sleep time<90% O2 saturation
Desaturation episodes were the markers of respiratory impairment. All-night recordings of arterial oxygen saturation were obtained using a cardio-respiratory pulse oximeter attached to the finger (SpO2).
Severity of obstructive sleep apnea was measured by the number of falls in SpO2 of more than 3-4% per hour of sleep. The equipment automatically selected the desaturation threshold (3 or 4%) according to the baseline SpO2 value. To further define the severity of OSA, the lowest SpO2 point and the percentage of time spent with SpO2<90% was determined.
Heart Rate Recording
The number and mean duration of tachycardia and bradycardia were recorded throughout the sleep study.
Tachycardia was defined as a rate>90 beats per minute (bpm), bradycardia as a rate<50 beats per minute (bpm).
The Epworth Sleepiness Scale (ESS)
This scale is the most widely index used to measure sleep apnea subjectively. It is a self-administered questionnaire that asks patients their likelihood of falling asleep in 8 situations ranked from 0 (no chance of dozing), 1 (slight chance of dozing), 2 (moderate chance of dozing) to 3 (high chance of dozing). The numbers are then added together to obtain a global score between 0 and 24. A value of 10 or below is considered normal.
Computerized Attention/Vigilance Tests
All the 3 tests were performed in complete darkness in the morning after the sleep recording. The patient was seated 1 meter in front of a ramp, the head immobilized at the temples with a headrest. Eye movements were recorded by using horizontal electro-oculography with bitemporal electrodes. Manual reaction times were obtained by pressing on a button placed in front of the patient. Data are stored and analyzed after the tests.
Reflexive Visually Guided Saccades
Reflexive guided saccades were realized with a gap paradigm. Patients were instructed to initially stare at a central target that was illuminated for 2.5 to 3.5 seconds, then to make a eye movement (saccade) towards a 25° lateral target that appeared randomly right or left after the extinction of the central fixation point. This was performed by blocks of 12 targets (6 on the right and 6 on the left). The main parameter analyzed was the saccade latency, which is the reaction time between the appearance of the target and the start of the saccade towards this target. This test was to be repeated 4 times, i.e, 48 latency values.
Antisaccades
The same stimulus condition as in the visually guided saccade task was used, but patients were instructed to look, as quickly as possible, in the direction opposite to the peripheral target, i.e, to perform an antisaccade, without instructions about saccade amplitude. This test implies an active participation of the patient and requires a high level of attention. This was to be performed by blocks of 12 targets (6 on the right and 6 on the left) and the test was repeated 4 times, i.e, 48 latency values. The measured parameters were the antisaccade latency and the percentage of errors (saccades made by mistake in direction of the target).
Sustained Attention Test
Patients were instructed to stare at a central point. Pairs of lateral targets appeared successively on the ramp. Both targets of each pair were equidistant from the middle of the ramp. They appeared most often near the middle (one at 10° on the left, the other one at 10° on the right) and more rarely far from the middle (one at 25° on the left, the other one at 25° on the right). The patients were instructed to press a button, as soon as they saw a pair of distant targets.
The measured parameters were the manual reaction time and the percentage of errors (responses for close targets and no response for distant targets). Optimal responses were obtained if the patients were able to have a high level of sustained attention during all the duration of the test. Each block of this paradigm included 10 pairs of distant targets. This test was repeated 5 times, i.e, 50 values for reaction time.
The tests were overviewed by trained staff. They were carried-out on the morning for about half an hour, whenever possible with the same timing at V2 and V3.
Laboratory Tests
TC, TG, HDL-C, glucose, fibrinogen and insulin were measured at inclusion and during the 2 hospital admissions before a lipid rich breakfast. Insulin was also measured before the lipid rich breakfast, each morning following the sleep study.
Post-prandial TG were measured 4 hours after a lipid rich breakfast.
Drug Concentration Measurements
Blood samples were collected on V2 morning on fasting state (24 hours after the last study drug intake) and on V3 on fasting state and on post-prandial state (4 hours after breakfast).
Concentrations of fenofibric acid (active metabolite of fenofibrate) in plasma were determined by High Performance Liquid Chromatography with ultra-violet (UV) detection. The lower limit of quantification (LLOQ) was 0.030 μg/mL.
2. STATISTICAL ANALYSIS
Raw values at baseline and V3 and absolute and % changes from baseline are provided for the variables analyzed in a continuous way, and frequencies at V3 are provided for the criteria analyzed in a categorical way.
Inferential statistics done depended on whether data were normally distributed or not.
If baseline data were normally distributed (Shapiro-Wilk test), an ANCOVA with the baseline value as covariate and the treatment effect as main factor was performed on V3 (end of treatment) data. The Least Square mean (LS-mean) of the difference fenofibrate—placebo at V3 with associated 95% confidence interval (CI) was provided.
If baseline data were not normally distributed (Shapiro-Wilk test), they were Log-transformed. If normality was then reached, the ANCOVA was performed on Log-transformed V3 data. The relative difference fenofibrate—placebo at V3 with associated 95% CI was provided.
If Log-transformed baseline data were not normally distributed (Shapiro-Wilk test), the 2 groups were compared at baseline and at V3 with the Wilcoxon test. No adjustment for multiplicity was done.
Complementary analyses included parametric (Pearson) and non parametric (Spearman) correlations between sleep study variables and V3 values or changes in fasting and post-prandial in TG.
3. RESULTS
Demographic and Other Baseline Characteristics
The mean age of patients (12 women and 22 men) was 55.6 years.
Their mean BMI value was 33.8 kg/m2 and their mean waist circumference value was 111.4 cm.
Most of the patients had obstructive/central/mixed sleep apnea or obstructive/mixed sleep apnea.
During all the study, 16 patients (47%) received a concomitant statine treatment.
Recordings of the first night of the sleep study at V2 (baseline) allowed to establish the presence of sleep apnea (AHI higher than 10).
Median values of main efficacy criteria at baseline are presented in Table 1 below.
TABLE 1
Number of apneas
36.0
Number of hypopneas
82.0
Number of desaturations
179.0
Number of central apneas
3.0
Number of mixed apneas
3.0
Number of obstructive apneas
20.0
Index of apnea/hypopnea/h
21.0
Index of apnea/h
5.0
Index of hypopnea/h
13.0
Percentage of time with SpO2 <90%
10.0
Number = total number during sleep recording.
Index = number per hour of sleep recording.
The median duration of apnea was 13 seconds and the median cumulated duration during the overnight sleep study was 8 minutes.
The median value of apnea/hypopnea index was 21.0 episodes per hour.
The median number of non-cortical micro-awakening indicators related to respiratory events was 24 per hour.
The SpO2 recorded during sleep was 93.0% (median), with a minimal value of 76.0%. The percentage of time with SpO2<90% varied between 0 and 70%, that with SpO2<85% varied between 0.0 and 14.0% (median: 1.0%), that with SpO2<80% varied between 0.0 and 9.0% (median: 0.0%).
The median number of tachycardia (>90 bpm) episodes was 3.0 and the median number of bradycardia (<50 bpm) was 6.0, with a duration (median) of 10.5 and 9.0 seconds, respectively.
The mean pulse rate was 64.0 bpm (minimum: 49.0 bpm, maximum: 95.0 bpm).
The median score on the ESS was 8.0.
Computerized attention and vigilance tests were considered as normal or near normal.
Mean (SD) and median values of laboratory efficacy variables at baseline are presented in Table 2:
TABLE 2
Fasting
Fasting TG
Post-prandial
TC
HDL-C
glucose
Fibrinogen
Insulin
(mmol/L)
TG (mmol/L)
(mmol/L)
(mmol/L)
(mmol/L)
(μmol/L)
(pmol/L)
3.47 (2.08)
5.52 (2.69)
5.65 (1.34)
1.04 (0.25)
5.70 (0.92)
10.88 (2.48)
94.8 (43.1)
2.50
4.60
5.66
0.99
5.60
10.29
82.9
Fasting and post-prandial TG values were in the moderately to severely elevated ranges. Mean and median TC values were in the elevated range according to the NCEP-ATPIII classification. HDL-C was close to normal in most of the patients. Mean and median values for FPG, fibrinogen and insulin were in normal range.
Efficacy Results:
Main Efficacy Analysis on the Primary Efficacy Criteria
All the primary efficacy variables were non-normally distributed at baseline. Except for the percentage of time with SPO2<90%, normality was achieved after Log-transformation. Then, the comparison between groups was performed with the ANCOVA on Log-transformed end-of-treatment (V3) values.
The results are presented in Table 3.
TABLE 3
Fenofibrate
Placebo
145 mg
Fenofibrate-Placebo at
Base.
End (V3)
Base.
End (V3)
end of treatment
Variables
(median)
(median)
(median)
(median)
Estimate [95% CI]
p
Number of
36.0
31.0
34.0
20.5
−35%
[−66%; 27%]
0.199
apneas
Number of
94.0
69.5
76.0
63.0
−46%
[−75%; 17%]
0.114
hypopneas
Number of
238.0
171.0
174.0
130.0
−23%
[−49%; 16%]
0.203
desaturations
Number of
4.0
0.0
2.0
1.0
−55%
[−92%; 158%]
0.333
central apneas
Number of
3.0
0.0
3.0
1.0
−25%
[−72%; 99%]
0.521
mixed apneas
Number of
29.0
30.5
18.5
15.0
−44%
[−69%; 0%]
0.048
obstructive
apneas
Index of apnea/
23.0
22.5
20.5
17.0
−14%
[−47%; 40%]
0.533
hypopnea
Index of apnea
5.0
4.0
6.5
2.5
−33%
[−67%; 38%]
0.264
Index of
14.0
11.0
13.0
9.5
−20%
[−53%; 36%]
0.401
hypopnea
Percentage of
10.0
11.5
9.0
3.5
ND
0.007
time with
SpO2 < 90%
ND: Not Done: non parametric test comparing V3 values; estimates with minus sign correspond with improvement in sleep apnea indices.
At end of treatment, there were trends to a lower number of episodes of apnea and hypopnea in the fenofibrate group compared with the placebo group, in particular there was a significant reduction in obstructive apneas (p=0.048).
This was accompanied with a significant reduction with fenofibrate in the percentage of time during sleep with SpO2<90% (p=0.007).
The improvement in sleep apnea and oxygen saturation indexes was observed in both the patients receiving a statin or not.
Complementary Analyses on the Primary Efficacy Criteria
The results are presented in Table 4.
TABLE 4
Fenofibrate
Placebo
145 mg
Base.
End (V3)
Base.
End (V3)
Fenofibrate-Placebo
Variables
(median)
(median)
(median)
(median)
Estimate [95% CI]
p
Cumulated
8.0
7.5
7.0
4.5
−31%
[−65%; 37%]
0.276
duration of
apnea (min)a
Mean duration
13.0
14.0
13.0
13.5
ND
0.931
of apnea (s)
Duration of the
24.0
30.0
21.0
23.5
ND
0.877
longest
apnea (s)
Non cortical
24.0
25.0
23.5
18.0
−10. 7
[−17.6; −3.8]
0.004
micro-
awakening per
hourb
Number of non
172.0
167.0
142.5
128.0
−75.7
[−126.6; −24.8]
0.005
cortical micro-
awakeningb
SpO2 in wake
95.0
94.5
95.5
95.0
ND
0.101
state (%)
Mean of SPO2
92.0
92.0
93.0
94.0
1.1
[0.2; 2.0]
0.019
on recording
(%)b
Minimum value
73.0
75.0
80.0
82.0
0.4
[−4.4; 5.2]
0.859
of SpO2 (%)b
Percentage time
0.0
0.0
0.0
0.0
ND
0.538
spent with
SpO2 < 80%
Percentage time
1.0
0.0
0.0
0.0
ND
0.041
spent with
SpO2 < 85%
Number of
4.0
3.05
1.5
3.0
22%
[−60%; 268%]
0.708
tachycardiaa
Mean duration
10.0
7.5
14.0
12.0
44%
[−27%; 184%]
0.276
of
tachycardia (s)a
Number of
9.0
2.0
2.0
2.5
282%
[−26%; 1860%]
0.100
bradycardiaa
Mean duration
10.0
10.0
8.0
10.0
19.8
[−2.2; 41.7]
0.074
of
bradycardia (s)b
Mean pulse rate
63.0
63.5
64.5
63.0
1.6
[−2.5; 5.7]
0.427
(bpm)b
Standard
5.6
5.6
5.0
5.7
ND
0.458
deviation pulse
rate (bpm)
Minimum pulse
47.0
49.0
50.0
48.5
1.7
[−3.1; 6.6]
0.471
rate (bpm)b
Maximum pulse
96.0
94.0
94.5
97.0
ND
0.467
rate (bpm)
aANCOVA on Log-transformed data and absolute difference fenofibrate-placebo,
bANCOVA on non-transformed data and relative difference fenofibrate-placebo,
ND: Not Done: non parametric test comparing V3 values; percent estimates with minus sign correspond with improvement.
The number of non cortical micro-awakening indicators related to respiratory events was significantly reduced at the end of treatment by fenofibrate as compared with placebo (p=0.005).
The difference between the groups was also statistically significant for the mean of SpO2 on sleep recording (p=0.019) and for the percentage of time with SpO2<85% (p=0.042). The other variables did not significantly differ between the 2 groups.
Epworth Sleepiness Scale (ESS)
The median of the ESS was 8.5 at baseline and at end of treatment in the fenofibrate group. In the placebo group, it was 7.5 at both assessments.
Computerized Attention/Vigilance Tests
Reflexive visually guided saccades and antisaccades
In the 2 groups, there were no meaningful changes in reflexive visually guided saccades and in reflexive visually guided antisaccades. For none of the parameters assessed were statistically significant differences observed between fenofibrate and placebo.
Reflexive visually guided sustained attention tests
Five (5) consecutive series of tests (sarters) were performed.
The results of the mean of the 5 tests are presented in Table 5.
TABLE 5
Fenofibrate
Placebo
145 mg
Baseline
End (V3)
Baseline
End (V3)
Fenofibrate-Placebo
Variables
(median)
(median)
(median)
(median)
Estimate [95% CI]
p
Mean latency all
404.8
411.3
432.0
409.7
3.6
[−20.7; 27.8]
0.766
sarter (ms)a
Standard
101.4
104.2
108.1
98.0
13.2
[−14.8; 41.3]
0.343
Deviation latency
all sarters (ms)a
Minimum latency
279.0
280.5
290.0
295.0
ND
0.242
all sarters (ms)
Maximum latency
791.0
769.5
770.5
750.0
7%
[−12%; 30%]
0.491
all sarters (ms)b
Percent false
1.1
1.1
1.1
1.1
ND
0.480
responses all
sarters
Percent omissions
0.0
0.0
0.0
0.0
ND
0.028
all sarters
aANCOVA on non-transformed data and absolute difference fenofibrate-placebo,
bANCOVA on Log-transformed data and relative difference fenofibrate-placebo,
ND: Not Done: non parametric test on V3 values; percent estimates with minus sign correspond with improvement.
Despite at least half of the patients did not omit any response to the tests, there was a statistically significant reduction in omissions with fenofibrate. The reduction of omissions in this sustained attention test, considered as the most discriminating vigilance test used in this study, is in favor of an improvement of vigilance in patients treated with fenofibrate.
Laboratory Efficacy Variables
The results are summarized in Table 6.
TABLE 6
Fenofibrate
Placebo
145 mg
Baseline
End (V3)
Baseline
End (V3)
Fenofibrate-Placebo
Variables
(median)
(median)
(median)
(median)
Estimate [95% CI]
p
Fasting Triglycerides
2.72
2.65
2.31
2.00
ND
0.018
(mmol/L)
Post-Prandial
4.77
4.68
4.03
3.27
−26%
[−42%; −7%]
0.012
Triglycerides
(mmol/L)a
Total Cholesterol
6.25
5.94
5.30
4.58
−0.8
[−1.2; −0.33]
0.001
(mmol/L)b
HDL-Cholesterol
0.96
1.08
0.99
1.05
2%
[−8%; 14%]
0.662
(mmol/L)a
Fasting Plasma
5.40
5.55
5.65
5.45
0.2
[−0.3; 0.7]
0.324
Glucose (mmol/L)b
Fibrinogen (μmol/L)b
10.29
10.00
10.59
8.82
−1.7
[−2.6; −0.8]
0.0004
Insulin (pmol/L)b
100.5
93.3
70.3
94. 4
12.1
[−12.3; 36.6]
0.318
aANCOVA on Log-transformed data and relative difference fenofibrate-placebo,
bANCOVA on non-transformed data and absolute difference fenofibrate-placebo.
ND: Not Done: non parametric test on V3 values; percent estimates with minus sign correspond with improvement.
Fasting TG, post-prandial TG, TC and fibrinogen were significantly reduced by fenofibrate compared with placebo. Fenofibrate had no effect on fasting plasma glucose (FPG). Changes in HDL-C were minor with fenofibrate in patients who had baseline values close to normal. Changes in insulin were highly variable; there was no statistically significant difference between the 2 groups.
Complementary Efficacy Analyses: Correlations Between Changes in TG and Apnea Variables
The Pearson test showed statistical significance for the correlation between % change in post-prandial TG and number of apneas (r=0.507, p=0.004), number of central apneas (r=0.422, p=0.040), number of mixed apneas (r=0.364, p=0.034), index of apnea (r=0.348, p=0.044), and total number of desaturations (r=0.423, p=0.013) at end of treatment.
The Spearman test was, however, never statistically significant.
Plasma Study Drug Concentration
In the fenofibrate group at V3, (end of treatment), the mean (SD) plasma fenofibric acid level was 6.2 (3.8) μg/mL before dosing and 9.3 (4.0) μg/mL 4 hours after dosing.
Safety Results:
There were no deaths during the study.
One (1) significant adverse event (SAE), for pulmonary embolism, was reported during the run-in period. The patient was not randomized.
One (1) SAE was reported during the treatment period. The patient, in the fenofibrate group, was hospitalized for assessment of metabolic syndrome. This SAE was considered as not related to the study treatment.
No patients prematurely terminated the study because of adverse event (AEs).
One (1) AE was reported in the placebo group and 6 AEs in 3 patients were reported in the fenofibrate group. The AE reported in the placebo group was lumbar pain, and was considered as not related to study treatment. The AEs reported in the fenofibrate group were bloating (n=1), rash (n=1), allergic rhinitis (n=1), metabolic syndrome (SAE, n=1), type 2 diabetes (n=1), and cystitis (n=1).
None of the AEs reported during the treatment period was considered as related to study treatment.
Median % change at end of treatment from baseline in RBC was −4.5% in the placebo group and −2.7% in the fenofibrate group, in hemoglobin: −4.7% and −3.8%, respectively, in hematocrit: −3.9% and −3.2%, in WBC: −12.7% and −11.6%, in platelets: −8.3% and +4.7% (p=0.007), and in creatinine: −9.1% and +5.9% (p=0.015). The other safety biological variables (ALT, AST, CK) did not differ between the 2 groups.
In either treatment group, there were no meaningful changes in mean values of pulse rate, diastolic blood pressure (DBP) or systolic blood pressure (SBP) between baseline and end of treatment. Mean values of body weight and body mass index (BMI) remained roughly unchanged at end of treatment compared to baseline.
4. CONCLUSION
This randomized, placebo-controlled study of 4-week treatment with fenofibrate 145 mg once daily in hypertriglyceridemic obese patients with sleep disturbances not requiring CPAP treatment led to an improvement in most sleep apnea indices with fenofibrate over placebo, in particular a reduction in number of obstructive apneas, and an increase in oxygen saturation during sleep. In parallel, an improvement in attention tests on the next morning was observed. Fenofibrate treatment was well tolerated.
This study shows that fibrates and in particular fenofibrate (or equivalent product that are metobolized by the body in fenofibric acid, such as salts of fenofibric acid) are useful active substances in the treatment of sleep apnea and sleep apnea syndrome, in particular obstructive sleep apnea or obstructive sleep apnea syndrome.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
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13143152
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fournier laboratories ireland limited
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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514/275
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Mar 31st, 2022 02:21PM
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Mar 31st, 2022 02:21PM
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AbbVie
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:abbv
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AbbVie
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Aug 12th, 2008 12:00AM
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Oct 23rd, 2001 12:00AM
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https://www.uspto.gov?id=US07410983-20080812
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Combination of fenofibrate and coenzyme q10 for the treatment of endothelial dysfunction
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The present invention relates to a combination of a peroxisome proliferator activated receptor (PPAR) activator and a benzoquinone and their use in treating and/or preventing disorders characterized by endothelial dysfunction, such as cardiovascular disease, strokes and myocardial infarction. According to a preferred embodiment of the invention the benzoquinone or precursor thereof is a ubiquinone or precursor thereof, more preferably, coenzyme Q10 or a precursor thereof, and the PPAR activator is a fibrate or a thiazolidinedione, more preferably fenofibrate.
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7410983
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1. A method for treating a disorder characterized by endothelial dysfunction in a mammal, the method comprising:
administering daily to the mammal a composition comprising:
about 200 mg of fenofibrate or a pharmaceutically acceptable salt thereof; and
about 200 mg of coenzyme Q10 or a pharmaceutically acceptable salt thereof;
the disorder being cardiovascular disease, hypertension, stroke, myocardial infarction, peripheral vascular disease, macro angiopathy in the mammal with diabetes, or micro angiopathy in the mammal with diabetes.
2. The method of claim 1, comprising administering daily to the mammal a composition comprising:
200 mg of fenofibrate or a pharmaceutically acceptable salt thereof; and
200 mg of coenzyme Q10 or a pharmaceutically acceptable salt thereof.
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2
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This application is a 371 of PCT/EP01/12425 filed Oct. 23, 2001.
FIELD OF THE INVENTION
The present invention relates to a combination of a peroxisome proliferator activated receptor (PPAR) activator and a benzoquinone and their use in treating and/or preventing disorders characterized by endothelial dysfunction, such as cardiovascular disease, strokes and myocardial infarction.
BACKGROUND TO THE INVENTION
The burden of cardiovascular disease is increasing in both developed and developing countries. This relates to an acceleration in the incidence of diabetes and obesity as well as to other cardiovascular risk factors, including hypercholesterolaemia, hypertension and smoking. All these conditions have in common a mechanism of vascular abnormality termed endothelial dysfunction (Rubanyi, 1993).
Nitric oxide (NO), a chemically unstable radical formed by enzymatic conversion of L-arginine in the presence of molecular oxygen, elicits relaxation of vascular smooth muscle cells. NO also counteracts platelet adhesion and aggregation. NO is released from endothelial cells by the action of acetylcholine (ACh). Failure of the vascular endothelium to elicit NO-mediated vasodilatation may be due to decreased formation of NO, increased degradation of NO and/or decreased biological sensitivity to NO. Irrespective of the mechanism this is referred to as endothelial dysfunction.
The vascular endothelium is also the site of formation of other vasodilator agents (e.g. prostacyclin, endothelium-derived hyperpolarizing factor), as well as vasoconstrictive factors (e.g. thromboxane A2, endothelin).
Endothelium dysfunction is highly relevant to vascular disease and occurs chiefly as a consequence of disturbances in the L-arginine/NO pathway.
Its occurrence in type 2 diabetes, for example, is extensively supported by both in vitro and in vivo studies (Cohen, 1993; Watts, 1998). Indeed, endothelial dysfunction may be the initiating event in the process of atherosclerosis eventually resulting in clinical coronary artery disease. In hypercholesterolemic subjects, impaired endothelium-dependent vasodilatation is evidenced before the development of atherosclerosis. In patients with type 2 diabetes endothelial function is abnormal even in the absence of elevated plasma LDL cholesterol concentration.
Endothelial dysfunction in diabetes may have implications not only for coronary artery disease, but also for peripheral vascular disease and retinopathy. Experimental and clinical studies support the concept that dyslipidemia (in particular increased circulatory concentrations of modified, small dense LDL), as well as hyperoxidative stress, are closely related to the development of endothelial dysfunction as a consequence of changes in the disposal of nitric oxide NO.
Oxidative stress represents a challenge to normal bodily functions. It may arise from an increase in exposure to free radicals/oxidants or may be a result of a decrease in anti-oxidant capacity. Oxidative stress is caused by reactive oxygen species which can be of both endogenous or exogenous origin. Endogenous sources of free radicals, such as the superoxide anion O2.−, include endothelial cells, activated neutrophils and mitochondria. The term reactive oxygen species includes not only oxygen-centred radicals (e.g. superoxide and hydroxyl), but also non-radical derivatives of oxygen (H2O2), singulet oxygen and HOCl. In diabetes, as well as in myocardial infarction, stroke and inflammation, there is an increase in plasma levels of lipid hydroperoxides which are formed through a free radical-mediated mechanism from polyunsaturated fatty acids.
Accordingly, given the association between oxidative stress, endothelial dysfunction and a range of important disorders there is a need to provide an effective treatment for endothelial dysfunction caused by oxidative stress. In particular, type 2 diabetes is associated with a markedly increased risk of cardiovascular disease, its major complication.
Treatments have not been shown to be effective. There is a major need for new preventative and therapeutic strategies for cardiovascular disease.
DISCLOSURE OF THE INVENTION
Accordingly, the present invention provides a composition comprising a peroxisome proliferator activated receptor (PPAR) activator and a benzoquinone of formula I:
in which:
R1, R2 and R3 independently are:
an alkyl group having 1 to 8 carbon atoms, or
an alcoxy group having 1 to 8 carbon atoms;
R4 is:
an hydrogen atom,
an hydrocarbyl group having 1 to 60 carbon atoms,
a OR5 radical,
an SR6 radical,
a N(R7)(R8) radical,
a nitro group, or
a carboxyl group;
R5, R6, R7 and R8 being independently:
a hydrogen atom, or
an alkyl group having 1 to 20 carbon atoms;
or a precursor thereof capable of being metabolized in the human or animal body to said benzoquinone;
or a pharmaceutically acceptable salt thereof.
In one preferred embodiment of the invention, said benzoquinone is of the formula (I) in which R4 is an alkenyl group or a polyalkenyl group, preferably a group of formula:
in which n is an integer of from 1 to 12, preferably from 6 to 11.
Preferably the benzoquinone or precursor thereof is a ubiquinone or precursor thereof, more preferably, coenzyme Q10 or a precursor thereof.
Preferably, the PPAR activator is a PPARα or a PPARγ activator.
Preferably, the PPAR activator is a fibrate or a thiazolidinedione, more preferably fenofibrate.
The PPAR activator, such as fenofibrate, may be co-micronised with a solid surfactant. Preferably, the solid surfactant is sodium lauryl sulphate.
The present invention also provides a pharmaceutical composition comprising a composition of the invention together with a pharmaceutically acceptable carrier or diluent.
The present invention further provides a method of treating or preventing a disorder characterized by endothelial dysfunction in an individual which method comprises administering to said individual an effective amount of a peroxisome proliferator activated receptor (PPAR) activator and a benzoquinone of formula I or a precursor thereof capable of being metabolized in the human or animal body.
Typically, the disorder is selected from cardiovascular disease, hypertension, stroke, myocardial infarction, peripheral vascular disease, angina pectoris, cardiac failure, diastolic and/or systolic ventricular dysfunction, macro and microangiopathy in patients with diabetes, and tissue damage related to ischemia or reperfusion.
The PPAR activator and benzoquinone may, for example, be administered separately, sequentially or concomitantly.
The present invention also provides a peroxisome proliferator activated receptor (PPAR) activator and a benzoquinone of formula I, or a precursor thereof capable of being metabolized in the human or animal body to said benzoquinone, for use in therapy.
Further, the present invention provides the use of a peroxisome proliferator activated receptor (PPAR) activator and a benzoquinone of formula I, or a precursor thereof capable of being metabolized in the human or animal body to said benzoquinone, in the manufacture of a medicament for use in treating a disorder characterized by endothelial dysfunction, as defined above.
Further still, the present invention provides a method for producing a composition of the invention which method comprises admixing said PPAR activator and benzoquinone.
The present invention also provides a method for producing a pharmaceutical composition of the invention which method comprises admixing said PPAR activator and benzoquinone with a pharmaceutically acceptable carrier or diluent.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the acetylcholine percent change in forearm blood flow ratio as a result of the administration of coenzyme Q10 and/or fenofibrate; and
FIG. 2 is a graph showing the sodium nitroprusside percent change in forearm blood flow ratio as a result of the administration of coenzyme Q10 and/or fenofibrate.
BEST MODE(S) FOR CARRYING OUT THE INVENTION
Throughout the specification, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
PPAR Activators
The peroxisome proliferator activated receptor (PPAR) (Issemann, 1990) is a member of the family of ligand-activated nuclear receptors including the estrogen receptor, the retinoic acid receptor (RXR) and the androgen receptor. These nuclear receptors are activated by the binding of a ligand, for example, estrogen, in the case of the estrogen receptor. The activation of the receptor enables the latter to then bind to a specific DNA sequence, termed the responsive element, in the promoter of a given gene leading thus to either an increase or in some cases a decrease in the transcription of the target gene.
PPAR is present as 2 main subtypes, PPARα and PPARγ. Both subtypes do not bind alone to the DNA promoter but must first dimerize with RXR. This heterodimer, composed of either PPARα and RXR or PPARγ and RXR then binds to a specific DNA sequence in the promoter, the peroxisome proliferator responsive element. The endogenous ligands for PPARα and PPARγ are not known but are thought to be long chain fatty acids and/or their metabolites (Keller, 1993). PPARα and PPARγ control the expression of genes involved in fatty acid and energy utilisation.
PPAR activators according to the present invention are activators of PPARα and PPARγ. A number of PPAR activators are known in the art including the fibrate and thiazolidinedione classes of drugs, for which fenofibrate and rosiglitazone, respectively, are well known examples. Activators of PPARα and PPARγ have overlapping as well as distinct pharmacological effects. In humans as well as in animal models, activation of PPARα with a fibrate, such as fenofibrate, or PPARγ with rosiglitazone leads to comparable lowering of serum triglycerides. Both PPARα and PPARγ are expressed in muscle, while PPARα is preferentially expressed in hepatocytes and PPARγ in adipocytes. Fibrates mainly activate PPARα but bezafibrate has been shown to activate both PPARα and PPARγ. Similarly, rosiglitazone, an activator of PPARγ can also modify the expression of genes normally controlled by PPARα.
Preferred PPAR activators according to the present invention are agonists of PPARα activity. It is particularly preferred to use fibrates, such as fenofibrate. A further example of a member of the fibrate family is given in U.S. Pat. No. 6,028,109.
Benzoquinones
Benzoquinones for use in the present invention are a benzoquinone of formula I:
in which:
R1, R2 and R3 independently are
an alkyl group having 1 to 8 carbon atoms, or
an alcoxy group having 1 to 8 carbon atoms;
R4 is:
an hydrogen atom,
an hydrocarbyl group having 1 to 60 carbon atoms,
a OR5 radical,
an SR6 radical,
a N(R7)(R8) radical,
a nitro group, or
a carboxyl group; or
R5, R6, R7 and R8 being independently:
a hydrogen atom,
an alkyl group having 1 to 20 carbon atoms;
or a precursor thereof capable of being metabolized in the human or animal body to said benzoquinone;
or a pharmaceutically acceptable salt thereof.
In the description and the claims, the term “hydrocarbyl” is understood as meaning an organic group comprising at least C and H. If the hydrocarbyl group comprises more than one C, then those carbon atoms may be linked to each other directly by a single, double or triple bond, or indirectly by the intermediary of a suitable element or hetero atoms such as for example oxygen, sulfur or nitrogen atoms or a suitable group such as a carbonyl group.
The hydrocarbyl group may optionally comprise one or more suitable substituants. Examples of such substituants may include a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alcoxy group having 1 to 8 carbon atoms, a nitro group, a bis alkyl group having 1 to 16 carbon atoms, a cyclic group having 1 to 16 carbon atoms, etc.
The hydrocarbyl group may be any one of an alkyl group, an alcoxy group, a polyalcoxy group, an aryl group, an acyl group, an alkenyl group, a polyalkenyl group, including combinations thereof (e.g. an arylalkyl group), which group may optionally contain one or more hetero atoms or one or more substituants on the chain or rings, as defined above.
The hydrocarbyl group is preferably a hydrocarbon group. Here the term “hydrocarbon” means any one of an alkyl group, an alkenyl group, an alkynyl group, which groups may be linear, branched or cyclic, or an aryl group, or combinations thereof (e.g. an arylalkyl group). The term hydrocarbon also includes those groups but wherein they have been optionally substituted. If the hydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
In one preferred embodiment of the invention R1, R2 and R3 are each independently a lower alkyl group or a lower alkoxy group. The term “lower alkyl group” means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and octyl groups. Among them, methyl, ethyl, propyl, isopropyl groups, etc., are preferable.
The term “lower alkoxy group” means a lower alkoxy group derived from the above-described lower alkyl group, such as methoxy, ethoxy and n-propoxy groups. Among them, a methoxy group is most preferred.
Preferably, R4 is an alkenyl group or a polyalkenyl group, i.e. a group having one or more double bonds in any portion of an alkyl group. R4 may comprise from 1 to 12, such as 6 to 11, preferably 9 or 10 repeats of an isoprenoid unit, such as 3-methyl-2-butene-1,4 diyl unit.
Preferably, R5, R6, R7 and R8 may each independently be H or C1 to C4 alkyl.
Compounds of the present invention may contain one or more asymmetric carbon atoms and/or one or more non-aromatic carbon-carbon double bonds and may therefore exist in two or more stereoisomeric forms. Thus, the present invention also provides individual stereoisomers of the compounds of the formula (I), as well as mixtures thereof, including compositions comprising the same.
Separation or diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or HPLC of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by HPLC of a racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of a racemate with a suitable optically active acid or base.
Benzoquinones for use in the therapeutic methods of the present invention should have antioxidant properties, such as the ability to scavenge active oxygen species. In addition, benzoquinones for use in the therapeutic methods of the present invention will clearly need to be physiologically acceptable upon administration and not cause excessive side effects. For example, they should not be unduly toxic to patients. The toxicity of benzoquinones may be determined using a variety of methods known in the art including in vitro whole cell assays and LD50 animal tests.
U.S. Pat. No. 5,229,385, for example, describes a range of benzoquinone derivatives having antioxidant properties which may be used therapeutically. EP-A-419905 also describes a number of benzoquinone derivatives suitable for therapeutic use.
It will be appreciated by the skilled person that since the benzoquinone coenzyme Q10 is synthesised in vivo from precursor molecules, it may be possible to administer a benzoquinone according to the present invention by means of a precursor that is capable of being converted to a benzoquinone by the same biosynthetic pathways that produce coenzyme Q10. Typically, a precursor will be an immediate precursor, that is to say a molecule structurally related to the benzoquinone and that needs to undergo only a small number of steps in the biosynthetic pathway before it is converted to a benzoquinone of formula I. It is generally preferred to administer precursors that are processed by parts of the coenzyme Q10 biosynthetic pathway which are unique to coenzyme Q. For example, chorismate is converted in the body to p-aminobutyric acid, p-hydroxybenzoic acid, prephenate (which leads to phenylalanine and tyrosine) and is therefore not an immediate precursor since it supplies several pathways. By contrast, p-hydroxybenzoic acid is used only in the synthesis of ubiquinones and may be considered to be an immediate precursor.
The skilled person will appreciate that the reason for preferring immediate precursors is to avoid effects on other biosythetic pathways which may have a deleterious effect on the patient.
The skilled person will also appreciate that the benzoquinones according to the present invention are reduced in the human or animal body to a benzoquinol. Consequently, since it may be possible to administer benzoquinones in their reduced or oxidised state, references to benzoquinones throughout mean both the quinone and reduced quinol forms.
It is particularly preferred to use coenzyme Q, a naturally occurring agent which acts as an electron carrier in the mitochondrial electron transfer in the respiratory chain and which possesses several other functions. CoQ is synthesised from condensation of a benzoquinone ring and a hydrophobic side chain varying in size between species with elongation through a trans-prenyl transferase with multiple repeats of isopentenyl diphosphate units. In humans the side chain is composed of ten such repeats, that is the origin of its designation as CoQ10.
In vivo the oxidized CoQ10 is converted to reduced CoQ10H2 or ubiquinol-10, a potent antioxidant in plasma, in lipoproteins and in tissues. It scavenges in plasma free radicals produced by lipid peroxidation. CoQ10 treatment has been previously demonstrated to be safe at doses up to 300 mg daily for the patient and in many countries different presentations are available over the counter. From previous evidence and as confirmed herein, CoQ10 plasma levels increase 3 to 4 fold after administration of 200 mg daily.
Administration
The amount of PPAR activator and benzoquinone or precursor thereof which is required to achieve the desired biological effect will, of course, depend on a number of factors, for example, the mode of administration and the precise clinical condition of the recipient. The following routes of administration and dosages described are intended only as a guide since a skilled practitioner will be able to determine readily the optimum route of administration and dosage for any particular patient and condition.
In general, the daily dose of each component will be in the range of 0.1 mg-100 mg/kg, typically 0.1-20 mg/kg. An intravenous dose may, for example, be in the range of 0.01 mg to 0.1 g/kg, typically 0.01 mg to 10 mg/kg, which may conveniently be administered as an infusion of from 0.1 μg to 1 mg, per minute. Infusion fluids suitable for this purpose may contain, for example, from 0.01 μg to 0.1 mg, per milliliter. Unit doses may contain, for example, from 0.1 μg to 1 g of each component. Thus ampoules for injection may contain, for example, from 0.1 μg to 0.1 g and orally administrable unit dose formulations, such as tablets or capsules, may contain, for example, from 0.1 mg to 1 g.
Preferably, the PPAR activator, particularly fenofibrate, is administered in an amount from about 50 to 450 mg daily and the benzoquinone or precursor thereof is administered in an amount from about 10 to 400 mg daily.
The PPAR activator and benzoquinone or precursor thereof may be administered as the compounds per se, but are preferably presented with an acceptable carrier or diluent in the form of a pharmaceutical composition. The carrier or diluent may be a solid or a liquid, or both, and is preferably formulated with the activator and benzoquinone as a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the active component.
The formulations include those suitable for oral, rectal, topical, buccal (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration.
Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges or tablets, each containing a predetermined amount of a PPAR activator and/or benzoquinone; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
In general, the formulations are prepared by uniformly and intimately admixing the active PPAR activator and/or benzoquinone with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or moulding a powder or granules of the PPAR activator and/or benzoquinone optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Moulded tablets may be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.
Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a PPAR activator and/or benzoquinone in a flavoured base, usually sucrose and acacia or tragacanth, and pastilles comprising the activator in an inert base such as gelatin and glycerin or sucrose and acacia.
Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of a PPAR activator and/or benzoquinone, preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the activator with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of the activator and 0.1 to 5% w/w of the benzoquinone.
Formulations suitable for rectal administration are preferably presented as unit-dose suppositories. These may be prepared by admixing a PPAR activator and/or benzoquinone with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The PPAR activator and/or benzoquinone are generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.
Preferably, the PPAR activator, such as fenofibrate is co-micronised with a solid surfactant (for example as described in AU-A-614577). A particularly preferred solid surfactant is sodium lauryl sulphate. Typically, the solid surfactant is used in an amount of from 1 to 4%.
The PPAR activator and benzoquinone may be administered separately, sequentially or simultaneously (such as when administered as a composition comprising both the PPAR activator and a benzoquinone).
In addition, it may also be desirable to administer, in addition to the PPAR activator and/or benzoquinone according to the present invention, further components, such as pharmaceutically active compounds that improve vascular condition. As specific examples, it may be desirable to administer aspirin, an antiotensin converting enzyme inhibitor and/oror a calcium channel blocker to the patients before or during treatment with the PPAR activator and benzoquinone.
Therapeutic Uses
The mechanism of the improvement of vascular function with the combination of a PPAR activator such as fenofibrate and a benzoquinone such as CoQ10 is likely to be due to a direct effect on the vascular wall, independent to a large extent from the lipid lowering effects of the PPAR activator. This synergy could be explained at least in part by either an interaction with the formation, diffusion or action of endogenous NO or endothelium-derived hyperpolarizing factor remains possible. This is supported by the findings with acetylcholine (Ach), sodium nitroprusside (SNP) and the co-infusion of ACh+NG-monomethyl-L-arginine (L-NMMA) in the setting of aspirin therapy. Pretreatment with aspirin also simulates best clinical practice of preventive medicine, given that aspirin has been shown to diminish cardiovascular events in patients with and without diabetes.
The improvement of endothelial dysfunction provided by the combination of a PPAR activator such as fenofibrate and a benzoquinone such as CoQ10 constitutes a new therapeutic approach which is easy to implement.
Beyond the synergy demonstrated herein with a combination of fenofibrate and coenzyme Q10, similar effects could be obtained with a combination of other benzoquinone antioxidants (or their precursors) and other fibrates or PPAR activators which share with fenofibrate an effect on the expression of multiple genes involved in atherosclerosis, lipid metabolism and regulation of vascular wall function.
Thus, a combination of a PPAR activator and a benzoquinone may be used to treat or prevent disorders characterised by endothelial dysfunction, or an increased risk of endothelial dysfunctions. Examples of such disorders include cardiovascular events, cardiovascular disease, hypertension, stroke, myocardial infarction, peripheral vascular disease, angina pectoris, cardiac failure, diastolic and/or systolic ventricular dysfunction, macro and microangiopathy in patients with diabetes, and tissue damage related to ischemia and reperfusion. In particular, a combination of a PPAR activator and a benzoquinone may be used to treat patients with type 2 diabetes.
More specifically, the physiological effects associated with the administration of a combination of a PPAR activator and a benzoquinone may result in one or more of the following: improved vessel tone, reduced blood clotting, reduced platelet aggregation, reduced blood pressure and increased blood flow to the heart, reduced smooth muscle cell proliferation and inhibition of leucocyte chemotaxis.
Accordingly the present invention also provides a method of improving vessel tone, reducing blood clotting, reducing platelet aggregation, reducing blood pressure and increasing blood flow to the heart, reducing smooth muscle cell proliferation, and/or inhibiting leucocyte chemotaxis in a patient which method comprises administering to said patient an effective amount of a PPAR activator and a benzoquinone.
Vessel tone, platelet aggregation, blood pressure and blood flow, smooth cell proliferation and leucocyte chemotaxis may be measured using standard techniques prior to and during treatment to determine whether the PPAR activator and a benzoquinone are achieving the desired effect (see for example Furchgott, 1980; Garg, 1989; Radomski, 1987 and Moncada, 1991).
The present invention will now be described further by way of examples which are intended to be illustrative only and non-limiting.
EXAMPLES
Introduction
We have tested a combination of a peroxisome proliferator activated receptor (PPAR) activator, namely fenofibrate, and coenzyme Q10 for the treatment of vascular dysfunction in a randomized clinical trial involving patients with type 2 diabetes.
The results obtained demonstrate for the first time a synergism between a lipid lowering agent (the PPAR activator) and a radical scavenger in reducing vascular dysfunction. This synergistic effect was considered to be both statistically significant and clinically relevant. Support for the clinical relevance of these finding is also provided by studies showing an association between endothelium dysfunction in peripheral arteries and endothelium dysfunction in the coronary arteries (Anderson, 1995; Sax, 1987) as well as longitudinal data showing that endothelial dysfunction predicts future coronary events (Suwaidi, 2000; Schachinger, 2000). Compared with treatment with fenofibrate alone, the combination of fenofibrate with Coenzyme Q improves endothelial dysfunction and potentially reduces the progression of macro- and microvascular disease in type 2 diabetes. We would anticipate this to result in improvements with respect to coronary heart disease, peripheral vascular disease, ischemic stroke, renal disease and retinopathy in diabetes patients and by extension, to subjects with insulin resistance, hypertension and obesity.
Study Design and Methods:
Eighty dyslipidaemic patients with well controlled type 2 diabetes were randomised double-blind in a 2×2 factorial study to receive fenofibrate (F), CoQ10 (Q), fenofibrate and CoQ10 (FQ), or placebo (P) for 12 weeks. Male or female patients aged less than 70 years and without severe obesity (Body Mass Index below 35 kg/m2) were included after a 6 week run-in period if they had Haemoglobin A1c below 9%, total cholesterol below 6.5 mmol/l and either triglyceride above 1.8 mmol/l or HDL cholesterol below 1 mmol/l. The two therapeutic agents alone or in combination were given each as 200 mg once daily. Capsules identical in appearance to each agent but containing placebo were given to maintain the double-blind nature of the study.
Evaluations of vascular function were carried out by bilateral venous occlusion plethysmography at weeks 0 and 12. These consisted of serial measurements of forearm blood flow before and after intra-brachial artery infusion of acetylcholine (ACh 7.5, 15 and 30 μg/min), sodium nitroprusside (SNP 1.5, 3 and 10 μg/min) and NG-monomethyl-L-arginine (L-NMMA 4 μmol/l). These tests were performed after discontinuation of agents that might have changed vascular function such as ACE inhibitors and calcium channel blockers. Pretreatment with acetylsalicylic acid (aspirin) (650 mg daily taken orally) was given for one week to block prostacyclin and thromboxane generation.
Plethysmography studies were performed during a 5 minute infusion of each agent, diluted in saline and infused at a rate of 1 mL/min into the brachial artery of the non-dominant arm via a thin plastic cannula Each infusion of vasoactive agents was preceded by a period of saline infusion. Bilateral forearm blood flow was measured simultaneously at 15 second intervals for the final two minutes of each 5 minute infusion period employing mercury-in-silastic strain gauges. During measurements hands were excluded from the circulation by inflation of wrist cuffs to 200 mmHg and venous occlusion was obtained by cyclical inflation of upper arm cuffs to 40 mmHg. Results were expressed as the area under the curve (AUC) of the percent increase in forearm blood flow ratio (infused arm versus control arm) to account for any systemic effect of these vasoactive drugs. The AUC provided integration over time of the dose response to the agent used. AUC for percent change in blood flow to ACh was a priori described as the primary efficacy criterion in this trial.
Statistical analyses were performed using 2 by 2 analysis of variance using SPSS package
Results:
Out of the 80 patients randomised, 77 completed the 12 week treatment period and paired blood flow data were available in 67; Three withdrawals occurred because of incidental medical conditions and one allergy to fenofibrate. 10 patients refused a second cannulation or could not be cannulated satisfactorily. The four groups were well matched in terms of baseline characteristics as shown on Table 1. Only 8 patients were on oral hypoglycaemic agents, none were on insulin. They presented with good diabetic control and with the typical characteristics of diabetic dyslipidemia.
TABLE 1
Patient characteristics: mean or distribution
PP
PQ
PF
FQ
group
group
group
group
Gender (M/F)
14 M/5 F
18 M/2 F
14 M/5 F
14 M/5 F
Age (years)
55
53
54
52
BMI (kg/m2)
31.0
29.9
30.0
30.6
BP (mm Hg)
137/78
128/76
131/74
132/77
HbA1c (%)
6.3
6.9
7.1
7.5
TC (mmol/l)
5.36
5.29
5.54
5.25
TG (mmol/l)
2.44
2.19
2.61
2.98
HDL-C (mmol/l)
1.02
0.95
0.95
0.93
Key: P = Placebo; F = Fenofibrate; Q = CoQ10
BMI = body mass index; HbA1c = glycosylated hemoglobin A1c
TC = total cholesterol; TG = Triglyceride;
HDL-C = high density lipoprotein cholesterol
Table 2 shows the main study results where changes in treatment are presented in a 2×2 table consistent with the factorial study design.
TABLE 2
mean changes and their 95% confidence interval on treatment
(Week 12-Week 0) in acetylcholine AUC percent increase in forearm
blood flow ratio
P
Q
F− v F+ [95% CI]
P
−23% [−143% to
−7% [−119%
−15% [−97% to 66%]
95%]
to 105%]
F
131% [8% to 253%]
419% [287% to
275% [185% to
550%]
365%]
Q− v Q+
53% [−31% to
206% [119% to
138%]
192% ]
Key: P = Placebo; F = Fenofibrate; Q = CoQ10
Analysis of variance Interaction p = 0.029, F effect p = 0.0001, Q effect p = 0.015
The combined effect of fenofibrate and CoQ10 treatment led to a 419% increase in forearm blood flow ratio, fenofibrate alone to a 131% increase while there was no change with CoQ10 alone or placebo. Thus, there was a clear synergism between fenofibrate and CoQ10 as evidenced by a significant interaction effect (p=0.029). Changes versus baseline were significant for the fenofibrate alone and the fenofibrate +CoQ10 groups but when the 4 groups were compared with each other only the combination treatment was significantly different from the 3 other groups (see FIG. 1)
When the vasodilatory response to ACh was reduced by co-infusion of L-NMMA similar results with a synergism between fenofibrate and coenzyme Q10 were observed (see Table 3).
TABLE 3
mean changes and their 95% confidence interval on treatment
(Week 12-Week 0) in acetylcholine percent increase in forearm blood
flow ratio with co-infusion of L-NMMA
P
Q
F− v F+ [95% CI]
P
58%[−2% to 118%]
−21% [−76% to
18% [−22% to 59% ]
33%]
F
47%[−10% to 47%]
118% [53% to
83% [39% to 126%]
183%]
Q− v Q+
53% [11% to 94%]
48% [6% to 90%]
Key: P = Placebo; F = Fenofibrate; Q = CoQ10
Analysis of variance Interaction p = 0.015, F effect p = 0.034, Q effect p = 0.884
TABLE 4
Mean changes and their 95% confidence interval on treatment
(Week 12-week 0) in sodium nitroprusside AUC percent increase in
forearm blood flow ratio (see Figure 2)
P
Q
F− v F+ [95% CI]
P
−240%[−632% to
50% [−641% to
−95%[−503%
152%]
740%]
to 313%]
F
−11%[−521% to
1594%[728% to
792% [352% to
500%]
2461%]
1232%]
Q− v
−126% [−841% to
822% [399% to
Q+
361%]
1245%]
Key: P = Placebo; F = Fenofibrate; Q = CoQ10
Analysis of variance Interaction p = 0.032, F effect p = 0.004, Q effect p = 0.002
These improvements in vascular endothelium function were not explained by any interaction between fenofibrate and CoQ10 on the lipid modifying properties of fenofibrate; an increase in HDL-cholesterol, a decrease in total cholesterol, LDL-cholesterol, triglyceride or fibrinogen. Furthermore plasma levels of CoQ10 after treatment did not differ between the CoQ10 alone and the combination groups. There was no change in diabetes control or blood pressure measurements with the combination of fenofibrate and CoQ10. CoQ10 alone had no lipid lowering effects.
All publications mentioned in the above specification are herein incorporated by reference.
Various modifications and variations of the described methods and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are apparent to those skilled in molecular biology or related fields are intended to be within the scope of the invention.
REFERENCES
ANDERSON T J, UEHATA A, GERHARD M D, et al. Close relationship of endothelial function in the human coronary and peripheral circulation. J Am Coll Cardiol 1995;26:1235-41.
COHEN R A. Dysfunction of vascular endothelium in diabetes mellitus. Circulation 1993;97(Suppl V):V67-V76.
ISSEMANN I, GREEN S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990;347:645-50.
FURCHGOTT R F, ZAWADZKI J V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980: 299:373-376.
GARG U C, HASSID A. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989: 83:1774-1777.
KELLER H., DREYER C., MEDIN J., MAHFOUDI A., OZATO K., WAHLI W. Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc. Natl. Acad. Sci. 1993; USA 90:2160-64.
MONCADA S, PALMER R M, HIGGS E A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev 1991: 43:109-142.
RADOMSKI M W, PALMER R M, MONCADA S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 1987: 2:1057:1058.
RUBANYI G M. The role of endothelium in cardiovascular homeostasis and diseases. J Cardiol Pharmacol 1993;22(suppl 4):51-514.
SAX F L, CANNON R O III, HANSON C, EPSTEIN S E. Impaired forearm vasodilator reseve in patients with microvascular angina. Evidence of a generalized disorder of vascular function? N Engl J Med 1987;317:1366-70.
SCHACHINGER V, BRITTEN M B, ZEIHER A M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000;101:1899-1906.
SUWAIDI J S, HAMASAKI S, HIGANO S T, et al. Long term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000;101:948-54.
WATTS G F, PLAYFORD D A. Dyslipoproteinemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis Atherosclerosis 1998;141:17-30.
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10399639
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fournier laboratories ireland limited
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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514/342
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Mar 31st, 2022 02:21PM
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Mar 31st, 2022 02:21PM
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AbbVie
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:abbv
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AbbVie
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May 11th, 2010 12:00AM
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Apr 28th, 2008 12:00AM
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https://www.uspto.gov?id=US07714163-20100511
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Process for preparing quaternary acid and ammonium salts
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A process for preparing a quaternary ammonium salt of a fibric acid, represented by the following reaction scheme:
is carried out in a single operation starting from a phenol of formula (I), an α-halogenated ester of formula (II) and a quaternary ammonium hydroxide of formula (III). This process makes it possible economically to prepare a choline salt of fenofibric acid in high purity that can be used directly as the active substance in a pharmaceutical composition intended for human consumption.
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7714163
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1. A process for preparing a quaternary ammonium salt of a fibric acid corresponding to formula IV:
wherein:
R1 is a chlorine atom, a 2-(4-chlorobenzoylamino)ethyl group, a 4-chlorobenzoyl group or a 2,2-dichlorocyclopropyl group,
R2 is a linear or branched C1-C4 alkyl group or a linear or branched C1-C4 hydroxyalkyl group, and
R is a linear C1-C3 alkyl group;
said process being represented by the following reaction scheme:
and
said process being carried out as a one-pot reaction in a continuous procedure without any isolation of intermediates starting from:
a phenol of formula (I), in which R1 is as defined above,
an α-halogenated ester of formula (II), in which X is a halogen and Ra is a linear or branched C1-C6 alkyl group, and
a quaternary ammonium hydroxide of formula (III), in which R and R2 are as defined above.
2. A process according to claim 1, wherein, in the compound of formula (I) given above, R1 is a 4-chlorobenzoyl group located in the para position relative to the oxygen.
3. A process according to claim 1, wherein, in the compound of formula (III) given above, R is a methyl group and R2 is a 2-hydroxyethyl group.
4. A process according to claim 1, wherein, in the compound of formula (II) given above, X is a bromine atom.
5. A process according to claim 1, wherein said process comprises:
reacting a phenol of formula (I) with an α-halogenated ester of formula (II), in the presence of a base, at a temperature between 80 and 160° C., for a period of 1 to 8 hours; then
reacting a quaternary ammonium hydroxide of formula (III) with the resulting reaction medium, in the presence of a solvent, at a temperature between 80 and 120° C., for a period of 1 to 5 hours; and
separating the resulting salt of formula (IV).
6. A process according to claim 5, wherein the α-halogenated ester of formula (II) is used in excess relative to stoichiometric conditions.
7. A process according to claim 5, wherein insoluble mineral compounds are removed from the reaction medium prior to reaction with the quaternary ammonium hydroxide of formula (III).
8. A process according to claim 5, wherein said solvent is a linear or branched propanol.
9. A process according to claim 5, wherein said process comprises:
reacting a phenol of formula (I) with a stoichiometrically at least equivalent amount of an ester of formula (II) at a temperature between 80 and 160° C., in the presence of a mineral base, for a period of 1 to 8 hours,
adding a solvent to the reaction medium,
carrying out a hot filtration to remove insoluble mineral compounds,
reacting the resulting solution with a quaternary ammonium hydroxide of formula (III) at a temperature between 80 and 120° C. for 1 to 5 hours, and
filtering the mixture hot and subsequently cooling it under conditions that allow the expected salt to crystallize, after which the crystals are filtered out and dried to give the expected salt with a purity of at least 99.5%.
10. A process according to claim 9, wherein the added solvent is an alcohol.
11. A process according to claim 10, wherein the alcohol is a linear or branched propanol.
12. A process according to claim 9, wherein said mineral base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and calcium carbonate.
13. A process according to claim 1, wherein R1 is located in the para position relative to the oxygen bonded to the aryl ring.
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13
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of international patent application no. PCT/FR2006/051118, filed Oct. 27, 2006 designating the United States of America, and published in French on May 3, 2007 as WO 2007/048986, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on French patent application no. FR 0 511 103, filed Oct. 28, 2005.
BACKGROUND OF THE INVENTION
The invention relates to a novel process for the synthesis of a salt of an organic acid and a base, especially a salt of an acid of the fibrate family and a base of the quaternary ammonium type, and more particularly the salt of fenofibric acid and choline.
PRIOR ART
Fenofibrate
is a known active substance for treating hypertriglyceridemia and hyper-cholesterolemia. This compound is an isopropyl ester, but in a biological medium the ester is rapidly hydrolyzed to give fenofibric acid, which is the active metabolite of fenofibrate.
It has recently been proposed (US 2005/0148594) to treat these diseases using a galenical formulation containing fenofibric acid itself as the active substance, and particularly preferably using a salt of fenofibric acid and an organic base, especially choline. The preparation of the choline salt is described in Examples 17A and 17B of the document cited above, and consists in using fenofibric acid as the starting compound and salifying it with choline hydroxide, which is used in the form of a solution in methanol.
The currently most economic process for the preparation of fenofibric acid consists in hydrolyzing fenofibrate, which is a commercial product and can be manufactured e.g. by reacting 4-chloro-4′-hydroxybenzophenone with isopropyl 2-bromo-2-methylpropanoate (EP0245156B1).
Preparations of choline salts are also described in the literature. For example, U.S. Pat. No. 3,897,485 describes the preparation of a salt with a dialkylacetic acid by combining the choline base with the acid. Likewise, published PCT application no. WO 96/16016 describes the preparation of a salt of ketoprofen and choline and European patent application no. EP 521,393 describes the preparation of a salt of diclofenac and choline, the processes recommended in these documents again using the acid as the starting material.
SUMMARY OF THE INVENTION
The present invention relates to a novel economic process for the preparation of a quaternary ammonium salt of a fibric acid of formula (IV), as defined below, which is capable of yielding, in a single operation, a product of high purity that is compatible with use in human therapeutics.
This process consists essentially in reacting an α-halogenated ester of 2-methylpropanoic acid (II) with a substituted phenol (I) and then, without isolating the intermediate formed, with a base of the quaternary ammonium type (III), and can be represented by the following reaction scheme:
in which:
R1 is a chlorine atom, a 2-(4-chlorobenzoylamino)ethyl group, a 4-chlorobenzoyl group or a 2,2-dichlorocyclopropyl group and is preferably located in the para-position relative to the OH group,
X is a halogen, preferably a bromine atom,
Ra is a linear or branched C1-C6 alkyl group,
R2 is a linear or branched C1-C4 alkyl group or a linear or branched C1-C4 hydroxyalkyl group, and
R is a linear C1-C3 alkyl group.
Thus the originality of the process according to the present invention consists in reacting a fibric acid precursor with a quaternary ammonium hydroxide in a single operation, i.e. without isolating the intermediate formed. Totally unexpectedly, a quaternary ammonium salt of fibrin acid is thus obtained directly with a very high purity in excess of 99.5% and can be used, without further purification, as the active substance of a drug for use in humans.
This process is particularly valuable for the preparation of a quaternary ammonium salt of fenofibric acid, especially a salt of fenofibric acid and choline.
In fact, in this case, in contrast to the currently known preparative processes, it is not necessary to use as the starting material a fenofibric acid originating from the hydrolysis of fenofibrate. The resulting process is consequently simpler to carry out and more economic.
In general, the process according to the present invention makes it possible in particular to prepare a quaternary ammonium salt of a fibric acid of the formula
in which Ar is a phenyl group substituted in the para position by a chlorine atom (in which case it is clofibric acid), a 4-chlorobenzoyl group (in which case it is fenofibric acid), a 2-(4-chlorobenzoylamino)ethyl group (in which case it is bezafibrate) or a 2,2-dichlorocyclopropyl group (in which case it is ciprofibrate).
Within the scope of the present patent application, linear or branched C1-C6 alkyl group is understood as meaning a linear or branched, saturated hydrocarbon chain containing 1 to 6 carbon atoms, selected e.g. from methyl, ethyl, propyl, butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl and hexyl groups.
C1-C4 hydroxyalkyl group is understood as meaning an alkyl chain containing 1 to 4 carbon atoms, such as defined above, and carrying at least one OH group bonded directly to any one of the carbon atoms.
In general, the chemical reactions involved in carrying out the process according to the invention can be performed either in the presence of a solvent, or in the absence of a solvent, or, advantageously, in the presence of a solvent for the second reaction. In fact, the final step of the process must advantageously be performed in the presence of a solvent, preferably in the presence of an alcohol, to give a compound of high purity.
In one preferred embodiment of the invention, a single solvent will be used for the final reaction and the purification of the salt produced. In particular, this solvent is a linear or branched propanol. Under these conditions the purity of the salt obtained is greater than 99.5% when assayed by HPLC (high performance liquid chromatography) for the acid content and by potentiometry for the quaternary ammonium content.
According to one particular characteristic, the process according to the invention comprises:
reacting a phenol of formula (I) with an α-halogenated ester of formula (II), advantageously used in excess relative to stoichiometric conditions, in the presence of a base, at a temperature between 80 and 160° C., for a period of 1 to 8 hours; then
reacting a quaternary ammonium hydroxide of formula (III) with the resulting reaction medium, in the presence of a solvent, preferably after removal of the insoluble mineral compounds, at a temperature between 80 and 120° C., for a period of 1 to 5 hours; and
separating out the resulting salt of formula (IV) which forms.
Advantageously, the above-mentioned solvent is a linear or branched propanol (n-propanol or isopropanol).
The process according to the present invention makes it possible in particular to prepare a quaternary ammonium salt of fenofibric acid by using the compound of formula (I) in which R1 is a 4-chlorobenzoyl group in the 4-position relative to the hydroxyl group, a compound of formula (II) in which Ra is a linear or branched C1-C3 alkyl group and the compound of formula (III) in which R is a methyl group and R2 is a 2-hydroxyethyl group.
One preferred embodiment of the invention comprises reacting 4-chloro-4′-hydroxybenzophenone with ethyl or (iso)propyl 2-bromo-2-methylpropanoate and then adding choline hydroxide to give the choline salt of fenofibric acid directly, i.e. without isolation of the intermediate formed, in a one-pot operation.
In one general embodiment of the process according to the invention, the first step is to prepare a mixture of the phenol of formula I, as defined above, with a stoichiometrically at least equivalent amount of the ester of formula II in which X is a halogen, preferably a bromine atom, and Ra is a linear or branched C1-C6 alkyl group. As the ester of formula II is a liquid at room temperature, it is not generally necessary to use a solvent at this stage of the process. However, if the reactor used does not allow sufficient agitation, it is entirely possible to carry out the reaction in the presence of a solvent such as an alcohol or a ketone, without these two examples implying a limitation. It will nevertheless be preferable in this case to use a solvent whose boiling point is at least 80° C. at atmospheric pressure.
The mixture of starting reactants is then heated to a temperature between 80 and 160° C. and a mineral base is added gradually, preferably in a substantially equimolar amount relative to the compound of formula I. This base is e.g. sodium or potassium carbonate or bicarbonate or calcium carbonate. This base can be added in the form of powder or pellets, said products generally being solid, but it can also be added in the form of a highly concentrated solution or a suspension in water. The rate of addition is conventionally fairly rapid and is limited only by the evolution of the carbon dioxide produced by the reaction.
The reaction time is between 1 hour and 8 hours, during which the water introduced or formed by the reaction is preferably removed by distillation.
According to one particular characteristic, a solvent for the organic compounds contained in the medium is then added and a hot filtration is advantageously carried out to remove the insoluble mineral compounds. This solvent is e.g. an alcohol, preferably a linear or branched propanol.
The solution, kept at the same temperature, is then brought into contact with the compound of formula III, in which R2 is a linear or branched C1-C4 alkyl group or a linear or branched C1-C4 hydroxyalkyl group and R is a linear C1-C3 alkyl group. This compound can be introduced pure or in solution in an appropriate solvent such as, preferably, water or an alcohol.
The reaction mixture is agitated at a temperature between 80 and 120° C. for 1 to 5 hours.
If the compound of formula III has been introduced in the form of an aqueous solution, the water is then removed by azeotropic distillation.
The final mixture, in the form of a solution, is then filtered hot and subsequently cooled under conditions that allow the expected salt to crystallize, after which the crystals are filtered off on a filter or aspirator and dried.
If this process according to the invention is followed, the expected salt is generally obtained with a purity consistent with direct use in pharmaceutical compositions intended for human consumption, i.e. a purity of at least 99.5%.
The invention further relates to the salt with a purity in excess of 99.5% that is obtained by the process of the invention, and to its use in therapeutics for the manufacture of drugs for human medicine. These drugs are preferably formulated for oral absorption, e.g. in the form of capsules or tablets. These dry galenical preparations, in the form of lozenges, ordinary or film-coated tablets, or capsules, are obtained by methods known to those skilled in the art, for example by mixing the salt with excipients to give e.g. granules, which can be compressed or introduced into capsules. In one preferred embodiment of the invention, the pure salt is a quaternary ammonium salt of fenofibric acid present in an amount of between 40 and 180 mg per dosage unit. Preferably, the quaternary ammonium compound which forms the salt with fenofibric acid is choline.
The present invention will be understood more clearly from the description of the following embodiments, which are presented here in order to illustrate the invention and must not be considered as implying a limitation.
EXAMPLE I
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic Acid Choline Salt
A mixture of 1108 g (5.28 mol) of isopropyl 2-bromo-2-methylpropanoate and 650 g (2.79 mol) of (4-chlorophenyl)(4-hydroxyphenyl)methanone is heated at 145° C. under a nitrogen atmosphere, with thorough stirring, in a 5 l reactor equipped for operation under reflux or distillation. 448 g (3.24 mol) of potassium carbonate are then added and the temperature of the reaction medium is raised to 155° C. The reaction mixture is stirred at this temperature for 4 hours. During this period the aqueous phase produced is collected in the distillate. The temperature of the reaction medium is reduced to 145° C. and the internal pressure of the reactor is lowered gradually so as to remove the excess brominated reactant by distillation. These conditions are maintained for about 2 hours, during which time all the distillates are collected in a receiver. The temperature of the mixture is then reduced to 120° C. and, with the reactor at atmospheric pressure, 1.95 l of propanol are added. The mixture is then at a temperature of about 80-90° C. and is filtered under nitrogen pressure. The residual solid is rinsed on the filter with about 0.75 l of hot propanol. The filtrates, maintained at the same temperature, are combined in the 5 l reactor and 790 g (2.93 mol) of a 45% aqueous solution of choline hydroxide are added gradually, followed by 0.80 l of propanol. The reaction mixture is then brought to the boil at atmospheric pressure and the distillate produced is collected until about 1.60 l of a propanol/water/isopropanol mixture have been obtained. The mixture is filtered on a clarifying filter and the filtrate is gradually cooled down to a temperature of about 10° C., with stirring, in order to crystallize the salt. The crystalline salt is separated off and washed with 0.65 l of cold propanol on an aspirator and then dried in an oven under reduced pressure.
This gives 824 g of the expected salt in the form of white crystals (yield=70%).
The purity of the salt obtained is checked by HPLC, the assay being performed by the method described for fenofibrate in the European Pharmacopeia or the US Pharmacopeia. The fenofibric acid can be assayed by chromatography against a reference sample. The choline present in the salt is assayed by potentiometry.
Analysis of the compound shows a purity in excess of 99.5% and the absence of impurities in a proportion greater than 0.1%.
M.p.=213° C.
EXAMPLE II
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic Acid Choline Salt
A mixture of 100 g (0.43 mol) of (4-chlorophenyl)(4-hydroxyphenyl)-methanone and 148 g (0.82 mol) of methyl 2-bromo-2-methylpropanoate is prepared in a 1 l reactor maintained under a nitrogen atmosphere. The mixture is heated to 145° C., with thorough stirring, and 69 g (0.5 mol) of potassium carbonate are added. The reaction medium is maintained at 145° C. for 3 hours, with thorough stirring, during which time the water formed by the reaction is collected in the distillate. The pressure in the reactor is then gradually reduced in order to remove the excess brominated reactant by distillation. The mixture is then cooled to about 100° C. and 300 ml of n-propanol are added. The resulting mixture is stirred for 10 mm at 90° C. and then filtered at this temperature to remove the insoluble mineral salts. The residual solid is rinsed with 100 ml of hot n-propanol, which is combined with the previous filtrates. The solution obtained is placed in the 1 l reactor under a nitrogen atmosphere and 121.5 g (0.45 mol) of a 45% aqueous solution of choline hydroxide are added. The reaction mixture is stirred for 3 hours under gentle reflux of the solvent and about 240 ml of solvent are then distilled, 130 ml of n-propanol being added to the reactor. The reactor contents are subsequently filtered on a clarifying filter and then cooled slowly to about 15° C. The resulting suspension is filtered on an aspirator and the isolated solid is rinsed with 100 ml of cold n-propanol and then dried in a vacuum oven.
This gives 122 g of the expected salt in the form of a white crystalline solid (yield=67.5%).
The purity of the salt obtained is greater than 99.5%.
EXAMPLE III
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic Acid Choline Salt
The reaction is carried out analogously to that described in Example II except that 159 g of ethyl 2-bromo-2-methylpropanoate are used.
This gives 127 g of the expected salt in the form of a white crystalline powder, this being a yield of 70%. The salt has a purity in excess of 99.8%.
The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.
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12110667
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fournier laboratories ireland ltd.
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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562/471
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Mar 31st, 2022 02:21PM
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Mar 31st, 2022 02:21PM
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AbbVie
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:abbv
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AbbVie
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Sep 14th, 2010 12:00AM
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Feb 28th, 2008 12:00AM
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https://www.uspto.gov?id=US07795297-20100914
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Indole compounds, method of preparing them and uses thereof
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Indole compounds corresponding to the formula (I):
as defined in the claims, pharmaceutically acceptable addition salts of such compounds, pharmaceutical compositions containing such compounds, the process for their preparation, and their use as pharmacologically active substances, especially in the treatment of hypertriglyceridemia, hyperlipidemia, hypercholesterolemia, diabetes, endothelial dysfunction, cardiovascular disease, inflammatory disease and neurodegeneration.
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7795297
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1. An indole compound corresponding to formula I:
wherein
Ra and Rb are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, CF3, CN, CO—R2, OR2 and phenyl optionally substituted by C1-C4 alkyl or CF3;
R2 is C1-C4 alkyl, CF3 or phenyl optionally substituted by C1-C4 alkyl or CF3;
R3 and R4 are independently hydrogen or C1-C4 alkyl;
R is hydrogen or C1-C3 alkyl;
n is 1, 2 or 3;
X is a single bond, an oxygen atom or a sulfur atom; and
Ar is an aromatic or heteroaromatic ring selected from the group consisting of phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3,4-dihydro-1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, phenyl, CF3, CN, CO—R2, OR2, SR2, NH—COR2, morpholinyl, amino and 4-morpholinosulfonyl;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein at least one of Ra and Rb is other than hydrogen.
3. A compound according to claim 1, wherein Ar is phenyl or a nitrogen-containing heteroaromatic group.
4. A compound according to claim 1, wherein n is 1 or 2.
5. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier or adjuvant.
6. A process for preparing an indole compound according to claim 1, said process comprising:
a) using the SONOGASHIRA reaction to react a compound of the formula
in which:
Ra and Rb independently are each a hydrogen, fluorine, chlorine or bromine atom or a C1-C6 alkyl, CF3, CN, CO—R2 or OR2 group; and
R2 is a C1-C4 alkyl or CF3 group or a phenyl group optionally substituted by a C1-C4 alkyl or CF3 group,
with an acetylenic derivative of the formula
in which:
n=1, 2 or 3;
R3 and R4 independently are each a hydrogen atom or a C1-C4 alkyl group;
R is a C1-C3 alkyl group; and
X is a single bond, an oxygen atom or a sulfur atom, in the presence of cuprous iodide, a palladium catalyst and an organic base, in a solvent, at a temperature between 0 and 60° C., for 2 to 24 hours, to give the compound of the formula
in which:
Ra, Rb, n, X, R3, R4 and R are as defined in the starting compounds;
b) reducing the “nitro” group carried by the compound of formula IV above, e.g. by reaction with stannous chloride in the presence of ethanol, in a solvent, at a temperature close to room temperature, for 1 to 24 hours, to give the aniline of the formula
in which:
Ra, Rb, n, X, R3, R4 and R are as defined in the starting compound;
c) reacting the compound of formula V with an arylsulfonyl chloride of the formula
Ar—SO2—Cl (VI)
in which:
Ar is an aromatic or heteroaromatic ring selected from phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3,4-dihydro-1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl groups optionally substituted by one or more atoms or groups of atoms selected from halogen atoms and C1-C6 alkyl, phenyl, CF3, CN, CO—R2, OR2, SR2, NH—COR2, morpholinyl, amino and 4-morpholinosulfonyl groups, in the presence of pyridine, at room temperature, for 10 to 120 min, to give the compound of the formula
in which:
Ra, Rb, n, X, R3, R4, R and Ar are as defined in the starting compounds;
d) cyclizing the compound of formula VII by reaction with copper(I) acetate in a solvent at a temperature close to the reflux temperature of the solvent, for 4 to 24 hours, to give the compound of the formula
in which:
Ra, Rb, n, X, R3, R3, R and Ar are as defined in the starting compounds; and
e) if necessary, hydrolyzing the ester group of the compound of formula Ia, and then treating the product with acid to give the compound of formula I in free acid form:
7. A process according to claim 6, wherein said palladium catalyst is tetrakis-(triphenylphosphine)palladium.
8. A process for preparing an indole compound according to claim 1, said process comprising:
a) halogenating an aniline of the formula
in which:
Ra and Rb independently are each a hydrogen atom, a halogen atom or a C1-C6 alkyl, CF3, CN, CO—R2 or OR2 group, and
R2 is a C1-C4 alkyl or CF3 group or a phenyl group optionally substituted by a C1-C4 alkyl or CF3 group,
with the aid of a halogenating agent in a solvent at room temperature, for 5 to 24 hours, to give the compound of the formula
in which:
Ra and Rb are as defined in the starting compounds;
b) reacting the compound of formula IX with an acetylenic derivative of the formula
in which:
n=1, 2 or 3;
R3 and R4 independently are each a hydrogen atom or a C1-C4 alkyl group;
R is a C1-C3 alkyl group; and
X is a single bond, an oxygen atom or a sulfur atom, in the presence of cuprous iodide, a palladium catalyst and an organic base, in a solvent, at a temperature between 0 and 60° C., for 2 to 24 hours, to give the compound of the formula
in which:
Ra, Rb, n, X, R3, R4 and R are as defined in the starting compound;
c) cyclizing the compound of formula V above by reaction with copper(II) acetate in a solvent at a temperature close to the reflux temperature of the solvent, for 4 to 24 hours to give an indole compound of the formula
in which:
Ra, Rb, n, X, R3, R4 and R are as defined in the starting compound;
d) reacting the compound of formula (X) above with an arylsulfonyl chloride of the formula
Ar—SO2—Cl (VI)
in which:
Ar is an aromatic or heteroaromatic ring selected from phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3,4-dihydro-1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl groups optionally substituted by one or more atoms or groups of atoms selected from halogen atoms and C1-C6 alkyl, phenyl, CF3, CN, CO—R2, OR2, SR2, NH—COR2, morpholinyl, amino and 4-morpholinosulfonyl groups,
in a solvent, at room temperature, for 1 to 12 hours, generally after activation of the indole compounds of formula (X) with sodium hydride, to give the compound of formula (Ia):
in which:
Ra, Rb, n, X, R3, R4, R and Ar are as defined in the starting compounds; and
e) if necessary, hydrolyzing the ester group of the compound of formula Ia by reaction with a base and then treating the product with acid to give the compound of formula I in free acid form:
9. A process according to claim 8, wherein in step a) said halogenating agent is benzyltrimethylammonium dichloroiodate, and said solvent is dichloromethane or methanol.
10. A process for preparing a compound according to claim 1, said process comprising:
a) reacting the compound of formula IX:
in which:
Ra and Rb independently are each a hydrogen, fluorine, chlorine or bromine atom or a C1-C6 alkyl, CF3, CN, CO—R2 or OR2 group; and
R2 is a C1-C4 alkyl or CF3 group or a phenyl group optionally substituted by a C1-C4 alkyl or CF3 group,
with an arylsulfonyl chloride of the formula
Ar—SO2—Cl (VI)
in which:
Ar is an aromatic or heteroaromatic ring selected from phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3,4-dihydro-1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl groups optionally substituted by one or more atoms or groups of atoms selected from halogen atoms and C1-C6 alkyl, phenyl, CF3, CN, CO—R2, OR2, SR2, NH—COR2, morpholinyl, amino and 4-morpholinosulfonyl groups,
in a solvent, at room temperature, for 1 to 12 hours, to give the compound of the formula
in which:
Ra, Rb and Ar are as defined in the starting compounds;
b) reacting the compound of formula XI with an acetylenic derivative of the formula
in which:
n=1, 2 or 3;
R3 and R4 independently are each a hydrogen atom or a C1-C4 alkyl group;
R is a C1-C3 alkyl group; and
X is a single bond, an oxygen atom or a sulfur atom, in the presence of cuprous iodide, a palladium catalyst and an organic base, in a solvent, at a temperature between 0 and 60° C., for 2 to 24 hours to give the compound of the formula
in which:
Ra, Rb, n, X, R3, R4, R and Ar are as defined in the starting compounds;
c) cyclizing the compound of formula VII above by reaction with copper(II) acetate in a solvent at a temperature close to the reflux temperature of the solvent, for 4 to 24 hours to give an indole compound of the formula
in which:
Ra, Rb, n, X, R3, R4, R and Ar are as defined in the starting compounds; and
d) if necessary, hydrolyzing the ester group of the compound of formula Ia by reaction with a mineral base and then treating the product with acid to give the compound of formula I in free acid form:
11. A process according to claim 10, wherein steps b) and c) are carried out in a single operation.
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11
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of international patent application no. PCT/FR2006/050818, filed Aug. 29, 2006, designating the United States of America and published in French on Mar. 8, 2007 as WO 2007/026097, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on French Patent application no. FR 0508858, filed Aug. 30, 2005.
SPECIFICATION
The present invention relates to novel indole compounds, to the process for their manufacture and to their use in therapeutics for the prevention or treatment of pathological conditions involving a dysfunction of the PPAR-type nuclear receptors.
PRIOR ART
It is known in therapeutics that diseases of the cardiovascular system are an important risk factor for health. These diseases are frequently the consequence of a high cholesterol and/or triglyceride level, so it is important to keep these levels below values currently accepted by the medical profession.
In the case of cholesterol, it is particularly necessary to evaluate the amounts of cholesterol bound to the different lipoproteins so as to adapt the treatments to eliminate the cholesterol bound to the LDLs. The known families of compounds used to regulate these parameters include statins, which are HMG CoA reductase inhibitors and which make it possible essentially to treat excessively high LDL-cholesterol levels, and compounds of the fibrate family, which act by activating the PPARα (peroxisome proliferator activated receptor alpha) nuclear receptors and make it possible to lower the triglyceride and cholesterol levels.
Study of the PPAR nuclear receptors has led to the identification of 3 subtypes called PPARα, PPARγ and PPARδ. By binding to precise fragments of the DNA, these different receptors regulate the expression of target genes that code for proteins involved in the mechanisms for regulating the lipid metabolism.
Thus:
PPARα is expressed essentially in the liver and is involved in the catabolism of the fatty acids by regulating the β- and ω-oxidation;
PPARδ is expressed ubiquitously, but is present mainly in the kidneys, skeletal muscles, heart and intestine.
Like the other PPAR-type receptors, PPARδ forms a heterodimer with RXR (retinoid X receptor) and is then capable of binding to certain elements of the target genes of the nucleus and controlling the transcription factors. Among the different studies dedicated to this nuclear receptor, it has been demonstrated, for example, that the activation of PPARδ makes it possible to increase the HDL-cholesterol level in the db/db mouse (FEBS Letters (2000), 473, 333-336) and the insulin-dependent obese rhesus monkey and favors the efflux of cholesterol via Apo A1 in human THP-1 cells (Proc. Nat. Ac. Sci. USA (2001), 98, 5306-5311).
As a result of the study of these different nuclear receptors, it seems that compounds which are capable of activating either the PPARα receptors, or the PPARδ receptors, or both these receptors simultaneously, might have an extremely valuable pharmacological profile for the treatment of pathological conditions such as hyperlipidemia, hypercholesterolemia and the various diseases of the cardiovascular system that are the consequence of a metabolic syndrome.
The known documents of the prior art that mention such compounds include e.g. the document WO 97/28149, which describes PPARδ receptor agonists, the document WO 01/60807, which describes PPARα receptor agonists, or the documents WO 05/009958 and WO 06/060535, which propose indole compounds that act on the PPAR receptors.
Other references include documents WO 02/071827 and Bioorg. Med. Chem. Lett., 14 (11) pp 2759-2763 (June/2004), which describe RXR receptor modulating derivatives and their use in therapeutics for the treatment of pathological conditions involved in the metabolic syndrome.
Moreover, various indole compounds have been described elsewhere in the prior art. Thus:
the documents WO 00/46196 and WO 99/07678 disclose compounds derived from indole-2-carboxylic acid for their anti-inflammatory activity;
the document WO 98/41092 describes indole-2-carboxamide derivatives that act on pain.
SUMMARY OF THE INVENTION
The present invention relates to novel compounds derived from indole which are PPAR activators and are selected from
i) the compounds of the formula
in which:
Ra and Rb independently are each a hydrogen atom, a halogen atom, a C1-C6 alkyl, CF3, CN, CO—R2 or OR2 group or a phenyl group optionally substituted by a C1-C4 alkyl or CF3 group;
R2 is a C1-C4 alkyl or CF3 group or a phenyl group optionally substituted by a C1-C4 alkyl or CF3 group;
R3 and R4 independently are each a hydrogen atom or a C1-C4 alkyl group;
R is a hydrogen atom or a C1-C3 alkyl group;
n=1, 2 or 3;
X is a single bond, an oxygen atom or a sulfur atom; and
Ar is an aromatic or heteroaromatic ring selected from phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3,4-dihydro-1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl groups optionally substituted by one or more atoms or groups of atoms selected from halogen atoms and C1-C6 alkyl, phenyl, CF3, CN, CO—R2, OR2, SR2, NH—COR2, morpholinyl, amino and 4-morpholinosulfonyl groups; and
ii) their pharmaceutically acceptable salts.
Preferred compounds according to the invention are the compounds of formula (I) given above in which at least one of the following conditions is met:
at least one of Ra and Rb is other than a hydrogen atom;
Ar is a phenyl or nitrogen-containing heteroaromatic group selected from quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, indolyl, 2,3-dihydroindolyl and benzoxazolyl groups optionally substituted by one or more atoms or groups of atoms selected from halogen atoms and C1-C6 alkyl, CF3, CN, CO—R2, OR2, SR2, NH—COR2, morpholinyl, amino and 4-morpholinosulfonyl groups; and
n is equal to 1 or 2.
A first particular family of compounds according to the invention consists of the compounds of formula (I) in which X is an oxygen atom, and their pharmaceutically acceptable salts.
A second particular family of compounds according to the invention consists of the compounds of formula I in which X is a single bond and at least one of R3 and R4 is a C1-C4 alkyl group, and their pharmaceutically acceptable salts.
A third particular family of compounds according to the invention consists of the compounds of formula I in which X is a single bond and R3 and R4 are a hydrogen atom, and their pharmaceutically acceptable salts.
According to a second feature, the invention relates to the above-mentioned compounds for their use as pharmacologically active substances, and to the pharmaceutical compositions in which they are present.
The invention further relates to the use of at least one compound of formula (I) or one of its pharmaceutically acceptable salts as an active principle for the preparation of a drug intended for use in therapeutics, especially for combating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance, diabetes or obesity, as well as cardiovascular diseases which are the consequence of a serum lipoprotein imbalance. The compounds according to the invention are also useful as active principles of drugs intended for the prevention or treatment of diseases associated with an endothelial dysfunction, atherosclerosis, myocardial infarction, hypertension, cerebrovascular problems, certain inflammatory diseases, e.g. rheumatoid arthritis, and neurodegeneration, such as Alzheimer's disease or Parkinson's disease in particular.
DETAILED DESCRIPTION
In the present description, C1-Cn alkyl group (n being an integer) is understood as meaning a linear, branched or cyclic hydrocarbon chain having from 1 to n carbon atoms. By way of example, and without implying a limitation, a C1-C6 alkyl group can be a linear or branched group of the general formula CnH2n+1, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 1,1-dimethylpropyl, 1-methylpentyl or 1,1-dimethylbutyl, or a cyclic group of the general formula CnH2n−1, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopentylmethyl. Halogen is understood as meaning a fluorine, chlorine, bromine or iodine atom, fluorine and chlorine atoms being preferred.
The compounds of formula (I) in which R is a hydrogen atom are carboxylic acids, which can be used in the form of free acids or in the form of salts, said salts being obtained by combining the acid with a pharmaceutically acceptable, non-toxic mineral or organic base. Examples of mineral bases which can be used are sodium, potassium, magnesium or calcium hydroxides. Examples of organic bases which can be used are amines, amino alcohols, basic amino acids, such as lysine or arginine, or compounds carrying a quaternary ammonium group, e.g. betaine or choline.
The compounds of formula (I) in which the substituents R3 and R4 are different have a center of asymmetry. Where these compounds are concerned, the invention covers both the racemic compound and each of the optical isomers, considered separately.
Preferred compounds according to the invention are those in which Ar is a phenyl group or a nitrogen-containing heterocycle. Other preferred compounds are those in which Ra is a halogen atom or a trifluoromethyl group, as well as those in which n is equal to 1 or 2.
The compounds according to the invention can be prepared by a first process that consists in
a) using the SONOGASHIRA reaction (see, for example, Tet. Lett., 1975, 4467) to react a compound of the formula
in which:
Ra and Rb independently are each a hydrogen, fluorine, chlorine or bromine atom or a C1-C6 alkyl, CF3, CN, CO—R2 or OR2 group; and
R2 is a C1-C4 alkyl or CF3 group or a phenyl group optionally substituted by a C1-C4 alkyl or CF3 group,
with an acetylenic derivative of the formula
in which:
n=1, 2 or 3;
R3 and R4 independently are each a hydrogen atom or a C1-C4 alkyl group;
R is a C1-C3 alkyl group; and
X is a single bond, an oxygen atom or a sulfur atom,
in the presence of cuprous iodide, a palladium-based catalyst, e.g. tetrakis-(triphenylphosphine)palladium, and an organic base, e.g. triethylamine, in a solvent, e.g. dimethylformamide (DMF), at a temperature between 0 and 60° C., for 2 to 24 hours, to give the compound of the formula
in which:
Ra, Rb, n, X, R3, R4 and R are as defined in the starting compounds;
b) reducing the “nitro” group carried by the compound of formula IV above, e.g. by reaction with stannous chloride in the presence of ethanol, in a solvent, e.g. ethyl acetate, at a temperature close to room temperature, for 1 to 24 hours, to give the aniline of the formula
in which:
Ra, Rb, n, X, R3, R4 and R are as defined in the starting compound;
c) reacting the compound of formula V with an arylsulfonyl chloride of the formula
Ar—SO2—Cl (VI)
in which:
Ar is an aromatic or heteroaromatic ring selected from phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3,4-dihydro-1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl groups optionally substituted by one or more atoms or groups of atoms selected from halogen atoms and C1-C6 alkyl, phenyl, CF3, CN, CO—R2, SR2, OR2, NH—COR2, morpholinyl, amino and 4-morpholinosulfonyl groups,
in the presence of pyridine, at room temperature, for 10 to 120 min, to give the compound of the formula
in which:
Ra, Rb, n, X, R3, R4, R and Ar are as defined in the starting compounds;
d) cyclizing the compound of formula VII, e.g. by reaction with copper(II) acetate (see, for example, J. Org. Chem., 2004, 69 (4), 1126-1136) in a solvent such as 1,2-dichloroethane, at a temperature close to the reflux temperature of the solvent, for 4 to 24 hours, to give the compound of the formula
in which:
Ra, Rb, n, X, R3, Ra, R and Ar are as defined in the starting compounds; and
e) if necessary, hydrolyzing the ester group of the compound of formula Ia, e.g. by reaction with a mineral base such as sodium hydroxide or lithium hydroxide, by procedures well known to those skilled in the art, and then treating the product with acid to give the compound of formula I in its free acid form:
In a first variant of the preparative process, the compounds of formula I can be obtained by a series of reactions consisting in
a) carrying out a halogenation reaction, preferably an iodination, on an aniline of the formula
in which:
Ra and Rb independently are each a hydrogen atom, a halogen atom or a C1-C6 alkyl, CF3, CN, CO—R2 or OR2 group; and
R2 is a C1-C4 alkyl or CF3 group or a phenyl group optionally substituted by a C1-C4 alkyl or CF3 group,
with the aid of a halogenating agent, e.g. benzyltrimethylammonium dichloroiodate, in a solvent such as dichloromethane or methanol, at room temperature, for 5 to 24 hours, to give the compound of the formula
in which:
Ra and Rb are as defined in the starting compounds;
b) reacting the compound of formula IX with an acetylenic derivative of the formula
in which:
n=1, 2 or 3;
R3 and R4 independently are each a hydrogen atom or a C1-C4 alkyl group;
R is a C1-C3 alkyl group; and
X is a single bond, an oxygen atom or a sulfur atom,
under conditions analogous to those described for step a) of the general process above, to give the compound of the formula
in which:
Ra, Rb, n, X, R3, R4 and R are as defined in the starting compound;
c) cyclizing the compound of formula V above, under conditions analogous to those described for carrying out step (d) of the general process above, to give the indole compound of the formula
in which:
Ra, Rb, n, X, R3, R4 and R are as defined in the starting compound;
d) reacting the compound of formula (X) above with an arylsulfonyl chloride of the formula
Ar—SO2—Cl (VI)
in which:
Ar is an aromatic or heteroaromatic ring selected from phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3,4-dihydro-1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl groups optionally substituted by one or more atoms or groups of atoms selected from halogen atoms and C1-C6 alkyl, phenyl, CF3, CN, CO—R2, SR2, OR2, NH—COR2, morpholinyl, amino and 4-morpholinosulfonyl groups,
in a solvent, e.g. dimethylformamide, at room temperature, for 1 to 12 hours, generally after activation of the indole compounds of formula (X) with sodium hydride, to give the compound of formula (Ia):
in which:
Ra, Rb, n, X, R3, R4, R and Ar are as defined in the starting compounds; and
e) if necessary, hydrolyzing the ester group of the compound of formula Ia, e.g. by reaction with a mineral base such as sodium hydroxide or lithium hydroxide, by procedures well known to those skilled in the art, and then treating the product with acid to give the compound of formula I in its free acid form:
In a second variant of the preparative process, the compounds of formula I can be obtained by a series of reactions consisting in
a) reacting the compound of formula IX:
in which:
Ra and Rb independently are each a hydrogen, fluorine, chlorine or bromine atom or a C1-C6 alkyl, CF3, CN, CO—R2 or OR2 group; and
R2 is a C1-C4 alkyl or CF3 group or a phenyl group optionally substituted by a C1-C4 alkyl or CF3 group,
with an arylsulfonyl chloride of the formula
Ar—SO2—Cl (VI)
in which:
Ar is an aromatic or heteroaromatic ring selected from phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3,4-dihydro-1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl groups optionally substituted by one or more atoms or groups of atoms selected from halogen atoms and C1-C6 alkyl, phenyl, CF3, CN, CO—R2, OR2, SR2, NH—COR2, morpholinyl, amino and 4-morpholinosulfonyl groups,
in a solvent, e.g. dimethylformamide, at room temperature, for 1 to 12 hours, to give the compound of the formula
in which:
Ra, Rb and Ar are as defined in the starting compounds;
b) reacting the compound of formula XI with an acetylenic derivative of the formula
in which:
n=1, 2 or 3;
R3 and R4 independently are each a hydrogen atom or a C1-C4 alkyl group;
R is a C1-C3 alkyl group; and
X is a single bond, an oxygen atom or a sulfur atom,
under conditions analogous to those described for step a) of the general process above, to give the compound of the formula
in which:
Ra, Rb, n, X, R3, R4, R and Ar are as defined in the starting compounds;
c) cyclizing the compound of formula VII above, under conditions analogous to those described for carrying out step (d) of the general process above, to give the indole compound of the formula
in which:
Ra, Rb, n, X, R3, R4, R and Ar are as defined in the starting compounds; and
d) if necessary, hydrolyzing the ester group of the compound of formula Ia, e.g. by reaction with a mineral base such as sodium hydroxide or lithium hydroxide, by procedures well known to those skilled in the art, and then treating the product with acid to give the compound of formula I in its free acid form:
During this last process, it is possible to carry out the two steps b) and c) in a single operation.
The compounds of formula I according to the invention in which Ra (this process also applies to Rb) is an optionally substituted phenyl ring can be obtained from the halogenated compound of the formula
in which:
Ra is a halogen atom, preferably a bromine atom, Rb is a hydrogen atom, a fluorine or chlorine atom or a C1-C6 alkyl, CF3, CN, CO—R2 or OR2 group;
R2 is a C1-C4 alkyl or CF3 group or a phenyl group optionally substituted by a C1-C4 alkyl or CF3 group;
R3 and R4 independently are each a hydrogen atom or a C1-C4 alkyl group;
R is a C1-C3 alkyl group;
n=1, 2 or 3;
X is a single bond, an oxygen atom or a sulfur atom; and
Ar is an aromatic or heteroaromatic ring selected from phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzothiazolyl, 2,1,3-benzothiadiazolyl, 3,4-dihydro-1,4-benzoxazinyl, 5,6,7,8-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-2-oxoquinolinyl, 3,4-dihydro-2H-benzopyranyl, indolyl, 2,3-dihydroindolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and benzoxazolyl groups optionally substituted by one or more atoms or groups of atoms selected from chlorine and fluorine atoms and C1-C6 alkyl, phenyl, CF3, CN, CO—R2, OR2, SR2, NH—COR2, morpholinyl, amino and 4-morpholinosulfonyl groups,
with a phenylboronic acid of the formula
in which:
Rx is a hydrogen atom or a C1-C4 alkyl or CF3 group, according to a SUZUKI reaction (see, for example, Chem. Rev., 1995, 95, 2457), in the presence of tetrakis(triphenylphosphine)palladium and a base, e.g. sodium carbonate, in a solvent, e.g. a mixture of tetrahydrofuran, methanol and water, at a temperature between 30° C. and the reflux temperature of the solvent, for 5 to 24 hours, to give a compound of formula Id:
in which:
R, Rb, Rx, X, R3, R4, n and Ar are as defined in the starting compounds.
The compounds of the invention in the form of salts of an acid of formula Ib with a mineral or organic base can be obtained in conventional manner by using the methods well known to those skilled in the art, e.g. by mixing stoichiometric amounts of the acid and the base in a solvent, e.g. water or a water/alcohol mixture, and then lyophilizing the solution obtained.
In some of the reaction steps described above, it is possible advantageously to replace the traditional heating methods, well known to those skilled in the art, by microwave heating using reactors adapted to this mode of reaction. In this case, those skilled in the art will understand that the “heating” times will be considerably reduced compared with the times required for conventional heating.
The following Examples of the preparation of compounds of formula (I) will afford a better understanding of the invention.
In these Examples, which do not limit the scope of the invention, ‘Preparation’ denotes the Examples that describe the synthesis of intermediates, and ‘Example’ denotes those that describe the synthesis of compounds of formula (I) according to the invention. Among the abbreviations, ‘mM’ denotes millimol. The melting points are measured on a Koffler bench or with a Mettler apparatus and the nuclear magnetic resonance spectral values are characterized by the chemical shift calculated relative to TMS, by the number of protons associated with the signal and by the shape of the signal (s for singlet, d for doublet, dd for doublet of doublets, t for triplet, q for quadruplet, quin for quintuplet, m for multiplet). The operating frequency and the solvent used are indicated for each compound. Room temperature is 20° C.±5° C. In certain cases, the structure of the compounds was confirmed by mass spectroscopy following liquid chromatography (LC/MS coupling); the measurements were made on an UPTISPHERE HDO column with an HDO phase (column: 50×2 mm×3 μm), flow rate: 0.6 ml/min (split: ⅓), mobile phase: A=H2O+0.5% TFA (trifluoroacetic acid), B=acetonitrile+0.5% TFA (gradient programming: B=10 to 90% in 7 min, then plateau at 90% for 2 min, then return to 10% in 1 min and stabilization at 10% for 3 min); working temperature: 45° C.; UV detection: 210 to 260 nm. The mass spectrum is obtained by ESI+, spray: 3500 V, source block temperature: 130° C., desolvation: 230° C., desolvation gas: 600 l/h, cone gas: 100 l/h, voltage: 10 V/30 V/60 V. The result is expressed by the mass (m/z) and the retention time (Tr).
Preparation 1
5-(5-Chloro-2-nitrophenyl)-4-pentynoic acid methyl ester
35.5 g (125 mM) of 4-chloro-2-iodo-1-nitrobenzene, 510 ml of triethylamine, 2.88 g (2.5 mM) of tetrakis(triphenylphosphine)palladium, 0.72 g of cuprous iodide and 50 ml of dimethylformamide (DMF) are mixed. 14 g (125 mM) of the methyl ester of 4-pentynoic acid are then added at room temperature, with stirring, and the reaction mixture is stirred for 24 hours at room temperature. 100 ml of toluene are added and the solvents are driven off under reduced pressure. The evaporation residue is taken up with 150 ml of ethyl acetate and 80 ml of N hydrochloric acid. The organic phase is separated off, washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The brown oil obtained is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (9/1; v/v) as the eluent to give 21.5 g of the expected product in the form of a yellow solid (yield=65%).
M.p.=75-78° C.
Preparation 2
5-(2-Amino-5-chlorophenyl)-4-pentynoic acid methyl ester
90.6 g (400 mM) of stannous chloride, 70 ml of ethyl acetate and 22 ml of ethanol are introduced into a round-bottomed flask. This mixture is stirred for 15 min at room temperature and a solution of 21.5 g (80 mM) of the compound obtained according to Preparation 1 is then added slowly. The reaction mixture is stirred for 24 hours at room temperature and then poured into a mixture of 200 g of ice and 200 ml of N sodium hydroxide solution. The mixture obtained is extracted twice with 200 ml of ethyl acetate; the combined organic phases are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oil obtained is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (80/20; v/v) as the eluent to give 9.1 g of the expected compound in the form of an orange-yellow solid (yield=30%).
M.p.=67° C.
Preparation 3
[5-Chloro-2-(phenylsulfonylamino)phenyl]-4-pentynoic acid methyl ester
A solution of 1.2 g (5 mM) of the compound obtained according to Preparation 2 in 15 ml of pyridine is prepared and 0.77 ml (6 mM) of benzenesulfonyl chloride is added. The mixture is stirred for 1 hour at room temperature and then concentrated under reduced pressure. The residual oil is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (8/2; v/v) as the eluent to give 1.8 g of the expected compound in the form of a beige solid (yield=95%).
1H NMR (DMSOd6, 300 MHz) δ=2.56 (s, 4H), 3.65 (s, 3H), 7.28-7.36 (m, 3H), 7.54-7.72 (m, 5H), 9.69 (s, 1H).
EXAMPLE 1
5-Chloro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
A solution of 300 mg (0.79 mM) of the ester obtained according to Preparation 3 in 35 ml of 1,2-dichloroethane is prepared, 15 mg (0.08 mM) of copper (cupric) acetate are added and the mixture is refluxed for 24 hours, with stirring. The solvent is then driven off under reduced pressure and the residual viscous solid is purified by chromatography on silica gel using a toluene/ethyl acetate mixture (9/1; v/v) as the eluent to give 230 mg of the compound obtained in the form of a yellow solid (yield=77%).
M.p.=93-96° C.
EXAMPLE 2
5-Chloro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid
180 mg (0.46 mM) of the ester obtained according to Example 1 are mixed with 16 ml of THF and 4 ml of water, and 20 mg (0.48 mM) of lithium hydroxide (LiOH.1H2O) are added. The mixture is stirred for 3 hours at room temperature and then concentrated under reduced pressure. The evaporation residue is taken up in 10 ml of water and the solution is acidified with 1 N hydrochloric acid solution. The white precipitate is extracted with ethyl acetate and the organic phase is separated off, dried over magnesium sulfate and concentrated under reduced pressure to give 160 mg of the expected product in the form of a yellow solid (yield=93%).
M.p.=165-168° C.
EXAMPLE 2a
5-Chloro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid sodium salt
114 mg (0.313 mM) of the acid obtained according to Example 2 are mixed with 10 ml of water and 0.313 ml of N sodium hydroxide solution. A few drops of methanol are added, with stirring, to give a solution. The mixture is stirred for 15 min at room temperature and then partially concentrated under reduced pressure. The residual solution is then filtered and lyophilized to give 115 mg of the expected salt in the form of a fine white powder (yield=95%).
M.p.≧250° C.
Preparation 4
2-Iodo-4-(trifluoromethyl)aniline
A solution of 5 g (31 mM) of 4-(trifluoromethyl)aniline in 90 ml of methanol and 30 ml of dichloromethane is prepared and 3.56 g (35.6 mM) of calcium carbonate are added. 14.9 g (42.7 mM) of trimethylbenzylammonium dichloroiodide are then added in portions at room temperature, with stirring. The reaction medium is stirred for 24 hours at room temperature and then filtered to remove the mineral salts. The filtrate is concentrated under reduced pressure and the crude product is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (8/2; v/v) as the eluent to give 6.65 g of the expected compound in the form of an orange oil (yield=75%).
1H NMR (CDCl3, 300 MHz) δ=5.0 (s, 2H), 6.82 (d, J=5.5 Hz, 1H), 7.38 (dd, J=5.5 Hz, 1.3 Hz, 1H), 7.79 (d, J=1.3 Hz, 1H).
Preparation 5
5-[2-Amino-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
A solution of 1.5 g (5.23 mM) of the compound obtained according to Preparation 4, 0.644 g (5.75 mM) of methyl 4-pentynoate and 90 mg (0.13 mM) of dichlorobis(triphenylphosphine)palladium in 1 ml of dimethylformamide and 2 ml of diethylamine is prepared and 50 mg (0.26 mM) of cuprous iodide are added. The reaction mixture is irradiated in a microwave oven at 120° C. for 10 minutes. The solvents are then driven off under reduced pressure and the evaporation residue is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (8/2; v/v) as the eluent to give 1.16 g of the expected compound in the form of an orange oil (yield=82%).
1H NMR (DMSOd6, 300 MHz) δ=2.65-2.75 (m, 4H), 3.64 (s, 3H), 5.99 (s, 2H), 6.78 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.33 (s, 1H).
Preparation 6
5-(Trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
A solution of 1.16 g (4.28 mM) of the ester obtained according to Preparation 5 in 5 ml of 1,2-dichloroethane is prepared and 1.3 g (6.4 mM) of cupric acetate are added. The reaction mixture is irradiated in a microwave oven at 150° C. for 30 minutes and then cooled and filtered. The filtrate is concentrated under reduced pressure to give 1 g of the expected compound in the form of a brown solid (yield=86%).
M.p.=106-108° C.
EXAMPLE 3
1-(Phenylsulfonyl)-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
0.18 g (4.6 mM) of sodium hydride (60% dispersion in oil) is added at 0° C. to a solution of 1 g (3.69 mM) of the ester obtained according to Preparation 6. This mixture is stirred for 15 min and 0.98 g (5.5 mM) of benzenesulfonyl chloride is added, still at 0° C. The mixture is stirred for 30 min at room temperature and 100 ml of 15% aqueous ammonium chloride solution are then added. The mixture is extracted 3 times with 50 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (8/2; v/v) as the eluent to give 0.95 g of the expected product in the form of an oil, which crystallizes into orange stars (yield=62%).
M.p.=81-83° C.
EXAMPLE 4
1-(Phenylsulfonyl)-5-(trifluoromethyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 3, the expected product is obtained in the form of a beige solid (yield 85%).
M.p.=170-172° C.
Preparation 7
5-(2-Amino-5-bromophenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from 4-bromo-2-iodoaniline, the expected compound is obtained in the form of a yellow oil (yield=23%).
1H NMR (DMSOd6, 250 MHz) δ=2.61-2.74 (m, 4H), 3.63 (s, 3H), 5.46 (s, 2H), 6.63 (dd, J=8.3 Hz, 0.7 Hz, 1H), 7.1-7.2 (m, 2H).
Preparation 8
5-Bromo-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 7, the expected compound is obtained in the form of a brown solid (yield=98%).
1H NMR (DMSOd6, 250 MHz) δ=2.75 (t, J=7.3 Hz, 2H), 2.98 (t, J=7.2 Hz, 2H), 3.60 (s, 3H), 6.14 (s, 1H), 7.1 (dd, J=8.5 Hz, 1.9 Hz, 1H), 7.2 (d, J=8.5 Hz, 1H), 7.58 (d, J=1.9 Hz, 1H), 11.1 (s, 1H).
EXAMPLE 5
5-Bromo-1-(phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 8, the expected compound is obtained in the form of a light brown solid (yield=25%).
M.p.=109-113° C.
EXAMPLE 6
5-Bromo-1-(phenylsulfonyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 5, the expected compound is obtained in the form of a beige solid (yield=81%).
M.p.=188-190° C.
EXAMPLE 7
1-(Phenylsulfonyl)-5-[4-(trifluoromethyl)phenyl]-1H-indole-2-propanoic acid methyl ester
A solution of 0.5 g (1.18 mM) of the ester obtained according to Example 5 and 0.68 g (0.59 mM) of tetrakis(triphenylphosphine)palladium in 5 ml of THF is prepared and a solution of 0.84 g (4.4 mM) of 4-(trifluoromethyl)phenylboronic acid in 2.5 ml of methanol is added, followed by a solution of 282 mg (2.6 mM) of sodium carbonate in 1 ml of water. The mixture is then stirred at the reflux temperature of the solvent for 24 hours. After it has returned to room temperature, the mixture is diluted with 20 ml of dichloromethane and dried over magnesium sulfate. The solution obtained is concentrated under reduced pressure and the evaporation residue is taken up in solution in 50 ml of ethyl ether. The solution obtained is washed 3 times with 15 ml of 1 N sodium hydroxide solution and then with water until the washings are neutral, dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (85/15; v/v) as the eluent to give 57 mg of the expected compound in the form of a beige oil (yield=10%).
1H NMR (DMSOd6, 250 MHz) δ=2.84 (t, J=7.1 Hz, 2H), 3.32 (d, J=7.2 Hz, 2H), 3.62 (s, 3H), 6.68 (s, 1H), 7.56-7.71 (m, 5H), 7.78-7.91 (m, 6H), 8.13 (d, 1H).
EXAMPLE 8
1-(Phenylsulfonyl)-5-[4-(trifluoromethyl)phenyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 7, the expected product is obtained in the form of a yellow solid (yield=76%).
M.p.=162° C.
Preparation 9
5-(2-Nitrophenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 1 starting from 1-iodo-2-nitrobenzene, the expected product is obtained in the form of a yellow solid (yield=53%).
M.p.=44-46° C.
Preparation 10
6-(5-Chloro-2-nitrophenyl)-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 1 starting from the methyl ester of 5-hexynoic acid, the expected product is obtained in the form of a brown oil (yield=73%).
1H NMR (DMSOd6, 250 MHz) δ=1.81 (m, 2H), 2.54 (m, 4H), 3.60 (s, 3H), 7.69 (dd, 1H), 7.81 (d, 1H), 8.09 (d, 1H).
Preparation 11
7-(5-Chloro-2-nitrophenyl)-6-heptynoic acid methyl ester
By following a procedure analogous to Preparation 1 starting from the methyl ester of 6-heptynoic acid, the expected product is obtained in the form of a brown oil (yield=98%).
1H NMR (DMSOd6, 250 MHz) δ=1.34-1.73 (m, 4H), 2.36 (t, 2H), 2.53 (t, 2H), 3.59 (s, 3H), 7.66 (dd, 1H), 7.79 (d, 1H), 8.09 (d, 1H).
Preparation 12
5-(2-Aminophenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 2 starting from the compound obtained according to Preparation 9, the expected product is obtained in the form of a colorless oil (yield=53%).
1H NMR (DMSOd6, 250 MHz) δ=2.67 (m, 4H), 3.63 (s, 3H), 5.25 (s, 2H), 6.46 (m, 1H), 6.65 (dd, 1H), 7.02 (m, 2H).
Preparation 13
6-(2-Amino-5-chlorophenyl)-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 2 starting from the compound obtained according to Preparation 10, the expected product is obtained in the form of a yellow solid (yield=41%).
1H NMR (DMSOd6, 250 MHz) δ=1.83 (m, 2H), 2.48 (m, 4H), 3.59 (s, 3H), 5.40 (s, 2H), 6.67 (d, 1H), 7.03 (dd, 1H), 7.08 (d, 1H).
Preparation 14
7-(2-Amino-5-chlorophenyl)-6-heptynoic acid methyl ester
By following a procedure analogous to Preparation 2 starting from the compound obtained according to Preparation 11, the expected product is obtained in the form of a yellow solid (yield=68%).
M.p.=66° C.
Preparation 15
5-(2-Amino-5-fluorophenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from 4-fluoro-2-iodoaniline, the expected product is obtained in the form of a brown solid (yield=45%).
1H NMR (DMSOd6, 300 MHz) δ=2.6-2.75 (m, 4H), 3.63 (s, 3H), 5.16 (s, 2H), 6.6-6.7 (m, 1H), 6.8-6.85 (m, 2H).
Preparation 16
5-(2-Amino-4,5-dichlorophenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from 4,5-dichloro-2-iodoaniline, the expected product is obtained in the form of beige crystals (yield=87%).
1H NMR (DMSOd6, 300 MHz) δ=2.65-2.75 (m, 4H), 3.63 (s, 3H), 5.70 (s, 2H), 6.87 (s, 1H), 7.24 (s, 1H).
Preparation 17
5-(2-Amino-5,6-dichlorophenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from 3,4-dichloro-2-iodoaniline, the expected product is obtained in the form of a colorless oil (yield=49%).
1H NMR (DMSOd6, 300 MHz) δ=2.6-2.8 (m, 4H), 3.63 (s, 3H), 5.74 (s, 2H), 6.65 (d, 1H), 7.20 (d, 1H).
Preparation 18
5-[2-Amino-4-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from 5-(trifluoromethyl)-2-iodoaniline, the expected product is obtained in the form of orange crystals (yield=71%).
M.p.=42° C.
Preparation 19
5-(2-Amino-5-acetylphenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from 4-amino-3-iodoacetophenone, the expected product is obtained in the form of a yellow solid (yield=39%).
1H NMR (DMSOd6, 300 MHz) δ=2.39 (s, 3H), 2.65-2.75 (m, 4H), 3.64 (s, 3H), 6.15 (s, 2H), 6.69 (d, 1H), 7.64 (dd, 1H), 7.69 (d, 1H).
Preparation 20
5-(2-Amino-4-chloro-5-fluorophenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from 5-chloro-4-fluoro-2-iodoaniline, the expected product is obtained in the form of brown crystals (yield=81%).
M.p.=67-68° C.
Preparation 21
5-(2-Amino-5-cyanophenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from 4-amino-3-iodobenzonitrile, the expected product is obtained in the form of a colorless oil (yield=52%).
1H NMR (DMSOd6, 300 MHz) δ=2.65-2.75 (m, 4H), 3.63 (s, 3H), 6.27 (s, 2H), 6.73 (d, 1H), 7.38 (dd, 1H), 7.46 (d, 1 Hz, 1H).
Preparation 22
5-(2-Amino-5-benzoylphenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from 4-amino-3-iodobenzophenone, the expected product is obtained in the form of a yellow oil (yield=54%).
1H NMR (DMSOd6, 300 MHz) δ=2.63-2.73 (m, 4H), 3.62 (s, 3H), 6.28 (s, 2H), 6.75 (d, 1H), 7.47-7.61 (m, 7H).
Preparation 23
5-(2-Amino-3,5-dichlorophenyl)-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from 2,4-dichloro-6-iodoaniline, the expected product is obtained in the form of a dark-colored oil (yield=87%).
1H NMR (DMSOd6, 300 MHz) δ=2.6-2.8 (m, 4H), 3.64 (s, 3H), 5.55 (s, 2H), 7.13 (d, 1H), 7.33 (d, 1H).
Preparation 24
5-[2-[(Phenylsulfonyl)amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from the compound obtained according to Preparation 12, the expected product is obtained in the form of a colorless oil (yield=82%).
1H NMR (DMSOd6, 300 MHz) δ=2.57 (s, 4H), 3.65 (s, 3H), 7.13 (m, 1H), 7.22-7.28 (m, 3H), 7.52-7.62 (m, 3H), 7.71 (dd, 2H), 9.49 (s, 1H).
Preparation 25
5-[5-Chloro-2-[[(4-methylphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from p-toluenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=85%).
1H NMR (DMSOd6, 250 MHz) δ=2.35 (s, 3H), 2.56 (s, 4H), 3.65 (s, 3H), 7.31 (m, 5H), 7.59 (d, 2H), 9.57 (s, 1H).
Preparation 26
5-[5-Chloro-2-[[(2,3-dichlorophenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 2,3-dichlorobenzenesulfonyl chloride, the expected product is obtained in the form of a yellow solid (yield=85%).
M.p.=64° C.
Preparation 27
5-[5-Chloro-2-[[(3-methylphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from m-toluenesulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=82%).
M.p.=69° C.
Preparation 28
5-[5-Chloro-2-[[(2,4-dichlorophenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 2,4-dichlorobenzenesulfonyl chloride, the expected product is obtained in the form of a colorless oil (yield=96%).
1H NMR (DMSOd6, 300 MHz) δ=2.56 (s, 4H), 3.64 (s, 3H), 7.27 (dd, J=8.4, 0.78 Hz, 1H), 7.36 (m, 2H), 7.58 (dd, 1H), 7.84 (d, 1H), 7.89 (s, 1H), 10.06 (s, 1H).
Preparation 29
5-[5-Chloro-2-[[[4-(trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-(trifluoromethyl)benzenesulfonyl chloride, the expected product is obtained in the form of a pink solid (yield=50%).
M.p.=80° C.
Preparation 30
5-[5-Chloro-2-[[(4-methoxyphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-methoxybenzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=84%).
1H NMR (DMSOd6, 300 MHz) δ=2.58 (s, 4H), 3.65 (s, 3H), 3.80 (s, 3H), 7.05 (m, 2H), 7.29 (m, 2H), 7.36 (dd, 1H), 7.63 (m, 2H), 9.47 (s, 1H).
Preparation 31
5-[5-Chloro-2-[[(4-acetylphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-acetylbenzenesulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=59%).
M.p.=88° C.
Preparation 32
5-[2-[([1,1′-Biphenyl]-4-ylsulfonyl)amino]-5-chlorophenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from (1,1′-biphenyl)-4-ylsulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=81%).
M.p.=93° C.
Preparation 33
5-[5-chloro-2-[[[2-(trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 2-(trifluoro-methyl)benzenesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=73%).
1H NMR (DMSOd6, 250 MHz) δ=2.56 (s, 4H), 3.63 (s, 3H), 7.27-7.42 (m, 3H), 7.83 (m, 2H), 7.96 (m, 2H), 9.95 (s, 1H).
Preparation 34
5-[5-Chloro-2-[[(3-methoxyphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 3-methoxybenzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=86%).
1H NMR (DMSOd6, 300 MHz) δ=2.56 (s, 4H), 3.65 (s, 3H), 3.76 (s, 3H), 7.12-7.31 (m, 4H), 7.37 (dd, 1H), 7.44 (m, 1H), 7.69 (s, 1H), 9.69 (s, 1H).
Preparation 35
5-[5-Chloro-2-[[(2,5-dimethoxyphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 2,5-dimethoxy-benzenesulfonyl chloride, the expected product is obtained in the form of a yellow solid (yield=92%).
LC/MS: m/z=438; Tr=5.97 min.
Preparation 36
5-[5-Chloro-2-[[[4-(1,1-dimethylethyl)phenyl]sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-tert-butylbenzenesulfonyl
chloride, the expected product is obtained in the form of a colorless oil (yield=88%).
LC/MS: m/z=434; Tr=6.89 min.
Preparation 37
5-[5-Chloro-2-[[(4-ethylphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-ethylbenzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=37%).
LC/MS: m/z=406; Tr=6.40 min.
Preparation 38
5-[5-Chloro-2-[[[4-(1-methylethyl)phenyl]sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-isopropylbenzenesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=92%).
LC/MS: m/z=420; Tr=6.95 min.
Preparation 39
5-[5-Chloro-2-[[(4-propylphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-propylbenzenesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=22%).
LC/MS: m/z=420; Tr=6.92 min.
Preparation 40
5-[5-Chloro-2-[[(4-pentylphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-pentylbenzenesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=88%).
LC/MS: m/z=448; Tr=7.61 min.
Preparation 41
5-[5-Chloro-2-[[(3,5-dimethylphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 3,5-dimethyl-benzenesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=92%).
LC/MS: m/z=406; Tr=6.70 min.
Preparation 42
5-[5-chloro-2-[[(2,4,6-trimethylphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 2,4,6-trimethylbenzene-sulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=23%).
LC/MS: m/z=420; Tr=6.66 min.
Preparation 43
5-[5-Chloro-2-[[(4-chlorophenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-chlorobenzenesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=56%).
LC/MS: m/z=412; Tr=6.27 min.
Preparation 44
5-[5-Chloro-2-[[(4-fluorophenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-fluorobenzenesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=28%).
LC/MS: m/z=396; Tr=5.99 min.
Preparation 45
5-[5-Chloro-2-[[(4-chloro-3-methylphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-chloro-3-methylbenzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=59%).
LC/MS: m/z=426; Tr=6.80 min.
Preparation 46
5-[5-Chloro-2-[[[3-(trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 3-(trifluoromethyl)benzenesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=50%).
LC/MS: m/z=446; Tr=6.58 min.
Preparation 47
5-[2-[[[4-(Acetylamino)phenyl]sulfonyl]amino]-5-chlorophenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-(acetylamino)-benzenesulfonyl chloride, the expected product is obtained in the form of an orange solid (yield=74%).
LC/MS: m/z=435; Tr=5.15 min.
Preparation 48
5-[5-Chloro-2-[[(4-cyanophenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-cyanobenzenesulfonyl chloride, the expected product is obtained in the form of a yellow solid (yield=87%).
LC/MS: m/z=403; Tr=5.71 min.
Preparation 49
5-[5-Chloro-2-[[(4-phenoxyphenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-phenoxybenzenesulfonyl chloride, the expected product is obtained in the form of a yellow solid (yield=71%).
LC/MS: m/z=470; Tr=6.67 min.
Preparation 50
5-[5-Chloro-2-[(1-naphthalenylsulfonyl)amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 1-naphthalenesulfonyl chloride, the expected product is obtained in the form of a brown oil (yield=89%).
1H NMR (DMSOd6, 300 MHz) δ=2.15 (t, 2H), 2.44 (t, 2H), 3.63 (s, 3H), 7.18 (s, 1H), 7.34 (s, 2H), 7.62 (m, 3H), 8.01 (dd, 1H), 8.04 (d, 1H), 8.22 (d, 1H), 8.72 (d, 1H), 10.01 (s, 1H).
Preparation 51
5-[5-Chloro-2-[(2-naphthalenylsulfonyl)amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 2-naphthalenesulfonyl chloride, the expected product is obtained in the form of a colorless oil (yield=22%).
LC/MS: m/z=428; Tr=6.63 min.
Preparation 52
5-[5-Chloro-2-[[(4-methyl-1-naphthalenyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 4-methyl-1-naphthalenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=77%).
1H NMR (DMSOd6, 250 MHz) δ=2.24 (t, 2H), 2.37 (t, 2H), 2.70 (s, 3H), 3.64 (s, 3H), 7.25 (s, 1H), 7.33 (s, 2H), 7.45 (dd, 1H), 7.68 (m, 2H), 7.93 (d, 1H), 8.15 (m, 1H), 8.75 (m, 1H), 9.91 (s, 1H).
Preparation 53
5-[2-[[[5-(Acetylamino)-1-naphthalenyl]sulfonyl]amino]-5-chlorophenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 5-(acetylamino)-1-naphthalenesulfonyl chloride, the expected product is obtained in the form of a colorless oil (yield=94%).
1H NMR (DMSOd6, 300 MHz) δ=2.18 (s, 3H), 2.23 (t, 2H), 2.41 (t, 2H), 3.62 (s, 3H), 7.18 (s, 1H), 7.32 (s, 2H), 7.62 (m, 2H), 7.76 (d, 1H), 8.04 (dd, 1H), 8.35 (d, 1H), 8.58 (d, 1H), 10.03 (s, 1H).
Preparation 54
5-[5-Chloro-2-[(8-quinolinylsulfonyl)amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 8-quinolinesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=76%).
LC/MS: m/z=429; Tr=5.96 min.
Preparation 55
6-[5-Chloro-2-[(phenylsulfonylamino)phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from the compound obtained according to Preparation 13, the expected product is obtained in the form of an orange solid (yield=66%).
M.p.=90° C.
Preparation 56
6-[5-Chloro-2-[[(2,3-dichlorophenyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2,3-dichloro-benzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=87%).
1H NMR (DMSOd6, 250 MHz) δ=1.72 (m, 2H), 2.35 (t, 2H), 2.43 (t, 2H), 3.60 (s, 3H), 7.25-7.36 (m, 2H), 7.39 (s, 1H), 7.48 (t, 1H), 7.79 (d, 1H), 7.90 (d, 1H), 10.28 (s, 1H).
Preparation 57
6-[5-Chloro-2-[[(4-methoxyphenyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 4-methoxybenzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=43%).
1H NMR (DMSOd6, 250 MHz) δ=1.73 (m, 2H), 2.35-2.48 (m, 4H), 3.62 (s, 3H), 3.81 (s, 3H), 7.04 (d, 2H), 7.25-7.35 (m, 3H), 7.60 (d, 2H), 9.57 (s, 1H).
Preparation 58
6-[5-Chloro-2-[(8-quinolinylsulfonyl)amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 8-quinolinesulfonyl chloride, the expected product is obtained in the form of a white powder (yield=48%).
1H NMR (DMSOd6, 300 MHz) δ=1.77 (m, 2H), 2.44 (m, 4H), 3.61 (s, 3H), 7.29 (s, 2H), 7.43 (d, 1H), 7.75 (m, 2H), 8.32 (d, 1H), 8.39 (d, 1H), 8.55 (d, 1H), 9.01 (s, 1H), 9.08 (d, 1H).
Preparation 59
6-[5-Chloro-2-[[[4-(1-methylethyl)phenyl]sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 4-isopropylbenzene-sulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=86%).
1H NMR (DMSOd6, 300 MHz) δ=1.20 (d, 6H), 1.71 (m, 2H), 2.34 (t, 2H), 2.41 (t, 2H), 2.73 (m, 1H), 3.61 (s, 3H), 7.26-7.62 (m, 5H), 9.71 (s, 1H).
Preparation 60
6-[5-Chloro-2-[(2-naphthalenylsulfonyl)amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2-naphthalenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=69%).
1H NMR (DMSOd6, 300 MHz) δ=1.59 (m, 2H), 2.20 (t, J=7.1 Hz, 2H), 2.32 (t, J=7.4 Hz, 2H), 3.61 (s, 3H), 7.08-7.34 (m, 3H), 7.63-7.74 (m, 3H), 7.99-8.33 (m, 3H), 9.91 (s, 1H).
Preparation 61
6-[5-Chloro-2-[[(3,5-dimethylphenyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 3,5-dimethylbenzene-sulfonyl chloride, the expected product is obtained in the form of a white powder (yield=71%).
M.p.=92-94° C.
Preparation 62
6-[5-Chloro-2-[[(3-methoxyphenyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 3-methoxybenzenesulfonyl chloride, the expected product is obtained in the form of a yellow powder (yield=82%).
M.p.=71-76° C.
Preparation 63
6-[5-Chloro-2-[[(2,5-dimethoxyphenyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2,5-dimethoxybenzene-sulfonyl chloride, the expected product is obtained in the form of a white powder (yield=80%).
M.p.=115-117° C.
Preparation 64
6-[5-Chloro-2-[(1-naphthalenylsulfonyl)amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 1-naphthalenesulfonyl chloride, the expected product is obtained in the form of a yellow powder (yield=81%).
M.p.=93-95° C.
Preparation 65
5-Fluoro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 15, the expected product is obtained in the form of a beige solid (yield=71%).
1H NMR (DMSOd6, 300 MHz) δ=2.75 (t, 2H), 2.98 (t, 2H), 3.61 (s, 3H), 6.14 (dd, 1H), 6.82 (ddd, 1H), 7.15 (dd, 1H), 7.25 (dd, 4.68 Hz, 1H), 11.02 (s, 1H).
Preparation 66
5,6-Dichloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 16, the expected product is obtained in the form of a brown solid (yield=100%).
M.p.=142° C.
Preparation 67
4,5-Dichloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 17, the expected product is obtained in the form of a brown solid (yield=90%).
1H NMR (DMSOd6, 300 MHz) δ=2.78 (t, 2H), 3.01 (t, 2H), 3.61 (s, 3H), 6.24 (s, 1H), 7.17 (d, 1H), 7.29 (d, 1H) 11.49 (s, 1H).
Preparation 68
6-(Trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 18, the expected product is obtained in the form of a beige solid (yield=91%).
M.p.=108-110° C.
Preparation 69
5-Acetyl-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 19, the expected product is obtained in the form of a beige solid (yield=91%).
1H NMR (DMSOd6, 250 MHz) δ=2.57 (s, 3H), 2.77 (t, 2H), 3.01 (t, 2H), 3.61 (s, 3H), 6.32 (s, 1H), 7.34 (d, 1H), 7.66 (dd, 1H), 8.15 (d, 1H), 11.33 (s, 1H).
Preparation 70
6-Chloro-5-fluoro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 20, the expected product is obtained in the form of a gray solid (yield=92%).
M.p.=138-139° C.
Preparation 71
5,7-Dichloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 23, the expected product is obtained in the form of a brown solid (yield=30%).
1H NMR (DMSOd6, 250 MHz) δ=2.77 (t, 2H), 3.02 (t, 2H), 3.61 (s, 3H), 6.26 (s, 1H), 7.15 (d, 1H), 7.47 (d, 1H), 11.47 (s, 1H).
Preparation 72
5-Cyano-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 21, the expected product is obtained in the form of a beige solid (yield=72%).
1H NMR (DMSOd6, 250 MHz) δ=2.77 (t, 2H), 3.02 (t, 2H), 3.60 (s, 3H), 6.33 (s, 1H), 7.35 (dd, 1H), 7.35 (dd, 1.6 Hz, 1H), 7.4 (d, 1H), 7.93 (d, 1H), 11.56 (s, 1H).
Preparation 73
5-Benzoyl-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 22, the expected product is obtained in the form of a brown solid (yield=44%).
1H NMR (DMSOd6, 250 MHz) δ=2.77 (t, 2H), 3.02 (t, 2H), 3.61 (s, 3H), 6.33 (s, 1H), 7.42 (d, 1H), 7.45-7.75 (m, 7H), 7.86 (d, 1H), 11.42 (s, 1H).
Preparation 74
7-[5-Chloro-2-[(phenylsulfonyl)amino]phenyl]-6-heptynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from the compound obtained according to Preparation 14, the expected product is obtained in the form of a colorless oil (yield=54%).
1H NMR (DMSOd6, 250 MHz) δ=1.55 (m, 4H), 2.33 (m, 4H), 3.60 (s, 3H), 7.22 (m, 3H), 7.61 (m, 5H), 9.75 (s, 1H).
Preparation 75
6-[5-Chloro-2-[[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 3,4-dihydro-4-methyl-2H-1,4-benzoxazine-7-sulfonyl chloride, the expected product is obtained in the form of a white powder (yield=88%).
M.p.=131-133° C.
Preparation 76
6-[5-Chloro-2-[[[1,2,3,4-tetrahydro-2-(trifluoroacetyl)-7-isoquinolinyl]sulfonyl]-amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 1,2,3,4-tetrahydro-2-(trifluoroacetyl)-7-isoquinolinesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=89%).
1H NMR (DMSOd6, 300 MHz) δ=1.70-1.75 (m, 2H), 2.35-2.45 (m, 4H), 3.0 (t, 2H), 3.85 (t, 2H), 4.80 (s, 2H), 7.30-7.35 (m, 4H), 7.60 (dd, 1H), 7.65 (d, 1H), 9.80 (s, 1H).
Preparation 77
6-[5-Chloro-2-[[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=95%).
1H NMR (DMSOd6, 250 MHz) δ=1.70-1.81 (m, 2H), 2.37-2.51 (m, 4H), 3.61 (s, 3H), 4.25-4.32 (m, 4H), 6.59-7.37 (m, 6H), 9.63 (s, 1H).
Preparation 78
6-[5-Chloro-2-[[(6-benzothiazolyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=63%).
1H NMR (DMSOd6, 300 MHz) δ=1.56-1.66 (m, 2H), 2.23 (t, 2H), 2.35 (t, 2H), 3.60 (s, 3H), 7.27-7.39 (m, 3H), 7.79 (d, 1H), 8.21 (d, 1H), 8.60 (s, 1H), 9.61 (s, 1H), 9.97 (s, 1H).
Preparation 79
6-[5-Chloro-2-[[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 6-(4-morpholinyl)-3-pyridinesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=66%).
1H NMR (DMSOd6, 300 MHz) δ=1.69-1.79 (m, 2H), 2.36-2.51 (m, 4H), 3.55-3.58 (m, 4H), 3.60 (s, 3H), 3.64-3.68 (m, 4H), 6.87 (d, 1H), 7.29-7.39 (m, 3H), 7.64 (dd, 1H), 8.30 (d, 1H), 9.58 (s, 1H).
Preparation 80
6-[5-Chloro-2-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 3,5-dimethyl-4-isoxazolesulfonyl chloride, the expected product is obtained in the form of a yellow powder (yield=62%).
M.p.=107-109° C.
Preparation 81
6-[5-Chloro-2-[[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=86%).
1H NMR (DMSOd6, 250 MHz) δ=1.73-1.81 (m, 2H), 2.05 (s, 3H), 2.15 (s, 3H), 2.36 (d, 2H), 2.42 (d, 2H), 3.61 (s, 3H), 3.62 (s, 3H), 7.31-7.41 (m, 3H), 9.38 (s, 1H).
Preparation 82
6-[5-Chloro-2-[[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 1-methyl-1H-imidazole-4-sulfonyl chloride, the expected product is obtained in the form of a yellow powder (yield=89%).
M.p.=76-79° C.
Preparation 83
6-[2-[[(2,1,3-Benzothiadiazol-4-yl)sulfonyl]amino]-5-chlorophenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2,1,3-benzothiadiazole-4-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=87%).
1H NMR (DMSOd6, 300 MHz) δ=1.49-1.59 (m, 2H), 2.03 (t, 2H), 2.32 (t, 2H), 3.60 (s, 3H), 7.25-7.38 (m, 3H), 7.82 (dd, 1H), 8.13 (dd, 1H), 8.37 (dd, 1H), 9.83 (s, 1H).
Preparation 84
6-[2-[[(2,1,3-Benzothiadiazol-5-yl)sulfonyl]amino]-5-chlorophenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2,1,3-benzothiadiazole-5-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=22%).
1H NMR (DMSOd6, 300 MHz) δ=1.52-1.62 (m, 2H), 2.20 (t, 2H), 2.33 (t, 2H), 3.59 (s, 3H), 7.31-7.40 (m, 3H), 7.95 (dd, 1H), 8.31 (dd, 1H), 8.36 (dd, 1H), 10.3 (s, 1H).
Preparation 85
6-[5-Chloro-2-[[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=88%).
1H NMR (DMSOd6, 300 MHz) δ=1.28 (s, 6H), 1.70-1.79 (m, 4H), 2.35-2.51 (m, 4H), 2.72 (t, 2H), 3.60 (s, 3H), 6.80 (d, 1H), 7.25-7.65 (m, 5H), 9.48 (s, 1H).
Preparation 86
6-[5-Chloro-2-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenesulfonyl chloride, the expected product is obtained in the form of a yellow powder (yield=65%).
M.p.=113-115° C.
Preparation 87
6-[2-[[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]amino]-5-chlorophenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride, the expected product is obtained in the form of a pasty solid (yield=88%).
1H NMR (DMSOd6, 250 MHz) δ=1.68-1.80 (m, 2H), 2.17 (s, 3H), 2.39 (t, 2H), 2.43 (t, 2H), 3.14 (t, 2H), 3.61 (s, 3H), 4.14 (t, 2H), 7.25 (dd, 1H), 7.32-7.37 (m, 2H), 7.48 (d, 1H), 7.52 (d, 1H), 8.07 (d, 1H), 9.59 (s, 1H).
Preparation 88
6-[5-Chloro-2-[[(2-methyl-6-benzothiazolyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2-methyl-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow solid (yield=68%).
M.p.=103-106° C.
Preparation 89
6-[2-[[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]amino]-5-chlorophenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2-(acetylamino)-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a white powder (yield=80%).
M.p.=138-140° C.
Preparation 90
6-[2-[[(2-Amino-6-benzothiazolyl)sulfonyl]amino]-5-chlorophenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2-amino-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of an orange solid (yield=96%).
M.p.=61-65° C.
Preparation 91
6-[5-Chloro-2-[[(2-methyl-6-benzoxazolyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2-methyl-6-benzoxazolesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=93%).
1H NMR (DMSOd6, 250 MHz) δ=1.65 (m, 2H), 2.15 (t, 2H), 2.39 (t, 2H), 2.65 (s, 3H), 3.61 (s, 3H), 7.26-7.39 (m, 3H), 7.65 (dd, 1H), 7.81 (d, 1H), 7.95 (s, 1H), 9.93 (s, 1H).
Preparation 92
6-[5-Chloro-2-[[(2,3-dihydro-5-benzofuranyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2,3-dihydro-5-benzofuransulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=99%).
1H NMR (DMSOd6, 300 MHz) δ=1.76 (m, 2H), 2.40-2.49 (m, 4H), 3.23 (t, 2H), 3.85 (s, 3H), 4.62 (t, 2H), 6.85 (d, 1H), 7.25-7.45 (m, 4H), 7.77 (s, 1H), 9.51 (s, 1H).
Preparation 93
6-[5-Chloro-2-[[(2-methyl-5-benzothiazolyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2-methyl-5-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow solid (yield=42%).
M.p.=68-72° C.
Preparation 94
6-[2-[[(2-Amino-6-benzoxazolyl)sulfonyl]amino]-5-chlorophenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2-amino-6-benzoxazolesulfonyl chloride, the expected product is obtained is the form of a white solid (yield=9%).
M.p.=135° C.
Preparation 95
6-[2-[[[2-(Acetylamino)-4-methyl-5-thiazolyl]sulfonyl]amino]-5-chlorophenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2-(acetylamino)-4-methyl-5-thiazolesulfonyl chloride, the expected product is obtained in the form of a white powder (yield=62%).
M.p.=147-149° C.
Preparation 96
6-[5-Chloro-2-[[(1,2,3,4-tetrahydro-2-oxo-6-quinolinyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 1,2,3,4-tetrahydro-2-oxo-6-quinolinesulfonyl chloride, the expected product is obtained in the form of a yellow powder (yield=27%).
M.p.=53-57° C.
Preparation 97
5-[2-[[(6-Benzothiazolyl)sulfonyl]amino]-5-chlorophenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=92%).
1H NMR (DMSOd6, 300 MHz) δ=2.44 (s, 4H), 3.63 (s, 3H), 7.26-7.39 (m, 3H), 7.25-7.65 (m, 5H), 7.80 (dd, 1H), 8.21 (dd, 1H), 8.62 (d, 1H), 9.62 (s, 1H), 9.88 (s, 1H).
Preparation 98
5-[2-[[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]amino]-5-chlorophenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 2-(acetylamino)-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=99%).
M.p.=85° C.
Preparation 99
5-[2-[[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]amino]-5-chlorophenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=84%).
M.p.=154° C.
Preparation 100
5-[2-[[(1,3-Benzodioxol-5-yl)sulfonyl]amino]-5-chlorophenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 3 starting from 1,3-benzodioxole-5-sulfonyl chloride, the expected product is obtained in the form of a brown oil (yield=98%).
1H NMR (DMSOd6, 300 MHz) δ=2.60 (s, 4H), 3.65 (s, 3H), 6.15 (s, 2H), 7.01 (d, J=8.73 Hz, 1H), 7.20 (dd, 2H), 7.27 (s, H), 7.30-7.38 (m, 2H).
Preparation 101
6-[2-[[(1,3-Benzodioxol-5-yl)sulfonyl]amino]-5-chlorophenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 1,3-benzodioxole-5-sulfonyl chloride, the expected product is obtained in the form of a brown oil (yield=89%).
1H NMR (DMSOd6, 300 MHz) δ=1.76 (m, 2H), 2.37-2.45 (m, 4H), 3.61 (s, 3H), 6.14 (s, 2H), 7.0 (d, 1H), 7.38-7.71 (m, 5H), 9.68 (s, 1H).
Preparation 102
6-[5-Chloro-2-[[[4-(4-morpholinylsulfonyl)phenyl]sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 4-(4-morpholinylsulfonyl)benzenesulfonyl chloride, the expected product is obtained in the form of a white solid (yield=66%).
M.p.=135-139° C.
Preparation 103
6-[2-Amino-5-(trifluoromethyl)phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 5 starting from the methyl ester of 5-hexynoic acid, the expected product is obtained in the form of a brown oil (yield=84%).
1H NMR (DMSOd6, 250 MHz) δ=1.86 (q, 2H), 2.45-2.54 (m, 4H), 3.6 (s, 3H), 5.96 (s, NH2), 6.78 (d, 1H), 7.30 (dd, 1H), 7.36 (d, 1H).
Preparation 104
5-[2-[[(6-Benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 97 starting from the methyl ester of 5-[2-amino-5-(trifluoromethyl)phenyl]-4-pentynoic acid (Preparation 5), the expected product is obtained in the form of an orange oil (yield=83%).
1H NMR (DMSOd6, 500 MHz) δ=2.53 (d, 2H), 2.55 (d, 2H), 3.65 (s, 3H), 6.80 (d, 1H), 7.54-7.66 (m, 3H), 7.90 (dd, J1H), 8.22 (d, 1H), 8.73 (d, 1H), 9.63 (s, 1H), 10.13 (s, 1H).
Preparation 105
6-[2-[[(2-Methyl-6-benzoxazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 91 starting from the methyl ester of 6-[2-amino-5-(trifluoromethyl)phenyl]-5-hexynoic acid (preparation 103) and 2-methyl-6-benzoxazolesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=54%).
1H NMR (DMSOd6, 300 MHz) δ=1.65-1.75 (m, 2H), 2.33-2.43 (m, 4H), 2.65 (s, 3H), 3.60 (s, 3H), 7.49 (d, 1H), 7.62 (s, 1H), 7.63 (d, 1H), 7.74 (dd, 1H), 7.82 (d, 1H), 8.07 (s, 1H), 10.16 (s, 1H).
Preparation 106
6-[2-[[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 105 starting from 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride, the expected product is obtained in the form of a pasty solid (yield=56%).
1H NMR (DMSOd6, 300 MHz) δ=1.74-1.83 (m, 2H), 2.16 (s, 3H), 2.43-2.48 (m, 4H), 3.15 (t, 2H), 3.61 (s, 3H), 4.13 (t, 2H), 7.44-7.47 (m, 1H), 7.58-7.61 (m, 4H), 8.07-8.10 (m, 1H), 9.86 (s, 1H).
Preparation 107
6-[2-[[(2,3-Dihydro-5-benzofuranyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 105 starting from 2,3-dihydro-5-benzofuransulfonyl chloride, the expected product is obtained in the form of a yellow paste (yield=19%).
1H NMR (DMSOd6, 250 MHz) δ=1.80 (t, 2H), 2.43-2.51 (m, 4H), 3.21 (t, 2H), 3.61 (s, 3H), 4.62 (t, 2H), 6.87 (d, 1H), 7.48 (d, 1H), 7.55 (dd, 1H), 7.60-7.67 (m, 3H), 9.77 (s, 1H).
Preparation 108
6-[2-[[(2-Methyl-5-benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 105 starting from 2-methyl-5-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow paste (yield=17%).
1H NMR (DMSOd6, 250 MHz) δ=1.61-1.73 (m, 2H), 2.32 (t, 2H), 2.38 (t, 2H), 2.83 (s, 3H), 3.60 (s, 3H), 7.52 (d, 1H), 7.60-7.66 (m, 3H), 7.72 (dd, 1H), 8.23 (d, 1H), 8.25 (s, 1H), 10.19 (s, 1H).
Preparation 109
5-[2-[[(2-Amino-6-benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 104 starting from 2-amino-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=69%).
1H NMR (DMSOd6, 250 MHz) δ=2.65 (m, 4H), 3.68 (s, 3H), 7.40 (d, 1H), 7.54-7.66 (m, 4H), 7.99 (s, 2H), 8.19 (d, 1H), 9.71 (s, 1H).
Preparation 110
5-[2-[[(2-Methyl-6-benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 104 starting from 2-methyl-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=24%).
1H NMR (DMSOd6, 300 MHz) δ=2.54 (m, 4H), 2.84 (s, 3H), 3.65 (s, 3H), 7.53 (m, 2H), 7.56 (m, 1H), 7.65 (dd, 1H), 7.83 (dd, 1H), 8.05 (dd, 1H), 8.57 (d, 1H), 10.05 (s, 1H).
Preparation 111
5-[2-[[(2-Methyl-5-benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 104 starting from 2-methyl-5-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=46%).
1H NMR (DMSOd6, 250 MHz) δ=2.55 (m, 4H), 2.83 (s, 3H), 3.65 (s, 3H), 7.55 (m, 2H), 7.66 (dd, 1H), 7.72 (dd, 1H), 8.24 (d, 1H), 8.30 (d, 1H), 10.09 (s, 1H).
Preparation 112
5-[2-[[(2-Methyl-6-benzoxazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 104 starting from 2-methyl-6-benzoxazolesulfonyl chloride, the expected product is obtained in the form of a white powder (yield=41%).
1H NMR (DMSOd6, 250 MHz) δ=2.56 (m, 4H), 2.66 (s, 3H), 3.65 (s, 3H), 7.55 (m, 2H), 7.62 (d, 1H), 7.75 (dd, 1H), 7.83 (dd, 1H), 8.12 (dd, 1H), 10.04 (s, 1H).
Preparation 113
5-[2-[[(2-Methyl-7-benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 104 starting from 2-methyl-7-benzothiazolesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=32%).
1H NMR (DMSOd6, 250 MHz) δ=2.40 (m, 4H), 2.78 (s, 3H), 3.64 (s, 3H), 7.68 (m, 3H), 8.17 (dd, 1H), 10.40 (s, 1H).
Preparation 114
5-[2-[[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 104 starting from 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride, the expected product is obtained in the form of a yellow solid (yield=32%).
1H NMR (DMSOd6, 300 MHz) δ=2.63 (m, 4H), 3.16 (t, 2H), 3.66 (s, 3H), 4.13 (t, 2H), 7.50 (d, 1H), 7.62 (m, 4H), 8.10 (d, 1H), 9.74 (s, 1H).
Preparation 115
5-[2-[[(2,3-Dihydro-5-benzofuranyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 104 starting from 2,3-dihydro-5-benzofuransulfonyl chloride, the expected product is obtained in form of a yellow oil (yield=53%).
1H NMR (DMSOd6, 250 MHz) δ=2.66 (m, 4H), 3.20 (t, 2H), 3.66 (s, 3H), 4.63 (t, 2H), 6.88 (d, 1H), 7.59 (m, 5H), 9.65 (s, 1H).
Preparation 116
5-[2-[[[4-(4-Morpholinylsulfonyl)phenyl]sulfonyl]amino]-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 104 starting from 4-(4-morpholinylsulfonyl)benzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=56%).
1H NMR (DMSOd6, 250 MHz) δ=2.60 (s, 4H), 2.88 (t, 4H), 3.60 (t, 4H), 3.65 (s, 3H), 7.53 (s, 1H), 7.58 (d, 1H), 7.92 (dd, 1H), 7.99 (dd, 2H), 10.37 (s, 1H).
Preparation 117
N-(4-chloro-2-iodophenyl)-2-pyridinesulfonamide
A solution of 1 g (3.95 mM) of 4-chloro-2-iodoaniline and 0.65 ml of pyridine in 10 ml of dichloromethane is prepared and 1.68 g (9.5 mM) of 2-pyridinesulfonyl chloride are added at 0° C., with stirring. The reaction mixture is subsequently stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residual oil is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (8/2; v/v) as the eluent to give 0.74 g of the expected product in the form of a white solid (yield=48%).
M.p.=112-124° C.
Preparation 118
6-[2-[[(6-Benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 105 starting from 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of an orange paste (yield=59%).
1H NMR (DMSOd6, 250 MHz) δ=1.62-1.73 (m, 2H), 2.32 (t, 2H), 2.39 (t, 2H), 3.60 (s, 3H), 7.51 (d, 1H), 7.61-7.65 (m, 2H), 7.89 (dd, 1H), 8.23 (d, 1H), 8.69 (s, 1H), 9.62 (s, 1H), 10.22 (s, 1H).
Preparation 119
5-(Trifluoromethyl)-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the ester obtained according to Preparation 103, the expected product is obtained in the form of a beige solid (yield=36%).
M.p.=115° C.
Preparation 120
N-(4-chloro-2-iodophenyl)benzenesulfonamide
A solution of 2 g (7.89 mM) of 4-chloro-2-iodoaniline in 30 ml of pyridine is prepared and 1.21 ml (9.5 mM) of benzenesulfonyl chloride are added at 0° C., with stirring. The reaction mixture is subsequently stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residual oil is taken up with 50 ml of ethyl acetate and the solution obtained is washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. Analysis of the crude product shows the presence of about 12% of N-(4-chloro-2-iodophenyl)-N-(phenylsulfonyl)benzenesulfonamide. The crude product is therefore taken up in solution in 60 ml of dioxane and treated with 19 ml of 3 M potassium hydroxide solution under gentle reflux for 8 hours. The solvent is driven off under reduced pressure and the residue is taken up with water and acidified to pH 2 with dilute hydrochloric acid solution. The precipitate formed is filtered off, washed with water on the filter and dried to give 2.79 g of the expected product in the form of a white solid (yield=90%).
M.p.=126-128° C.
Preparation 121
N-[2-iodo-4-(trifluoromethyl)phenyl]benzenesulfonamide
By following a procedure analogous to Preparation 120 starting from 2-iodo-4-(trifluoro-methyl)aniline, the expected product is obtained in the form of a white solid (yield=74%).
M.p.=84-86° C.
Preparation 122
2-[[3-(2-Amino-5-chlorophenyl)-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
A mixture of 2 g (7.89 mM) of 4-chloro-2-iodoaniline, 75 mg (0.395 mM) of cuprous iodide, 277 mg (0.39 mM) of bis(triphenylphosphine)dichloropalladium, 221 mg (0.79 mM) of tri-(cyclohexyl)phosphine, 3.08 g (19.7 mM) of the methyl ester of 2-methyl-2-(2-propynyloxy)-propanoic acid and 15 ml of tert-butylamine is prepared. The reaction mixture is refluxed gently for 16 hours and then cooled, hydrolyzed in 60 ml of water and extracted with 3×40 ml of dichloromethane. The combined organic phases are washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is purified by chromatography on silica gel using a dichloromethane/ethyl acetate mixture (98/2; v/v) as the eluent to give 1.84 g of the expected product in the form of an orange oil (yield=83%).
1H NMR (DMSOd6, 250 MHz) δ=1.41 (s, 6H), 3.66 (s, 3H), 4.40 (s, 2H), 5.22 (broad s, 2H), 6.69 (d, 1H), 7.07 (dd, 1H), 7.13 (d, 1H).
Preparation 123
2-[[3-[2-[[(6-Benzothiazolyl)sulfonyl]amino]-5-chlorophenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Preparation 117 starting from the compound obtained according to Preparation 122 and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=53%).
1H NMR (DMSOd6, 300 MHz) δ=1.63 (s, 6H), 3.67 (s, 3H), 4.14 (s, 2H), 7.30 (d, 1H), 7.38 (d, 1H), 7.41 (dd, 1H), 7.85 (dd, 1H), 8.23 (d, 1H), 8.62 (d, 1H), 9.61 (s, 1H), 10.05 (s, 1H).
Preparation 124
2-[[3-[2-Amino-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methyl-propanoic acid methyl ester
By following a procedure analogous to Preparation 122 starting from 2-iodo-5-(trifluoro-methyl)aniline, the expected product is obtained in the form of an orange oil (yield=80%).
1H NMR (DMSOd6, 300 MHz) δ=1.42 (s, 6H), 3.65 (s, 3H), 4.41 (s, 2H), 6.08 (s, 2H), 6.79 (d, 1H), 7.34 (d, 1H), 7.39 (s, 1H).
Preparation 125
2-[[3-[2-[[(6-Benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Preparation 123 starting from the compound obtained according to Preparation 124 and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow paste (yield=23%).
1H NMR (DMSOd6, 300 MHz) δ=1.38 (s, 6H), 3.67 (s, 3H), 4.25 (s, 2H), 7.52 (d, 1H), 7.66 (d, 2H), 7.94 (dd, 1H), 8.24 (dd, 1H), 8.72 (d, 1H), 9.63 (s, 1H), 10.33 (s, 1H).
Preparation 126
2-[[3-[2-[[(2-Methyl-6-benzothiazolyl)sulfonyl]amino]-5-chlorophenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Preparation 117 starting from the compound obtained according to Preparation 122 and 2-methyl-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow paste (yield=58%).
1H NMR (DMSOd6, 250 MHz) δ=1.36 (s, 6H), 2.84 (s, 3H), 3.68 (s, 3H), 4.14 (s, 2H), 7.28 (d, 1H), 7.36 (d, 1H), 7.40 (dd, 1H), 7.78 (dd, 1H), 8.03 (d, 1H), 8.46 (d, 1H), 9.96 (s, 1H).
Preparation 127
2-[[3-[2-[[(2-Methyl-5-benzothiazolyl)sulfonyl]amino]-5-chlorophenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Preparation 117 starting from the compound obtained according to Preparation 122 and 2-methyl-5-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=45%).
1H NMR (DMSOd6, 300 MHz) δ=1.36 (s, 6H), 2.83 (s, 3H), 3.67 (s, 3H), 4.11 (s, 2H), 7.30 (d, 1H), 7.36 (d, 1H), 7.41 (dd, 1H), 7.66 (dd, 1H), 8.18 (d, 1H), 8.21 (d, 1H), 10.01 (s, 1H).
Preparation 128
2-[[3-(2-Amino-5-chlorophenyl)-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Preparation 122 starting from the ethyl ester of 2-(2-propynyloxy)propanoic acid, the expected product is obtained in the form of an orange oil (yield=69%).
1H NMR (DMSOd6, 300 MHz) δ=1.19 (t, 3H), 1.31 (d, 3H), 4.13 (q, 2H), 4.25 (q, 1H), 4.42 (d, 1H), 4.53 (d, 1H), 5.56 (s, 2H), 6.69 (d, 1H), 7.08 (dd, 1H), 7.14 (d, 1H).
Preparation 129
2-[[3-[2-[[(6-Benzothiazolyl)sulfonyl]amino]-5-chlorophenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Preparation 123 starting from the compound obtained according to Preparation 128 and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a white solid (yield=82%).
M.p.=166-168° C.
Preparation 130
6-[2-[[(1,3-Benzodioxol-5-yl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 118 starting from 1,3-benzodioxole-5-sulfonyl chloride, the expected product is obtained in the form of a brown oil, which is used in the next step without further purification (yield=73%).
Preparation 131
5-[2-[[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]amino]-5-(trifluoromethyl)phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Preparation 104 starting from 2-(acetylamino)-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a brown oil, which is used in the next step without further purification (yield=66%).
Preparation 132
2-[[3-[2-[[(2-Methyl-5-benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 2-methyl-5-benzothiazolesulfonyl chloride, the expected product is obtained in the form of an orange oil (yield=16%).
1H NMR (DMSOd6, 300 MHz) δ=10.30 (s, 1H), 8.27 (m, 2H), 7.76 (dd, 1H), 7.69 (m, 2H), 7.53 (d, 1H), 4.22 (s, 2H), 3.67 (s, 3H), 2.83 (s, 3H), 1.39 (s, 6H).
Preparation 133
2-[[3-[2-[(1,3-Benzodioxol-5-ylsulfonyl)amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 1,3-benzodioxole-5-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=21%).
1H NMR (DMSOd6, 250 MHz) δ=9.99 (s, 1H), 7.69 (m, 2H), 7.47 (d, 1H), 7.34 (m, 2H), 7.04 (d, 1H), 6.15 (s, 2H), 4.37 (s, 2H), 3.68 (s, 3H), 1.43 (s, 6H).
Preparation 134
2-[[3-[2-[[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 2-(acetylamino)-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a white solid (yield=63%).
M.p.=104-106° C.
Preparation 135
2-[[3-[2-[(2,3-Dihydrobenzofuran-5-ylsulfonyl)amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 2,3-dihydro-5-benzofuransulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=87%).
1H NMR (DMSOd6, 250 MHz) δ=9.88 (s, 1H), 7.68 (m, 3H), 7.61 (m, 1H), 7.49 (dd, 1H), 6.88 (d, 1H), 4.63 (t, 2H), 4.38 (s, 2H), 3.68 (s, 3H), 3.22 (t, 2H), 1.43 (s, 6H).
Preparation 136
2-[[3-[2-[[(2-Methyl-7-benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 2-methyl-7-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=44%).
1H NMR (DMSOd6, 250 MHz) δ=10.57 (s, 1H), 8.15 (d, 1H), 7.75 (m, 1H), 7.64 (m, 3H), 7.46 (d, 1H), 4.06 (s, 2H), 3.68 (s, 3H), 2.79 (s, 3H), 1.37 (s, 6H).
Preparation 137
2-[[3-[2-[[(2,3-Dihydro-1,4-benzodioxin-6-yl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 2,3-dihydro-1,4-benzodioxin-6-sulfonyl chloride, the expected product is obtained in the form of a beige paste (yield=79%).
1H NMR (DMSOd6, 250 MHz) δ=9.98 (s, 1H), 7.68 (m, 2H), 7.48 (d, 1H), 7.31 (m, 2H), 7.02 (d, 1H), 4.37 (s, 2H), 4.29 (m, 4H), 3.68 (s, 3H), 1.43 (s, 6H).
Preparation 138
2-[[3-[2-[[(3,4-Dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 3,4-dihydro-4-methyl-2H-1,4-benzoxazine-7-sulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=69%).
M.p.=98-100° C.
Preparation 139
2-[[3-[2-[[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=44%).
M.p.=134-136° C.
Preparation 140
2-[[3-[2-[[(3,5-Dimethylphenyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 3,5-dimethylbenzenesulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=70%).
M.p.=128-130° C.
Preparation 141
2-[[3-[2-[[(2,5-Dimethoxyphenyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 2,5-dimethoxybenzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=76%).
1H NMR (DMSOd6, 300 MHz) δ=9.13 (s, 1H), 7.13 (s, 1H), 7.66 (d, 1H), 7.56 (d, 1H), 7.32 (d, 1H), 7.20 (dd, 1H), 7.15 (d, 1H), 4.42 (s, 2H), 3.76 (s, 3H), 3.74 (s, 3H), 3.68 (s, 3H), 1.42 (s, 6H).
Preparation 142
2-[[3-[2-[[[4-(1-Methylethyl)phenyl]sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 124 and 4-(1-methylethyl)benzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=77%).
1H NMR (DMSOd6, 250 MHz) δ=10.08 (s, 1H), 8.23 (d, 1H), 8.03 (s, 1H), 7.92 (dd, 1H), 7.76 (d, 2H), 7.67 (m, 2H), 7.46 (m, 4H), 4.33 (s, 2H), 3.67 (s, 3H), 2.96 (hep, 1H), 1.42 (s, 6H), 1.19 (d, 6H).
Preparation 143
2-[[3-[2-[(1,3-Benzodioxol-5-ylsulfonyl)amino]-5-chlorophenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 1,3-benzodioxole-5-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=55%).
1H NMR (DMSOd6, 250 MHz) δ=9.71 (s, 1H), 7.39 (m, 2H), 7.23 (m, 3H), 7.02 (d, 1H), 6.15 (s, 2H), 4.30 (s, 2H), 3.67 (s, 3H), 1.42 (s, 6H).
Preparation 144
2-[[3-[2-[[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]amino]-5-chlorophenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 2-(acetylamino)-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow solid (yield=50%).
M.p.=80° C.
Preparation 145
2-[[3-[2-[[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]amino]-5-chlorophenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl chloride, the expected product is obtained in the form of a yellow paste (yield=44%).
1H NMR (DMSOd6, 300 MHz) δ=9.68 (s, 1H), 8.08 (d, 1H), 7.54 (m, 2H), 7.38 (m, 2H), 7.27 (dd, 1H), 4.30 (s, 2H), 4.13 (t, 2H), 3.67 (s, 3H), 2.17 (s, 3H), 1.41 (s, 6H).
Preparation 146
2-[[3-[5-Chloro-2-[(2,3-dihydrobenzofuran-5-ylsulfonyl)amino]phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 2,3-dihydro-5-benzofuransulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=49%).
1H NMR (DMSOd6, 300 MHz) δ=9.59 (s, 1H), 7.61 (d, 1H), 7.48 (dd, 1H), 7.39 (m, 2H), 7.27 (d, 1H), 6.85 (d, 1H), 4.62 (t, 2H), 4.28 (s, 2H), 3.64 (s, 3H), 3.21 (t, 2H), 1.42 (s, 6H).
Preparation 147
2-[[3-[5-Chloro-2-[[(2-methyl-7-benzothiazolyl)sulfonyl]amino]phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 2-methyl-7-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=33%).
1H NMR (DMSOd6, 300 MHz) δ=10.30 (s, 1H), 8.14 (dd, 1H), 7.64 (m, 2H), 7.41 (dd, 1H), 7.32 (d, 1H), 7.26 (d, 1H), 3.91 (s, 2H), 3.67 (s, 3H), 2.79 (s, 3H), 1.34 (s, 6H).
Preparation 148
2-[[3-[5-Chloro-2-[[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]amino]phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 2,3-dihydro-1,4-benzodioxin-6-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=94%).
1H NMR (DMSOd6, 250 MHz) δ=9.70 (s, 1H), 7.40 (m, 2H), 7.24 (m, 3H), 6.97 (d, 1H), 4.28 (m, 6H), 3.67 (s, 3H), 1.41 (s, 6H).
Preparation 149
2-[[3-[5-Chloro-2-[[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-amino]phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 3,4-dihydro-4-methyl-2H-1,4-benzoxazin-7-sulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=69%).
M.p.=98-100° C.
Preparation 150
2-[[3-[5-Chloro-2-[[[4-(1-methylethyl)phenyl]sulfonyl]amino]phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 4-(1-methylethyl)benzenesulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=86%).
M.p.=65-67° C.
Preparation 151
2-[[3-[5-Chloro-2-[[(3,5-dimethylphenyl)sulfonyl]amino]phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 3,5-dimethylbenzenesulfonyl chloride, the expected product is obtained in the form of a white solid (yield=62%).
M.p.=78-80° C.
Preparation 152
2-[[3-[5-Chloro-2-[[(2,5-dimethoxyphenyl)sulfonyl]amino]phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 2,5-dimethoxybenzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=90%).
1H NMR (DMSOd6, 250 MHz) δ=8.93 (s, 1H), 7.43 (d, 1H), 7.35 (m, 2H), 7.25 (d, 1H), 7.17 (m, 2H), 4.36 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), 1.41 (s, 6H).
Preparation 153
2-[[3-[5-Chloro-2-[[(4-methoxyphenyl)sulfonyl]amino]phenyl]-2-propynyl]oxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 122 and 4-methoxybenzenesulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=83%).
M.p.=98-100° C.
Preparation 154
2-[[3-[5-Chloro-2-[[(2-methyl-6-benzothiazolyl)sulfonyl]amino]phenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 128 and 2-methyl-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow paste (yield=49%).
1H NMR (DMSOd6, 300 MHz) δ=10.04 (s, 1H), 8.45 (d, 1H), 8.03 (d, 1H), 7.78 (dd, 1H), 7.41 (m, 2H), 7.27 (dd, 1H), 4.34 (d, 1H), 4.16 (m, 4H), 2.83 (s, 3H), 1.29 (d, 3H), 1.19 (t, 3H).
Preparation 155
2-[[3-[5-Chloro-2-[[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]amino]phenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 128 and 2,3-dihydro-1,4-benzodioxin-6-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=65%).
1H NMR (DMSOd6, 300 MHz) δ=9.78 (s, 1H), 7.43 (dd, 2H), 7.25 (d, 1H), 7.19 (m, 2H), 6.97 (d, 1H), 4.45 (d, 1H), 4.29 (m, 6H), 4.14 (m, 2H), 1.33 (d, 3H), 1.21 (t, 3H).
Preparation 156
2-[[3-[5-Chloro-2-[[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-amino]phenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 128 and 3,4-dihydro-4-methyl-2H-1,4-benzoxazine-7-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=63%).
1H NMR (DMSOd6, 300 MHz) δ=9.57 (s, 1H), 7.41 (m, 2H), 7.26 (d, 1H), 6.93 (m, 2H), 6.74 (d, 1H), 4.45 (d, 1H), 4.26 (m, 4H), 4.15 (m, 2H), 3.26 (m, 2H), 2.79 (s, 3H), 1.32 (d, 3H), 1.21 (t, 3H).
Preparation 157
2-[[3-[5-Chloro-2-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]phenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 128 and 3,5-dimethyl-4-isoxazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=30%).
1H NMR (DMSOd6, 300 MHz) δ=10.29 (s, 1H), 7.52 (m, 2H), 7.37 (d, 1H), 4.43 (d, 1H), 4.26 (m, 2H), 4.15 (m, 2H), 2.27 (s, 3H), 2.16 (s, 3H), 1.32 (d, 3H), 1.22 (t, 3H).
Preparation 158
2-[[3-[5-Chloro-2-[[(2,5-dimethoxyphenyl)sulfonyl]amino]phenyl]-2-propynyl]-oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 128 and 2,5-dimethoxybenzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=62%).
1H NMR (DMSOd6, 300 MHz) δ=9.11 (s, 1H), 7.46 (d, 1H), 7.37 (d, 1H), 7.29 (m, 1H), 7.24 (m, 1H), 7.16 (m, 2H), 4.49 (d, 1H), 4.36 (d, 1H), 4.24 (q, 1H), 4.16 (m, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 1.31 (d, 3H), 1.21 (t, 3H).
Preparation 159
2-[[3-[2-Amino-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Preparation 122 starting from the compound obtained according to Preparation 4 and the ethyl ester of 2-(2-propynyloxy)propanoic acid, the expected product is obtained in the form of an orange oil (yield=82%).
1H NMR (DMSOd6, 300 MHz) δ=7.42 (d, 1H), 7.35 (dd, 1H), 6.80 (d, 1H), 6.11 (s, 2H), 4.54 (d, 1H), 4.43 (d, 1H), 4.27 (q, 1H), 4.11 (m, 2H), 1.32 (d, 3H), 1.20 (t, 3H).
Preparation 160
2-[[3-[2-[[(2-Methyl-6-benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 159 and 2-methyl-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=44%).
1H NMR (DMSOd6, 300 MHz) δ=10.33 (s, 1H), 8.55 (d, 1H), 8.06 (d, 1H), 7.87 (dd, 1H), 6.68 (m, 2H), 7.50 (d, 1H), 4.43 (d, 1H), 4.26 (m, 2H), 4.15 (m, 2H), 2.84 (s, 3H), 1.31 (d, 3H), 1.20 (t, 3H).
Preparation 161
2-[[3-[2-[[(6-Benzothiazolyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 159 and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a pale yellow solid (yield=28%).
M.p.=112-114° C.
Preparation 162
2-[[3-[2-[[(2,3-Dihydro-1,4-benzodioxin-6-yl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 159 and 2,3-dihydro-1,4-benzodioxin-6-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=68%).
1H NMR (DMSOd6, 300 MHz) δ=10.07 (s, 1H), 7.70 (m, 2H), 7.48 (d, 1H), 7.29 (m, 2H), 7.00 (d, 1H), 4.51 (d, 1H), 4.38 (d, 1H), 4.31 (m, 5H), 4.16 (m, 2H), 1.34 (d, 3H), 1.20 (t, 3H).
Preparation 163
2-[[3-[2-[[(3,4-Dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 159 and 3,4-dihydro-4-methyl-2H-1,4-benzoxazine-7-sulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=57%).
1H NMR (DMSOd6, 300 MHz) δ=9.88 (s, 1H), 7.69 (m, 2H), 7.49 (d, 1H), 7.02 (m, 2H), 7.78 (d, 1H), 4.51 (d, 1H), 4.37 (d, 1H), 4.28 (m, 3H), 4.15 (m, 2H), 3.27 (m, 2H), 2.80 (s, 3H), 1.33 (d, 3H), 1.20 (t, 3H).
Preparation 164
2-[[3-[2-[[(2,5-Dimethoxyphenyl)sulfonyl]amino]-5-(trifluoromethyl)phenyl]-2-propynyl]oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 159 and 2,5-dimethoxybenzenesulfonyl chloride, the expected product is obtained in the form of a yellow oil (yield=65%).
1H NMR (DMSOd6, 250 MHz) δ=9.29 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.56 (d, 1H), 7.31 (d, 1H), 7.18 (m, 2H), 4.55 (d, 1H), 4.41 (d, 1H), 4.25 (q, 1H), 4.13 (m, 2H), 3.74 (s, 6H), 1.32 (d, 3H), 1.20 (t, 3H).
Preparation 165
(2S)-2-[[3-[2-amino-5-chlorophenyl]-2-propynyl]oxy]propanoic acid ethyl ester
a)—Ethyl ester of (2S)-2-(2-propynyloxy)propanoic acid: This compound is obtained with a yield of 24% by reacting propargyl bromide with the ethyl ester of (S)-(−)-lactic acid which has been treated beforehand with sodium hydride in tetrahydrofuran (b.p.=70-73° C. under 13 hPa).
b)—By following a procedure analogous to Preparation 122 starting from the ethyl ester of (2S)-2-(2-propynyloxy)propanoic acid, the expected product is obtained in the form of a yellow oil (yield=99%).
1H NMR (DMSOd6, 300 MHz) δ=7.14 (d, 1H), 7.08 (dd, 1H), 6.69 (d, 1H), 5.56 (s, 2H), 4.53 (d, 1H), 4.42 (d, 1H), 4.25 (q, 1H), 4.13 (m, 2H), 1.30 (d, 3H), 1.21 (t, 3H).
Preparation 166
(2S)-2-[[3-[5-chloro-2-[[(6-benzothiazolyl)sulfonyl]amino]phenyl]-2-propynyl]-oxy]propanoic acid ethyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 165 and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a white solid (yield=43%).
1H NMR (DMSOd6, 300 MHz) δ=10.11 (s, 1H), 9.61 (s, 1H), 8.60 (d, 1H), 8.22 (d, 1H), 7.84 (dd, 1H), 7.40 (m, 2H), 7.30 (d, 1H), 4.32 (d, 1H), 4.15 (m, 4H), 1.28 (d, 3H), 1.21 (t, 3H).
Preparation 167
(2R)-2-[[3-[2-amino-5-chlorophenyl]-2-propynyl]oxy]propanoic acid methyl ester
a)—Methyl ester of (2R)-2-(2-propynyloxy)propanoic acid: This compound is obtained with a yield of 9.5% by reacting propargyl bromide with the methyl ester of (R)-(+)-lactic acid which has been treated beforehand with sodium hydride in tetrahydrofuran (b.p.=81-88° C. at atmospheric pressure).
b)—By following a procedure analogous to Preparation 122 starting from the methyl ester of (2R)-2-(2-propynyloxy)propanoic acid, the expected product is obtained in the form of a yellow oil (yield=89%).
1H NMR (DMSOd6, 300 MHz) δ=7.14 (d, 1H), 7.08 (dd, 1H), 6.69 (d, 1H), 5.57 (s, 2H), 4.53 (d, 1H), 4.41 (d, 1H), 4.25 (q, 1H), 3.66 (s, 3H), 1.31 (d, 3H).
Preparation 168
(2R)-2-[[3-[5-chloro-2-[[(6-benzothiazolyl)sulfonyl]amino]phenyl]-2-propynyl]-oxy]propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 167 and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a white solid (yield=65%).
M.p.=136° C.
Preparation 169
6-[5-Chloro-2-[[(2-methyl-7-benzothiazolyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 2-methyl-7-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a brown oil (yield=97%).
1H NMR (DMSOd6, 300 MHz) δ=10.21 (s, 1H), 8.13 (m, 1H), 7.60 (m, 2H), 7.38 (dd, 1H), 7.28 (m, 2H), 3.61 (s, 3H), 2.78 (s, 3H), 2.33 (t, 2H), 2.04 (t, 2H), 1.55 (quin, 2H).
Preparation 170
6-[2-[[(1-Acetyl-1H-indol-5-yl)sulfonyl]amino]-5-chlorophenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 1-acetyl-1H-indole-5-sulfonyl chloride, the expected product is obtained in the form of a brown oil (yield=79%).
1H NMR (DMSOd6, 300 MHz) δ=9.72 (s, 1H), 8.42 (d, 1H), 8.00 (d, 1H), 7.99 (d, 1H), 7.62 (dd, 1H), 7.33 (m, 3H), 6.87 (d, 1H), 3.59 (s, 3H), 2.67 (s, 3H), 2.35 (t, 2H), 2.27 (y, 2H), 1.64 (quin, 2H).
Preparation 171
5-[5-Chloro-2-[[(2-methyl-7-benzothiazolyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 2 and 2-methyl-7-benzothiazolesulfonyl chloride, the expected product is obtained in the form of an amorphous solid (yield=45%).
1H NMR (DMSOd6, 300 MHz) δ=10.15 (s, 1H), 8.15 (m, 1H), 7.60 (m, 2H), 7.40 (dd, 1H), 7.31 (d, 1H), 7.23 (d, 1H), 3.63 (s, 3H), 2.79 (s, 3H), 2.37 (m, 2H), 2.25 (m, 2H).
Preparation 172
5-[2-[[(2-Amino-6-benzoxazolyl)sulfonyl]amino]-5-chlorophenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 2 and 2-amino-6-benzoxazolesulfonyl chloride, the expected product is obtained in the form of a white solid (yield=9%).
M.p.=170-171° C.
Preparation 173
5-[5-Chloro-2-[[(2,3-dihydro-5-benzofuranyl)sulfonyl]amino]phenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 2 and 2,3-dihydro-5-benzofuransulfonyl chloride, the expected product is obtained in the form of an amorphous solid (yield=98%).
1H NMR (DMSOd6, 300 MHz) δ=9.39 (s, 1H), 7.60 (d, 1H), 7.44 (dd, 1H), 7.31 (m, 3H), 6.85 (d, 1H), 4.62 (t, 2H), 3.65 (s, 3H), 3.21 (t, 2H), 2.60 (m, 4H).
Preparation 174
5-[2-[[(2-Amino-6-benzothiazolyl)sulfonyl]amino]-5-chlorophenyl]-4-pentynoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 2 and 2-amino-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a white solid (yield=93%).
M.p.=175° C.
Preparation 175
N-(2-bromo-4-methylphenyl)-6-benzothiazolesulfonamide
By following a procedure analogous to Example 3 starting from 2-bromo-4-methylaniline and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of an orange solid (yield=76%).
M.p.=171-174° C.
Preparation 176
N-(2-bromo-4-methylphenyl)benzenesulfonamide
By following a procedure analogous to Preparation 120 starting from 2-bromo-4-methylaniline, the expected product is obtained in the form of a beige solid (yield=95%).
1H NMR (DMSOd6, 250 MHz) δ=9.75 (s, 1H), 7.69 (m, 3H), 7.63 (m, 2H), 7.40 (s, 1H), 7.09 (d, 1H), 7.02 (d, 1H), 2.23 (s, 3H).
Preparation 177
N-(4-chloro-2-iodophenyl)-6-benzothiazolesulfonamide
By following a procedure analogous to Preparation 120 starting from 6-benzothiazolesulfonyl chloride and using tetrabutylammonium fluoride in reaction in THF to remove the dicondensed compound, the expected product is obtained in the form of a yellow solid (yield=91%).
M.p.=162° C.
Preparation 178
6-[5-Chloro-2-[[(4-fluoro-3-nitrophenyl)sulfonyl]amino]phenyl]-5-hexynoic acid methyl ester
By following a procedure analogous to Preparation 55 starting from 4-fluoro-3-nitrobenzenesulfonyl chloride and using triethylamine as a basic agent, the expected product is obtained in the form of an orange oil (yield=98%).
1H NMR (DMSOd6, 300 MHz) δ=10.31 (s, 1H), 8.38 (dd, 1H), 8.00 (m, 1H), 7.81 (dd, 1H), 7.41 (s, 1H), 7.38 (m, 1H), 7.23 (m, 1H), 3.60 (s, 3H), 2.41 (t, 2H), 2.34 (t, 2H), 1.68 (quin, 2H).
EXAMPLE 9
1-(Phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 24, the expected product is obtained in the form of a white solid (yield=75%).
M.p.=95-99° C.
EXAMPLE 10
1-(Phenylsulfonyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 9, the expected product is obtained in the form of a white solid (yield=99%).
M.p.=180-185° C.
EXAMPLE 11
5-Chloro-1-[(4-methylphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 25, the expected product is obtained in the form of a beige solid (yield=89%).
M.p.=100-103° C.
EXAMPLE 12
5-Chloro-1-[(4-methylphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 11, the expected product is obtained in the form of a beige solid (yield=93%).
M.p.=165-168° C.
EXAMPLE 13
5-Chloro-1-[(2,3-dichlorophenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 26, the expected product is obtained in the form of a yellow oil (yield=96%).
1H NMR (DMSOd6, 300 MHz) δ=2.77 (t, 2H), 3.15 (t, 2H), 3.59 (s, 3H), 6.65 (s, 1H), 7.26 (dd, 1H), 7.67 (m, 3H), 7.84 (dd, 1H), 8.04 (dd, 1H).
EXAMPLE 14
5-Chloro-1-[(2,3-dichlorophenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 13, the expected product is obtained in the form of a white solid (yield=76%).
M.p.=163-166° C.
EXAMPLE 15
5-Chloro-1-[(3-methylphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 27, the expected product is obtained in the form of a beige solid (yield=68%).
M.p.=105-108° C.
EXAMPLE 16
5-Chloro-1-[(3-methylphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 15, the expected product is obtained in the form of a white solid (yield=92%).
M.p.=161-165° C.
EXAMPLE 17
5-Chloro-1-[(2,4-dichlorophenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 28, the expected product is obtained in the form of a yellow oil (yield=83%).
1H NMR (DMSOd6, 300 MHz) δ=2.76 (t, 2H), 3.15 (t, 2H), 3.59 (s, 3H), 6.63 (s, 1H), 7.26 (dd, 1H), 7.71 (m, 3H), 7.94 (m, 2H).
EXAMPLE 18
5-Chloro-1-[(2,4-dichlorophenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 17, the expected product is obtained in the form of a white solid (yield 76%).
M.p.=179-181° C.
EXAMPLE 19
5-Chloro-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 29, the expected product is obtained in the form of a yellow solid (yield=97%).
M.p.=82-86° C.
EXAMPLE 20
5-Chloro-1-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 19, the expected product is obtained in the form of a beige solid (yield=78%).
M.p.=179-182° C.
EXAMPLE 21
5-Chloro-1-[(4-methoxyphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 30, the expected product is obtained in the form of a yellow solid (yield=68%).
M.p.=98-99° C.
EXAMPLE 22
5-Chloro-1-[(4-methoxyphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 21, the expected product is obtained in the form of a white solid (yield=86%).
M.p.=95-98° C.
EXAMPLE 23
1-[(4-Acetylphenyl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 31, the expected product is obtained in the form of a yellow solid (yield=93%).
M.p.=83-87° C.
EXAMPLE 24
1-[(4-Acetylphenyl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 23, the expected product is obtained in the form of a yellow solid (yield=70%).
M.p.=159-161° C.
EXAMPLE 25
5-Chloro-1-[(4-phenylphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 32, the expected product is obtained in the form of a yellow oil (yield=58%).
1H NMR (DMSOd6, 250 MHz) δ=2.84 (t, 2H), 3.37 (t, 2H), 3.62 (s, 3H), 6.62 (s, 1H), 7.34 (dd, 1H), 7.47 (m, 3H), 7.61 (s, 1H), 7.68 (dd, 2H), 7.88 (d, 4H), 8.07 (d, 1H).
EXAMPLE 26
5-Chloro-1-[(4-phenylphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 25, the expected product is obtained in the form of a white solid (yield=78%).
M.p.=160-162° C.
EXAMPLE 27
5-Chloro-1-[(3-methoxyphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 34, the expected product is obtained in the form of a yellow solid (yield=63%).
M.p.=106-109° C.
EXAMPLE 28
5-Chloro-1-[(3-methoxyphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 27, the expected product is obtained in the form of a white solid (yield=62%).
M.p.=182-184° C.
EXAMPLE 29
5-Chloro-1-[(2,5-dimethoxyphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 35, the expected product is obtained in the form of a yellow solid (yield=85%).
M.p.=120-124° C.
EXAMPLE 30
5-Chloro-1-[(2,5-dimethoxyphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 29, the expected product is obtained in the form of a white solid (yield=88%).
M.p.=185-189° C.
EXAMPLE 31
5-Chloro-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 36, the expected product is obtained in the form of a beige solid (yield=87%).
M.p.=130-133° C.
EXAMPLE 32
5-Chloro-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 31, the expected product is obtained in the form of a white solid (yield=98%).
M.p.=169-171° C.
EXAMPLE 33
5-Chloro-1-[(4-ethylphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 37, the expected product is obtained in the form of a yellow oil (yield=86%).
1H NMR (DMSOd6, 300 MHz) δ=1.12 (t, J=7.56 Hz, 3H), 2.63 (q, 2H), 2.81 (t, J=7.62 Hz, 2H), 3.28 (t, J=4.08 Hz, 2H), 3.61 (s, 3H), 6.57 (s, 1H), 7.31 (dd, J=8.9 Hz, 2.22 Hz, 1H), 7.45 (d, J=12.8 Hz, 2H), 7.59 (s, 1H), 7.74 (d, J=12.78 Hz, 2H), 8.02 (d, J=8.91, 1H).
EXAMPLE 34
5-Chloro-1-[(4-ethylphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 33, the expected product is obtained in the form of a white solid (yield=70%).
M.p.=130-133° C.
EXAMPLE 35
5-Chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 38, the expected product is obtained in the form of a white solid (yield=58%).
M.p.=90-94° C.
EXAMPLE 36
5-Chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 35, the expected product is obtained in the form of a white solid (yield=70%).
M.p.=150-154° C.
EXAMPLE 37
5-Chloro-1-[(4-propylphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 39, the expected product is obtained in the form of a white solid (yield=87%).
M.p.=85-88° C.
EXAMPLE 38
5-Chloro-1-[(4-propylphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 37, the expected product is obtained in the form of a yellow solid (yield=92%).
M.p.=144-148° C.
EXAMPLE 39
5-Chloro-1-[(4-pentylphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 40, the expected product is obtained in the form of a yellow oil (yield=76%).
1H NMR (DMSOd6, 300 MHz) δ=0.81 (t, 3H), 1.22 (m, 4H), 1.50 (m, 2H), 2.58 (t, 2H), 2.81 (t, 2H), 3.28 (t, 2H), 3.61 (s, 3H), 6.58 (s, 1H), 7.31 (dd, 1H), 7.39 (d, 2H), 7.59 (d, 1H), 7.72 (d, 2H), 8.02 (d, 1H).
EXAMPLE 40
5-Chloro-1-[(4-pentylphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 39, the expected product is obtained in the form of a white solid (yield=79%).
M.p.=131-134° C.
EXAMPLE 41
5-Chloro-1-[(3,5-dimethylphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 41, the expected product is obtained in the form of a white solid (yield=90%).
M.p.=146-150° C.
EXAMPLE 42
5-Chloro-1-[(3,5-dimethylphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 41, the expected product is obtained in the form of a white solid (yield=88%).
M.p.=189-193° C.
EXAMPLE 43
5-Chloro-1-[(2,4,6-trimethylphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 42, the expected product is obtained in the form of a white solid (yield=75%).
M.p.=145-148° C.
EXAMPLE 44
5-Chloro-1-[(2,4,6-trimethylphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 43, the expected product is obtained in the form of a white solid (yield 50%).
M.p.=132-134° C.
EXAMPLE 45
5-Chloro-1-[(4-chlorophenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 43, the expected product is obtained in the form of a white solid (yield=98%).
M.p.=89-92° C.
EXAMPLE 46
5-Chloro-1-[(4-chlorophenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 45, the expected product is obtained in the form of a white solid (yield=81%).
M.p.=158-160° C.
EXAMPLE 47
5-Chloro-1-[(4-fluorophenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 44, the expected product is obtained in the form of a white solid (yield=79%).
M.p.=129-131° C.
EXAMPLE 48
5-Chloro-1-[(4-fluorophenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 47, the expected product is obtained in the form of a white solid (yield=78%).
M.p.=145-148° C.
EXAMPLE 49
5-Chloro-1-[(4-chloro-3-methylphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 45, the expected product is obtained in the form of a yellow oil (yield=59%).
1H NMR (DMSOd6, 300 MHz) δ=2.35 (s, 3H), 2.82 (t, 2H), 3.27 (t, 2H), 3.60 (s, 3H), 6.61 (s, 1H), 7.31 (dd, 1H), 7.62 (m, 3H), 7.90 (s, 1H), 8.00 (d, J=9.48, 1H).
EXAMPLE 50
5-Chloro-1-[(4-chloro-3-methylphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 49, the expected product is obtained in the form of a white solid (yield=81%).
M.p.=160-164° C.
EXAMPLE 51
5-Chloro-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 46, the expected product is obtained in the form of a white solid (yield=39%).
M.p.=98-100° C.
EXAMPLE 52
5-Chloro-1-[[3-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 51, the expected product is obtained in the form of a white solid (yield=81%).
M.p.=203-206° C.
EXAMPLE 53
1-[[4-(Acetylamino)phenyl]sulfonyl]-5-chloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 47, the expected product is obtained in the form of a beige solid (yield=71%).
M.p.=154-157° C.
EXAMPLE 54
5-Chloro-1-[(4-cyanophenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 48, the expected product is obtained in the form of a beige solid (yield=72%).
M.p.=155-159° C.
EXAMPLE 55
5-Chloro-1-[(4-phenoxyphenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 49, the expected product is obtained in the form of a yellow oil (yield=80%).
1H NMR (DMSOd6, 300 MHz) δ=2.81 (t, 2H), 3.27 (t, 2H), 3.61 (s, 3H), 6.59 (s, 1H), 7.02-7.13 (m, 4H), 7.30 (m, 2H), 7.45 (m, 2H), 7.60 (s, 1H), 7.83 (d, 2H), 8.01 (d, 1H).
EXAMPLE 56
5-Chloro-1-[(4-phenoxyphenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 55, the expected product is obtained in the form of a white solid (yield 93%).
M.p.=70-75° C.
EXAMPLE 57
5-Chloro-1-[(1-naphthalenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 50, the expected product is obtained in the form of a yellow solid (yield=80%).
M.p.=88-93° C.
EXAMPLE 58
5-Chloro-1-[(1-naphthalenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 57, the expected product is obtained in the form of a white solid (yield=98%).
M.p.=165-175° C.
EXAMPLE 59
5-Chloro-1-[(2-naphthalenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 51, the expected product is obtained in the form of a yellow oil (yield=90%).
1H NMR (DMSOd6, 300 MHz) δ=2.84 (t, 2H), 3.35 (t, 2H), 3.60 (s, 3H), 6.59 (s, 1H), 7.31 (dd, 1H), 7.57 (s, 1H), 7.69 (m, 3H), 7.99-8.2 (m, 4H), 8.72 (s, 1H).
EXAMPLE 60
5-Chloro-1-[(2-naphthalenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 59, the expected product is obtained in the form of a white solid (yield=48%).
M.p.=160° C.
EXAMPLE 61
5-Chloro-1-[(4-methyl-1-naphthalenyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 52, the expected product is obtained in the form of a yellow oil (yield=94%).
1H NMR (DMSOd6, 300 MHz) δ=2.72 (t, 5H), 3.14 (t, 2H), 3.57 (s, 3H), 6.64 (s, 1H), 7.30 (dd, 1H), 7.53 (m, 2H), 7.69 (m, 3H), 7.92 (d, 1H), 8.21 (m, 1H), 8.37 (m, 1H).
EXAMPLE 62
5-Chloro-1-[(4-methyl-1-naphthalenyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 61, the expected product is obtained in the form of a white solid (yield=95%).
M.p.=190-196° C.
EXAMPLE 63
5-Chloro-1-[[5-(aminoacetyl)-1-naphthalenyl]sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 53, the expected product is obtained in the form of a yellow solid (yield=66%).
M.p.=206-210° C.
EXAMPLE 64
5-Chloro-1-[[5-(aminoacetyl)-1-naphthalenyl]sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 63, the expected product is obtained in the form of a white solid (yield=96%).
M.p.=130-135° C.
EXAMPLE 65
5-Chloro-1-[(8-quinolinyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 54, the expected product is obtained in the form of a brown solid (yield=78%).
M.p.=157-161° C.
EXAMPLE 66
5-Chloro-1-[(8-quinolinyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 65, the expected product is obtained in the form of a brown solid (yield=80%).
M.p.=215-222° C.
EXAMPLE 67
5-Chloro-1-(phenylsulfonyl)-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 55, the expected product is obtained in the form of a white solid (yield=81%).
M.p.=109-112° C.
EXAMPLE 68
5-Chloro-1-(phenylsulfonyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 67, the expected product is obtained in the form of a pale pink solid (yield=92%).
M.p.=198-202° C.
EXAMPLE 69
5-Chloro-1-[(2,3-dichlorophenyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 56, the expected product is obtained in the form of a pink powder (yield=72%).
M.p.=115-117° C.
EXAMPLE 70
5-Chloro-1-[(2,3-dichlorophenyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 69, the expected product is obtained in the form of a white powder (yield=93%).
M.p.=195-197° C.
EXAMPLE 71
5-Chloro-1-[(4-methoxyphenyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 57, the expected product is obtained in the form of a yellow powder (yield=98%).
M.p.=97-98° C.
EXAMPLE 72
5-Chloro-1-[(4-methoxyphenyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 71, the expected product is obtained in the form of a pink powder (yield=96%).
M.p.=138-142° C.
EXAMPLE 73
5-Chloro-1-[(8-quinolinyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 58, the expected product is obtained in the form of a pink powder (yield=93%).
M.p.=120-124° C.
EXAMPLE 74
5-Chloro-1-[(8-quinolinyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 73, the expected product is obtained in the form of a white powder (yield=64%).
M.p.=217-219° C.
EXAMPLE 75
5-Chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 59, the expected product is obtained in the form of a pink powder (yield=81%).
M.p.=95-97° C.
EXAMPLE 76
5-Chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 75, the expected product is obtained in the form of a white powder (yield=95%).
M.p.=148° C.
EXAMPLE 77
5-Chloro-1-[(2-naphthalenyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 60, the expected product is obtained in the form of a white powder (yield=71%).
M.p.=116-118° C.
EXAMPLE 78
5-Chloro-1-[(2-naphthalenyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 77, the expected product is obtained in the form of a white powder (yield=90%).
M.p.=166° C.
EXAMPLE 79
5-Chloro-1-[(3,5-dimethylphenyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 61, the expected product is obtained in the form of a white powder (yield=81%).
M.p.=140-143° C.
EXAMPLE 80
5-Chloro-1-[(3,5-dimethylphenyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 79, the expected product is obtained in the form of a white powder (yield=91%).
M.p.=204-206° C.
EXAMPLE 81
5-Chloro-1-[(3-methoxyphenyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 62, the expected product is obtained in the form of a white powder (yield=87%).
M.p.=107-109° C.
EXAMPLE 82
5-Chloro-1-[(3-methoxyphenyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 81, the expected product is obtained in the form of a white powder (yield=79%).
M.p.=170-172° C.
EXAMPLE 83
5-Chloro-1-[(2,5-dimethoxyphenyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 63, the expected product is obtained in the form of a white powder (yield=92%).
M.p.=152-154° C.
EXAMPLE 84
5-Chloro-1-[(2,5-dimethoxyphenyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 83, the expected product is obtained in the form of a white powder (yield=92%).
M.p.=201-209° C.
EXAMPLE 85
5-Chloro-1-[(1-naphthalenyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 64, the expected product is obtained in the form of a cream-colored powder (yield=44%).
M.p.=94-97° C.
EXAMPLE 86
5-Chloro-1-[(1-naphthalenyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 85, the expected product is obtained in the form of a white powder (yield=89%).
M.p.=206-210° C.
EXAMPLE 87
5-Fluoro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 65, the expected product is obtained in the form of beige crystals (yield=58%).
M.p.=79-80° C.
EXAMPLE 88
5,6-Dichloro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 66, the expected product is obtained in the form of a white solid (yield=23%).
M.p.=280° C.
EXAMPLE 89
5,6-Dichloro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 88, the expected product is obtained in the form of a fine pink powder (yield=61%).
M.p.=192-198° C.
EXAMPLE 90
4,5-Dichloro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 67, the expected product is obtained in the form of a yellow solid (yield=68%).
M.p.=142° C.
EXAMPLE 91
4,5-Dichloro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 90, the expected product is obtained in the form of a white powder (yield=52%).
M.p.=220° C.
EXAMPLE 92
1-(Phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 68, the expected product is obtained in the form of white crystals (yield=38%).
M.p.=112-114° C.
EXAMPLE 93
1-(Phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 92, the expected product is obtained in the form of white crystals (yield=72%).
M.p.=168-169° C.
EXAMPLE 94
5-Acetyl-1-(phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 69, the expected product is obtained in the form of a white solid (yield=41%).
M.p.=122-127° C.
EXAMPLE 95
5-Acetyl-1-(phenylsulfonyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 94, the expected product is obtained in the form of a white powder (yield=83%).
M.p.=175-181° C.
EXAMPLE 96
6-Chloro-5-fluoro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 70, the expected product is obtained in the form of a beige solid (yield=51%).
M.p.=127-130° C.
EXAMPLE 97
6-Chloro-5-fluoro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 96, the expected product is obtained in the form of a brown solid (yield=94%).
M.p.=199-204° C.
EXAMPLE 98
5,7-Dichloro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 71, the expected product is obtained in the form of a yellow oil (yield=74%).
1H NMR (DMSOd6, 250 MHz) δ=2.77 (t, 2H), 3.24 (t, 2H), 3.61 (s, 3H), 6.73 (s, 1H), 7.40 (d, 1H), 7.55-7.65 (m, 3H), 7.65-7.8 (m, 3H).
EXAMPLE 99
5,7-Dichloro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 98, the expected product is obtained in the form of a yellow oil (yield=73%).
1H NMR (DMSOd6, 250 MHz) δ=2.63 (t, 2H), 3.19 (t, 2H), 6.71 (s, 1H), 7.40 (d, 1H), 7.55-7.85 (m, 6H).
EXAMPLE 100
5-Cyano-1-(phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 72, the expected product is obtained in the form of a yellow oil (yield=12%).
1H NMR (DMSOd6, 250 MHz) δ=2.84 (t, 2H), 3.31 (t, 2H), 3.61 (s, 3H), 6.72 (s, 1H), 7.55-7.9 (m, 6H), 8.07 (d, 1H), 8.20 (d, 1H).
EXAMPLE 101
5-Cyano-1-(phenylsulfonyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 100, the expected product is obtained in the form of a white solid (yield=67%).
M.p.=187-190° C.
EXAMPLE 102
5-Benzoyl-1-(phenylsulfonyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 73, the expected product is obtained in the form of a yellow solid (yield=43%).
M.p.=37-51° C.
EXAMPLE 103
5-Benzoyl-1-(phenylsulfonyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 102, the expected product is obtained in the form of a yellow solid (yield=83%).
M.p.=138° C.
EXAMPLE 104
5-Chloro-1-(phenylsulfonyl)-1H-indole-2-pentanoic acid methyl ester
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 74, the expected product is obtained in the form of a beige solid (yield=75%).
M.p.=95-98° C.
EXAMPLE 105
5-Chloro-1-(phenylsulfonyl)-1H-indole-2-pentanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 104, the expected product is obtained in the form of a white solid (yield=79%).
M.p.=144-148° C.
EXAMPLE 106
1-(Phenylsulfonyl)-5-(trifluoromethoxy)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparations 1, 2 and 3 and Example 1 starting from 2-iodo-4-(trifluoromethoxy)-1-nitrobenzene, the expected product is obtained in the form of a yellow oil (yield of the final step=64%).
1H NMR (DMSOd6, 300 MHz) δ=2.82 (t, 2H), 3.30 (t, 2H), 3.62 (s, 3H), 6.66 (s, 1H), 7.28 (ddd, 1H), 7.53-7.57 (m, 1H), 7.57-7.64 (m, 1H), 7.68-7.75 (m, 1H), 7.83-7.88 (m, 1H), 8.11 (d, J=9.1 Hz, 1H).
EXAMPLE 107
1-(Phenylsulfonyl)-5-(trifluoromethoxy)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 106, the expected product is obtained in the form of a beige solid (yield=98%).
M.p.=138-146° C.
EXAMPLE 108
5-Chloro-1-(phenylsulfonyl)-1H-indole-2-propanoic acid 1-methylethyl ester
A mixture of 130 mg (0.34 mM) of the methyl ester obtained according to Example 1, 3 ml of isopropanol (1-methylethanol) and 8.6 mg (0.34 mM) of dibutyltin oxide is refluxed for 40 hours. The reaction medium is then concentrated under reduced pressure and the residual oil is taken up in 10 ml of ethyl acetate. The organic phase obtained is washed with sodium bicarbonate solution and then with water and finally dried over magnesium sulfate and concentrated under reduced pressure. The product obtained is purified by chromatography on silica gel using a toluene/ethyl acetate mixture (9/1; v/v) as the eluent to give 96 mg of the expected ester in the form of a yellow oil (yield=69%).
1H NMR (DMSOd6, 300 MHz) δ=1.14 (d, 6H), 2.75 (t, 2H), 3.26 (t, 2H), 4.89 (m, 1H), 6.57 (s, 1H), 7.31 (dd, 1H), 7.58 (m, 3H), 7.69 (d, 1H), 7.82 (d, 2H), 8.02 (d, 1H).
EXAMPLE 109
5-Chloro-1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 75, the expected product is obtained in the form of a white powder (yield=90%).
M.p.=139-140° C.
EXAMPLE 110
5-Chloro-1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 109, the expected product is obtained in the form of a white powder (yield=94%).
M.p.=164-166° C.
EXAMPLE 111
5-Chloro-1-[[1,2,3,4-tetrahydro-2-(trifluoroacetyl)-7-isoquinolinyl]sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 76, the expected product is obtained in the form of a pink powder (yield=89%).
M.p.=111-114° C.
EXAMPLE 112
5-Chloro-1-[[1,2,3,4-tetrahydro-7-isoquinolinyl]sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 111, the expected product is obtained in the form of a white powder (yield=74%).
M.p.=176-182° C.
EXAMPLE 113
5-Chloro-1-[[1,2,3,4-tetrahydro-7-isoquinolinyl]sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 using 1.6 equivalents of lithium hydroxide and starting from the compound obtained according to Example 112, the expected product is obtained in the form of a white powder (yield=63%).
M.p.>250° C.
EXAMPLE 114
5-Chloro-1-[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 77, the expected product is obtained in the form of a pink solid (yield=87%).
M.p.=101-104° C.
EXAMPLE 115
5-Chloro-1-[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 114, the expected product is obtained in the form of a white powder (yield=95%).
M.p.=131-134° C.
EXAMPLE 116
5-Chloro-1-[(6-benzothiazolyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 78, the expected product is obtained in the form of a yellow powder (yield=61%).
M.p.=121-123° C.
EXAMPLE 117
5-Chloro-1-[(6-benzothiazolyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 116, the expected product is obtained in the form of a pale yellow powder (yield=83%).
M.p.=74-80° C.
EXAMPLE 118
5-chloro-1-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 79, the expected product is obtained in the form of a white powder (yield=89%).
M.p.=130-132° C.
EXAMPLE 119
5-Chloro-1-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 118, the expected product is obtained in the form of a white powder (yield=99%).
M.p.=78-82° C.
EXAMPLE 120
5-Chloro-1-[(3,5-dimethyl-4-isoxazolyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 80, the expected product is obtained in the form of a yellow powder (yield=91%).
M.p.=96-98° C.
EXAMPLE 121
5-Chloro-1-[(3,5-dimethyl-4-isoxazolyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 120, the expected product is obtained in the form of a white powder (yield=98%).
M.p.=150-154° C.
EXAMPLE 122
5-Chloro-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 81, the expected product is obtained in the form of a white powder (yield=73%).
M.p.=125-127° C.
EXAMPLE 123
5-Chloro-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 122, the expected product is obtained in the form of a pinkish powder (yield=98%).
M.p.=142-145° C.
EXAMPLE 124
5-Chloro-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 82, the expected product is obtained in the form of a beige powder (yield=42%).
M.p.=163-165° C.
EXAMPLE 125
5-Chloro-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 124, the expected product is obtained in the form of a beige powder (yield=87%).
M.p.=222-225° C.
EXAMPLE 126
5-Chloro-1-[(2,1,3-benzothiadiazol-4-yl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 83, the expected product is obtained in the form of a yellow powder (yield=89%).
M.p.=123-126° C.
EXAMPLE 127
5-Chloro-1-[(2,1,3-benzothiadiazol-4-yl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 126, the expected product is obtained in the form of a yellow powder (yield=89%).
EXAMPLE 128
5-Chloro-1-[(2,1,3-benzothiadiazol-5-yl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 84, the expected product is obtained in the form of a yellow powder (yield=83%).
M.p.=103-106° C.
EXAMPLE 129
5-Chloro-1-[(2,1,3-benzothiadiazol-5-yl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 128, the expected product is obtained in the form of a brown powder (yield=92%).
M.p.=172-175° C.
EXAMPLE 130
5-Chloro-1-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 85, the expected product is obtained in the form of a pink powder (yield=94%).
M.p.=126-129° C.
EXAMPLE 131
5-Chloro-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 130, the expected product is obtained in the form of a white powder (yield=88%).
M.p.=166-169° C.
EXAMPLE 132
5-Chloro-1-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 86, the expected product is obtained in the form of an oil (yield=89%).
1H NMR (DMSOd6, 300 MHz) δ=1.12 (s, 6H), 1.17 (s, 6H), 1.58 (s, 4H), 1.90-2.00 (m, 2H), 2.41 (t, 2H), 3.00 (t, 2H), 3.58 (s, 3H), 6.61 (s, 1H), 7.33 (dd, 1H), 7.46-7.62 (m, 4H), 8.09 (d, 1H).
EXAMPLE 133
5-Chloro-1-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 132, the expected product is obtained in the form of a white powder (yield=95%).
M.p.=64-66° C.
EXAMPLE 134
1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 87, the expected product is obtained in the form of a white powder (yield=82%).
M.p.=162-165° C.
EXAMPLE 135
1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 134, the expected product is obtained in the form of a white powder (yield=94%).
M.p.=115-117° C.
EXAMPLE 136
5-Chloro-1-[(2-methyl-6-benzothiazolyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 88, the expected product is obtained in the form of a white powder (yield=74%).
M.p.=151-153° C.
EXAMPLE 137
5-Chloro-1-[(2-methyl-6-benzothiazolyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 136, the expected product is obtained in the form of a white powder (yield=85%).
M.p.=163-165° C.
EXAMPLE 138
1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-chloro-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 89, the expected product is obtained in the form of a beige powder (yield=63%).
M.p.=120° C.
EXAMPLE 139
1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-chloro-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 138, the expected product is obtained in the form of a white solid (yield=70%).
M.p.>250° C.
EXAMPLE 140
5-Chloro-1-[(2-methyl-6-benzoxazolyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 91, the expected product is obtained in the form of a white solid (yield=83%).
M.p.=100-110° C.
EXAMPLE 141
5-Chloro-1-[(2,3-dihydro-5-benzofuranyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 92, the expected product is obtained in the form of a white solid (yield=85%).
M.p.=132-137° C.
EXAMPLE 142
5-Chloro-1-[(2,3-dihydro-5-benzofuranyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 141, the expected product is obtained in the form of a white solid (yield=98%).
M.p.=174-179° C.
EXAMPLE 143
5-Chloro-1-[(2-methyl-5-benzothiazolyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 93, the expected product is obtained in the form of a yellow powder (yield=77%).
M.p.=136-138° C.
EXAMPLE 144
5-Chloro-1-[(2-methyl-5-benzothiazolyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 143, the expected product is obtained in the form of a white powder (yield=98%).
M.p.=164° C.
EXAMPLE 145
1-[(2-Amino-6-benzoxazolyl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 94, the expected product is obtained in the form of a yellow powder (yield=46%).
M.p.=238° C.
EXAMPLE 146
1-[(2-Amino-6-benzoxazolyl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 145, the expected product is obtained in the form of a yellow powder (yield=76%).
M.p.=220° C.
EXAMPLE 147
1-[[2-(Acetylamino)-4-methyl-5-thiazolyl]sulfonyl]-5-chloro-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 95, the expected product is obtained in the form of a yellow powder (yield=36%).
M.p.=156-160° C.
EXAMPLE 148
1-[[2-(Acetylamino)-4-methyl-5-thiazolyl]sulfonyl]-5-chloro-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 147, the expected product is obtained in the form of a white powder (yield=74%).
M.p.=231-233° C.
EXAMPLE 149
5-Chloro-1-[(1,2,3,4-tetrahydro-2-oxo-6-quinolinyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 96, the expected product is obtained in the form of a white powder (yield=19%).
M.p.=198-205° C.
EXAMPLE 150
1-[(2-Acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid methyl ester
A solution of 1.25 g (2.8 mM) of the compound obtained according to Example 112 in 12 ml of dichloromethane is prepared and 0.860 ml (6.17 mM) of triethylamine is added, followed by the dropwise addition of 0.2 ml of acetyl chloride. The reaction mixture is stirred at room temperature for 2 hours and then poured into 15 ml of iced water. The mixture is decanted, the aqueous phase is extracted with 20 ml of dichloromethane and the combined organic phases are washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is purified by chromatography on silica gel using a dichloromethane/methanol mixture (99/1; v/v) as the eluent. This gives 0.93 g of the expected compound in the form of a white powder (yield=67%).
M.p.=50-52° C.
EXAMPLE 151
1-[(2-acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 150, the expected product is obtained in the form of a white powder (yield=98%).
M.p.=95-97° C.
EXAMPLE 152
5-Chloro-1-[(2-pyridinyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
A solution of 350 mg (0.89 mM) of N-(4-chloro-2-iodophenyl)-2-pyridinesulfonamide (Preparation 117) in 6 ml of dimethylformamide is prepared and 10 ml of diethylamine, 8 mg (0.042 mM) of cuprous iodide, 16 mg (0.02 mM) of bis(triphenylphosphine)dichloropalladium and, finally, 134 mg (1.06 mM) of the methyl ester of 5-hexynoic acid are added. The mixture is stirred at the reflux temperature of the solvents for 1 hour and then at room temperature overnight. After hydrolysis in 20 ml of water, the mixture is extracted with 40 ml of ethyl acetate. The organic phase obtained is washed with N hydrochloric acid solution and then with sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (80/20; v/v) as the eluent to give 0.23 g of the expected compound in the form of a brown solid (yield=84%).
M.p.=94° C.
EXAMPLE 153
5-Chloro-1-[(2-pyridinyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 152, the expected product is obtained in the form of a white powder (yield=97%).
M.p.=192° C.
EXAMPLE 154
1-[(6-Benzothiazolyl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 97, the expected product is obtained in the form of a yellow powder (yield=73%).
M.p.=134-138° C.
EXAMPLE 155
1-[(6-Benzothiazolyl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 154, the expected product is obtained in the form of a white powder (yield=96%).
M.p.=96-100° C.
EXAMPLE 156
1-[[2-(acetylamino)-6-benzothiazolyl]sulfonyl]-5-chloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 98, the expected product is obtained in the form of a beige powder (yield 60%).
M.p.=217-221° C.
EXAMPLE 157
1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-chloro-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 156, the expected product is obtained in the form of a white powder (yield=88%).
M.p.>250° C.
EXAMPLE 158
1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 99, the expected product is obtained in the form of a beige powder (yield=89%).
M.p.=129° C.
EXAMPLE 159
1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 158, the expected product is obtained in the form of a white powder (yield=94%).
M.p.=220-223° C.
EXAMPLE 160
1-[(1,3-Benzodioxol-5-yl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 100, the expected product is obtained in the form of a beige powder (yield=90%).
M.p.=122-129° C.
EXAMPLE 161
1-[(1,3-Benzodioxol-5-yl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 160, the expected product is obtained in the form of a white powder (yield=98%).
M.p.=207° C.
EXAMPLE 162
1-[(1,3-Benzodioxol-5-yl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 101, the expected product is obtained in the form of a beige powder (yield=97%).
M.p.=98-103° C.
EXAMPLE 163
1-[(1,3-Benzodioxol-5-yl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 162, the expected product is obtained in the form of a white powder (yield=96%).
M.p.=154-156° C.
EXAMPLE 164
5-Chloro-1-[[4-(4-morpholinylsulfonyl)phenyl]sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 102, the expected product is obtained in the form of a yellow powder (yield=94%).
M.p.=54° C.
EXAMPLE 165
5-Chloro-1-[[4-(4-morpholinylsulfonyl)phenyl]sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 164, the expected product is obtained in the form of a white powder (yield=93%).
M.p.=181° C.
EXAMPLE 166
5-Chloro-1-[(2-pyridinyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 152 starting from the methyl ester of 4-pentynoic acid, the expected product is obtained in the form of an orange solid (yield=72%).
M.p.=121° C.
EXAMPLE 167
5-Chloro-1-[(2-pyridinyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 166, the expected product is obtained in the form of a white powder (yield=90%).
M.p.=189° C.
EXAMPLE 168
1-[(6-Benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 118, the expected product is obtained in the form of a yellow powder (yield=49%).
M.p.=117-121° C.
EXAMPLE 169
1-[(6-Benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 168, the expected product is obtained in the form of a beige powder (yield=97%).
M.p.=175-181° C.
EXAMPLE 170
1-[(6-Benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 104, the expected product is obtained in the form of a yellow powder (yield=64%).
M.p.=130-132° C.
EXAMPLE 171
1-[(6-Benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 170, the expected product is obtained in the form of a yellow powder (yield=97%).
EXAMPLE 172
1-[(2-methyl-6-benzoxazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 105, the expected product is obtained in the form of a beige powder (yield=90%).
M.p.=78-82° C.
EXAMPLE 173
1-[(2-Methyl-6-benzoxazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 172, the expected product is obtained in the form of a beige powder (yield=31%).
M.p.=214-220° C.
EXAMPLE 174
1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 106, the expected product is obtained in the form of a beige powder (yield=70%).
M.p.=135-139° C.
EXAMPLE 175
1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 174, the expected product is obtained in the form of a white solid (yield=45%).
M.p.=183° C.
EXAMPLE 176
1-[(2,3-dihydro-5-benzofuranyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 107, the expected product is obtained in the form of a colorless paste (yield=47%).
1H NMR (DMSOd6, 300 MHz) δ=1.95-2.03 (m, 2H), 2.45 (t, 2H), 3.06 (t, 2H), 3.16 (t, 2H), 3.59 (s, 3H), 4.60 (t, 2H), 6.74 (s, 1H), 6.90 (d, 1H), 7.60 (dd, 1H), 7.66 (dd, 1H), 7.75 (s, 1H), 7.92 (s, 1H), 8.23 (d, 1H).
EXAMPLE 177
1-[(2,3-Dihydro-5-benzofuranyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 176, the expected product is obtained in the form of a white solid (yield=98%).
M.p.=144-149° C.
EXAMPLE 178
1-[(2-Methyl-5-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 108, the expected product is obtained in the form of a brown paste (yield=70%).
1H NMR (DMSOd6, 300 MHz) δ=1.99 (t, 2H), 2.46 (t, 2H), 2.81 (s, 3H), 3.11 (t, 2H), 3.58 (s, 3H), 6.77 (s, 1H), 7.63 (dd, 1H), 7.80 (dd, 1H), 7.92 (s, 1H), 8.27 (d, 1H), 8.31 (d, 1H), 8.34 (s, 1H).
EXAMPLE 179
1-[(2-Methyl-5-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 178, the expected product is obtained in the form of a beige powder (yield=98%).
M.p.=171-178° C.
EXAMPLE 180
1-[(2-amino-6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 109, the expected product is obtained in the form of a yellow powder (yield=62%).
M.p.=135-136° C.
EXAMPLE 181
1-[(2-Amino-6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 180, the expected product is obtained in the form of a white powder (yield=19%).
M.p.>250° C.
EXAMPLE 182
1-[(2-Methyl-6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 110, the expected product is obtained in the form of a white powder (yield=44%).
M.p.=214-215° C.
EXAMPLE 183
1-[(2-Methyl-6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 182, the expected product is obtained in the form of a pale yellow powder (yield=62%).
M.p.=186-187° C.
EXAMPLE 184
1-[(2-Methyl-5-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 111, the expected product is obtained in the form of a beige powder (yield=53%).
1H NMR (DMSOd6, 300 MHz) δ=2.81 (s, 3H), 2.85 (d, 2H), 3.32 (d, 2H), 3.61 (s, 3H), 6.74 (s, 1H), 7.63 (dd, 1H), 7.81 (dd, 1H), 7.93 (s, 1H), 8.27-8.31 (m, 2H), 8.35 (d, 1H).
EXAMPLE 185
1-[(2-Methyl-5-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 184, the expected product is obtained in the form of a white powder (yield=80%).
M.p.=235-236° C.
EXAMPLE 186
1-[(2-Methyl-6-benzoxazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 112, the expected product is obtained in the form of a yellow oil (yield=56%).
1H NMR (DMSOd6, 300 MHz) δ=2.63 (s, 3H), 2.84 (d, 2H), 3.33 (d, 2H), 353 (s, 3H), 6.73 (s, 1H), 7.61 (dd, 1H), 7.78-7.93 (m, 3H), 8.29 (d, 1H), 8.35 (s, 1H).
EXAMPLE 187
1-[(2-Methyl-7-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 113, the expected product is obtained in the form of a yellow powder (yield=83%).
M.p.=106-108° C.
EXAMPLE 188
1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 114, the expected product is obtained in the form of an oil (yield=66%).
1H NMR (DMSOd6, 300 MHz) δ=2.1 (s, 3H), 2.8 (t, 2H), 3.1 (t, 2H), 3.3 (t, 2H), 3.61 (s, 3H), 4.1 (t, 2H), 6.7 (s, 1H), 7.6 (dd, 1H), 7.7 (s, 1H), 7.7 (dd, 1H), 7.9 (d, 1H), 8.2 (d, 1H).
EXAMPLE 189
1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 188, the expected product is obtained in the form of a white powder (yield=40%).
M.p.=205-207° C.
EXAMPLE 190
1-[(2,3-Dihydro-5-benzofuranyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 115, the expected product is obtained in the form of a colorless paste (yield=79%).
1H NMR (DMSOd6, 300 MHz) δ=2.83 (t, 2H), 3.19 (t, 2H), 3.32 (t, 2H), 3.62 (s, 3H), 4.61 (t, 2H), 6.71 (d, 1H), 6.90 (d, 1H), 7.60 (dd, 1H), 7.68 (dd, 1H), 7.76 (d, 1H), 7.93 (d, 1H), 8.23 (dd, 1H).
EXAMPLE 191
1-[(2,3-Dihydro-5-benzofuranyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 190, the expected product is obtained in the form of a beige powder (yield=34%).
M.p.=161-164° C.
EXAMPLE 192
1-[[4-(4-Morpholinylsulfonyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 116, the expected product is obtained in the form of a white solid (yield=78%).
M.p.=186-187° C.
EXAMPLE 193
1-[[4-(4-Morpholinylsulfonyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 192, the expected product is obtained in the form of a white powder (yield=36%).
M.p.=238-239° C.
EXAMPLE 194
1-[(2-Amino-6-benzothiazolyl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 90, the expected product is obtained in the form of a yellow solid (yield=44%).
M.p.=235-239° C.
EXAMPLE 195
1-[(2-Amino-6-benzothiazolyl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 194, the expected product is obtained in the form of a beige powder (yield=49%).
M.p.=155-162° C.
EXAMPLE 196
1-[(2,3-Dihydro-1H-indol-5-yl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 (except that 4 equivalents of lithium hydroxide are used) starting from the compound obtained according to Example 174, the expected product is obtained in the form of a beige solid (yield=36%).
M.p.=175° C.
EXAMPLE 197
1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 3 starting from the compound obtained according to Preparation 119 and 2-(acetylamino)-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a yellow solid (yield=14%).
M.p.=215° C.
EXAMPLE 198
1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 197, the expected product is obtained in the form of a white powder (yield=57%).
M.p.>250° C.
EXAMPLE 199
1-[(2-Methyl-6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 197 starting from 2-methyl-6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a beige solid (yield=12%).
M.p.=163-168° C.
EXAMPLE 200
1-[(2-Methyl-6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 199, the expected product is obtained in the form of a beige solid (yield=87%).
M.p.=184-187° C.
EXAMPLE 201
2-[[5-Chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
A mixture of 600 mg (1.52 mM) of N-(4-chloro-2-iodophenyl)benzenesulfonamide (Preparation 120) and 0.5 ml of dimethylformamide is prepared in a microwave reaction tube and 14 mg (0.076 mM) of cuprous iodide, 27 mg (0.038 mM) of bis(triphenylphosphine)dichloropalladium, 357 mg (2.3 mM) of the ethyl ester of 2-(2-propynyloxy)propanoic acid and, finally, 0.5 ml of diethylamine are added. The mixture is heated by microwaves at 130° C. for 15 min and then cooled and hydrolyzed with 10 ml of water. The mixture is extracted three times with 15 ml of ethyl acetate and the combined organic phases are washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (95/5; v/v) as the eluent to give 0.44 g of the expected compound in the form of a yellow oil (yield=69%).
1H NMR (DMSOd6, 300 MHz) δ=1.17 (t, 3H), 1.32 (d, 3H), 4.13 (q, 2H), 4.22 (q, 1H), 4.87 (d, 1H), 4.99 (d, 1H), 6.85 (s, 1H), 7.36 (dd, 1H), 7.58 (t, 2H), 7.68 (d, 1H), 7.70 (t, 1H), 7.96 (d, 2H), 7.99 (d, 1H).
EXAMPLE 202
2-[[5-Chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 201, the expected product is obtained in the form of a pasty white solid (yield=85%).
1H NMR (DMSOd6, 300 MHz) δ=1.31 (d, 3H), 4.14 (q, 1H), 4.84 (d, 1H), 5.02 (d, 1H), 6.85 (d, 1H), 7.35 (dd, 1H), 7.57 (t, 2H), 7.67 (d, 1H), 7.70 (tt, 1H), 7.96 (dt, 2H), 7.99 (d, 1H), 12.80 (broad m, 1H).
EXAMPLE 203
[[5-Chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methoxy]acetic acid methyl ester
By following a procedure analogous to Example 201 starting from the methyl ester of (2-propynyloxy)acetic acid, the expected compound is obtained in the form of a pale yellow solid (yield=71%).
M.p.=98-100° C.
EXAMPLE 204
[[5-Chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methoxy]acetic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 203, the expected product is obtained in the form of a white solid (yield=98%).
M.p.=140-142° C.
EXAMPLE 205
2-[[5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid ethyl ester
By following a procedure analogous to Example 201 starting from the methyl ester of 2-methyl-2-(2-propynyloxy)propanoic acid, the expected compound is obtained in the form of a yellow oil (yield=59%).
1H NMR (DMSOd6, 300 MHz) δ=1.45 (s, 6H), 3.66 (s, 3H), 4.83 (s, 2H), 6.82 (s, 1H), 7.35 (dd, 1H), 7.61 (t, 2H), 7.68 (m, 2H), 7.96 (dt, 2H), 8.01 (d, 1H).
EXAMPLE 206
2-[[5-Chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 205, the expected product is obtained in the form of a pasty white solid (yield=83%).
1H NMR (DMSOd6, 300 MHz) δ=1.43 (s, 6H), 4.86 (s, 2H), 6.81 (s, 1H), 7.33 (dd, 1H), 7.58 (t, 2H), 7.67 (m, 2H), 7.94 (dt, 2H), 7.99 (d, 1H), 12.80 (broad m, 1H).
EXAMPLE 207
[[1-(Phenylsulfonyl)-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]acetic acid methyl ester
By following a procedure analogous to Example 203 starting from the sulfonamide obtained according to Preparation 121, the expected compound is obtained in the form of a yellow solid (yield=50%).
M.p.=90-92° C.
EXAMPLE 208
[[1-(Phenylsulfonyl)-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]acetic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 207, the expected product is obtained in the form of a yellow solid (yield=85%).
M.p.=158-160° C.
EXAMPLE 209
2-[[1-(Phenylsulfonyl)-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 201 starting from the sulfonamide obtained according to Preparation 121, the expected compound is obtained in the form of a yellow oil (yield=74%).
1H NMR (DMSOd6, 300 MHz) δ=1.19 (t, 3H), 1.32 (d, 3H), 4.13 (q, 2H), 4.24 (d, 1H), 4.91 (d, 1H), 5.03 (d, 1H), 7.01 (s, 1H), 7.60 (t, 2H), 7.69 (dd, 1H), 7.72 (t, 1H), 8.01 (dt, 2H), 8.21 (d, 1H).
EXAMPLE 210
2-[[1-(Phenylsulfonyl)-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 209, the expected product is obtained in the form of a white solid (yield=50%).
M.p.=72-74° C.
EXAMPLE 211
2-Methyl-2-[[1-(phenylsulfonyl)-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 205 starting from the sulfonamide obtained according to Preparation 121, the expected compound is obtained in the form of a beige solid (yield=46%).
M.p.=62-64° C.
EXAMPLE 212
2-Methyl-2-[[1-(phenylsulfonyl)-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 211, the expected product is obtained in the form of a white solid (yield=50%).
M.p.=134-136° C.
EXAMPLE 213
[2-[5-Chloro-1-(phenylsulfonyl)-1H-indol-2-yl]ethoxy]acetic acid ethyl ester
By following a procedure analogous to Example 201 starting from the ethyl ester of (3-butynyloxy)acetic acid, the expected compound is obtained in the form of an orange solid (yield=79%).
M.p.=60-62° C.
EXAMPLE 214
[2-[5-Chloro-1-(phenylsulfonyl)-1H-indol-2-yl]ethoxy]acetic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 213, the expected product is obtained in the form of a white solid (yield=97%).
M.p.=135-137° C.
EXAMPLE 215
2-Methyl-2-[[1-[(6-benzothiazolyl)sulfonyl]-5-chloro-1H-indol-2-yl]methoxy]propanoic acid methyl ester
A mixture of 126 mg (0.26 mM) of the ester obtained according to Preparation 123 and 1 ml of 1,2-dichloroethane is prepared in a microwave reaction tube and 48 mg (0.26 mM) of copper (cupric) acetate are added. The mixture is heated by microwaves at 150° C. for 15 minutes and then cooled, diluted with 6 ml of dichloromethane and filtered on Whatman paper. The filtrate is concentrated under reduced pressure and the crude product is purified by chromatography on silica gel using a dichloromethane/ethyl acetate mixture (97/3; v/v) as the eluent to give 79 mg of the expected compound in the form of a pasty yellow solid (yield=63%).
1H NMR (DMSOd6, 300 MHz) δ=1.46 (s, 6H), 3.65 (s, 3H), 4.88 (s, 2H), 6.83 (s, 1H), 7.35 (dd, 1H), 7.66 (d, 1H), 8.02 (dd, 1H), 8.07 (d, 1H), 8.23 (d, 1H), 9.07 (d, 1H), 9.66 (s, 1H).
EXAMPLE 216
2-Methyl-2-[[1-[(6-benzothiazolyl)sulfonyl]-5-chloro-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 215, the expected product is obtained in the form of a white solid (yield=94%).
M.p.=74° C.
EXAMPLE 217
2-Methyl-2-[[1-[(6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]-methoxy]propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 125, the expected product is obtained in the form of a yellow oil (yield=72%).
1H NMR (DMSOd6, 250 MHz) δ=1.46 (s, 6H), 3.65 (s, 3H), 4.92 (s, 2H), 6.98 (s, 1H), 7.65 (dd, 1H), 8.02 (s, 1H), 8.07 (dd, 1H), 8.26 (t, 2H), 9.12 (d, 1H), 9.66 (s, 1H).
EXAMPLE 218
2-Methyl-2-[[1-[(6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]-methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 217, the expected product is obtained in the form of a white solid (yield=98%).
M.p.=98-100° C.
EXAMPLE 219
2-Methyl-2-[[1-[(2-methyl-6-benzothiazolyl)sulfonyl]-5-chloro-1H-indol-2-yl]-methoxy]propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 126, the expected product is obtained in the form of a white paste (yield=73%).
1H NMR (DMSOd6, 250 MHz) δ=1.46 (s, 6H), 2.83 (s, 3H), 3.66 (s, 3H), 4.87 (s, 2H), 6.82 (s, 1H), 7.35 (dd, 1H), 7.66 (d, 1H), 7.96 (dd, 1H), 8.03 (d, 1H), 8.06 (d, 1H), 8.92 (d, 1H).
EXAMPLE 220
2-Methyl-2-[1-[[(2-methyl-6-benzothiazolyl)sulfonyl]-5-chloro-1H-indol-2-yl]-methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 219, the expected product is obtained in the form of a white solid (yield=86%).
M.p.=172-174° C.
EXAMPLE 221
2-Methyl-2-[[1-[(2-methyl-5-benzothiazolyl)sulfonyl]-5-chloro-1H-indol-2-yl]-methoxy]propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 127, the expected product is obtained in the form of a white solid (yield=71%).
M.p.=132-134° C.
EXAMPLE 222
2-Methyl-2-[[1-[(2-methyl-5-benzothiazolyl)sulfonyl]-5-chloro-1H-indol-2-yl]-methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 221, the expected product is obtained in the form of a white solid (yield=86%).
M.p.=134-136° C.
EXAMPLE 223
2-[[1-[(6-Benzothiazolyl)sulfonyl]-5-chloro-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 129, the expected product is obtained in the form of yellow oil (yield=89%).
1H NMR (DMSOd6, 250 MHz) δ=1.17 (t, 3H), 1.32 (d, 3H), 4.11 (q, 2H), 4.22 (q, 1H), 4.92 (d, 1H), 5.03 (d, 1H), 6.86 (s, 1H), 7.36 (dd, 1H), 7.67 (d, 1H), 8.04 (dd, 1H), 8.08 (d, 1H), 8.21 (d, 1H), 9.08 (d, 1H), 9.66 (s, 1H).
EXAMPLE 224
2-[[1-[(6-Benzothiazolyl)sulfonyl]-5-chloro-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 223, the expected product is obtained in the form of a white solid (yield=98%).
M.p.=102-104° C.
EXAMPLE 225
1-[(1,3-Benzodioxol-5-yl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 130, the expected product is obtained in the form of a beige paste (yield=43%).
1H NMR (DMSOd6, 250 MHz) δ=1.95-2.03 (m, 2H), 2.4 (t, 2H), 3.06 (t, 2H), 3.59 (s, 3H), 6.14 (s, 2H), 6.75 (s, 1H), 7.05 (d, 1H), 7.33 (s, 1H), 7.48 (dd, 1H), 7.59 (dd, 1H), 7.93 (s, 1H), 8.23 (d, 1H).
EXAMPLE 226
1-[(1,3-Benzodioxol-5-yl)sulfonyl]-5-(trifluoromethyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 225, the expected product is obtained in the form of a pink powder (yield=59%).
M.p.=171-175° C.
EXAMPLE 227
1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Preparation 6 starting from the compound obtained according to Preparation 131, the expected product is obtained in the form of a yellow powder (yield=20%).
1H NMR (DMSOd6, 500 MHz) δ=2.24 (s, 3H), 2.87 (t, 2H), 3.40 (t, 2H), 3.64 (s, 3H), 6.75 (s, 1H), 7.64 (d, 1H), 7.85 (s, 2H), 7.95 (s, 1H), 8.29 (d, 1H), 8.80 (s, 1H), 12.68 (s, 1H).
EXAMPLE 228
1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-(trifluoromethyl)-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 227, the expected product is obtained in the form of a yellow powder (yield=73%).
M.p.>290-292° C.
EXAMPLE 229
2-Methyl-2-[[1-[(2-methyl-5-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 132, the expected product is obtained in the form of a white solid (yield=57%).
M.p.=164-166° C.
EXAMPLE 230
2-Methyl-2-[[1-[(2-methyl-5-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 229, the expected product is obtained in the form of a white solid (yield=97%).
M.p.=188-190° C.
EXAMPLE 231
2-[[1-(1,3-Benzodioxol-5-ylsulfonyl)-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 133, the expected product is obtained in the form of a colorless oil (yield=71%).
1H NMR (DMSOd6, 250 MHz) δ=8.19 (d, 1H), 8.02 (d, 1H), 7.64 (m, 2H), 7.57 (d, 1H), 7.08 (d, 1H), 6.97 (d, 1H), 6.14 (s, 2H), 4.85 (s, 2H), 3.68 (s, 3H), 1.49 (s, 6H).
EXAMPLE 232
2-[[1-(1,3-Benzodioxol-5-ylsulfonyl)-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 231, the expected product is obtained in the form of a white solid (yield=94%).
M.p.=130-132° C.
EXAMPLE 233
2-[[1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 134, the expected product is obtained in the form of a white solid (yield=52%).
M.p.=212-214° C.
EXAMPLE 234
2-[[1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 233, the expected product is obtained in the form of a beige solid (yield=86%).
M.p.=144-146° C.
EXAMPLE 235
2-[[1-[(2,3-Dihydro-5-benzofuranyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 135, the expected product is obtained in the form of a colorless oil (yield=75%).
1H NMR (DMSOd6, 250 MHz) δ=8.19 (d, 1H), 8.02 (s, 1H), 7.92 (d, 1H), 7.83 (dd, 1H), 7.63 (dd, 1H), 6.94 (s, 1H), 6.91 (d, 1H), 4.87 (s, 2H), 4.61 (t, 2H), 3.68 (s, 3H), 3.19 (t, 2H), 1.48 (s, 6H).
EXAMPLE 236
2-[[1-[(2,3-Dihydro-5-benzofuranyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 235, the expected product is obtained in the form of a white solid (yield=99%).
M.p.=92-94° C.
EXAMPLE 237
2-Methyl-2-[[1-[(2-methyl-7-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 136, the expected product is obtained in the form of a beige solid (yield=75%).
M.p.=118-120° C.
EXAMPLE 238
2-Methyl-2-[[1-[(2-methyl-7-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 237, the expected product is obtained in the form of a white solid (yield=91%).
M.p.=98-100° C.
EXAMPLE 239
2-[[1-[(2,3-Dihydro-1,4-benzodioxin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 137, the expected product is obtained in the form of a white solid (yield=81%).
M.p.=128-130° C.
EXAMPLE 240
2-[[1-[(2,3-Dihydro-1,4-benzodioxin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 239, the expected product is obtained in the form of a white solid (yield=95%).
M.p.=75° C.
EXAMPLE 241
2-[[1-[(3,4-Dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 138, the expected product is obtained in the form of a white solid (yield=85%).
M.p.=96-98° C.
EXAMPLE 242
2-[[1-[(3,4-Dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 241, the expected product is obtained in the form of a white solid (yield=99%).
M.p.=148-150° C.
EXAMPLE 243
2-[[1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 139, the expected product is obtained in the form of a white solid (yield=84%).
M.p.=154-156° C.
EXAMPLE 244
2-[[1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 243, the expected product is obtained in the form of a white solid (yield=61%).
M.p.=176-178° C.
EXAMPLE 245
2-[[1-[(3,5-Dimethylphenyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 140, the expected product is obtained in the form of a white solid (yield=86%).
M.p.=132-134° C.
EXAMPLE 246
2-[[1-[(3,5-Dimethylphenyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 245, the expected product is obtained in the form of a white solid (yield=82%).
M.p.=150-152° C.
EXAMPLE 247
2-[[1-[(2,5-Dimethoxyphenyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 141, the expected product is obtained in the form of a white solid (yield=84%).
M.p.=130-132° C.
EXAMPLE 248
2-[[1-[(2,5-Dimethoxyphenyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 247, the expected product is obtained in the form of a white solid (yield=50%).
M.p.=186-188° C.
EXAMPLE 249
2-[[1-[[4-(1-Methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 142, the expected product is obtained in the form of a colorless oil (yield=86%).
1H NMR (DMSOd6, 250 MHz) δ=8.23 (d, 1H), 8.02 (d, 1H), 7.91 (dt, 2H), 7.65 (dd, 1H), 7.49 (dt, 2H), 6.96 (d, 1H), 4.86 (s, 2H), 3.68 (s, 3H), 2.92 (hep, 1H), 1.46 (s, 6H), 1.15 (d, 6H).
EXAMPLE 250
2-[[1-[[4-(1-Methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 249, the expected product is obtained in the form of a white solid (yield=74%).
M.p.=132-134° C.
EXAMPLE 251
2-[[1-(1,3-Benzodioxol-5-ylsulfonyl)-5-chloro-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 143, the expected product is obtained in the form of a white solid (yield=83%).
M.p.=90-92° C.
EXAMPLE 252
2-[[1-(1,3-Benzodioxol-5-ylsulfonyl)-5-chloro-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 251, the expected product is obtained in the form of a white solid (yield=99%).
M.p.=174-176° C.
EXAMPLE 253
2-[[1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-chloro-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 144, the expected product is obtained in the form of a yellow solid (yield=34%).
M.p.=112-114° C.
EXAMPLE 254
2-[[1-[[2-(Acetylamino)-6-benzothiazolyl]sulfonyl]-5-chloro-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 253, the expected product is obtained in the form of a white solid (yield=90%).
M.p.=162-164° C.
EXAMPLE 255
2-[[1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-chloro-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 145, the expected product is obtained in the form of a beige solid (yield=90%).
M.p.=128-130° C.
EXAMPLE 256
2-[[1-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-5-chloro-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 255, the expected product is obtained in the form of a white solid (yield=95%).
M.p.=142-144° C.
EXAMPLE 257
2-[[5-Chloro-1-[(2,3-dihydro-5-benzofuranyl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 146, the expected product is obtained in the form of a colorless oil (yield=80%).
1H NMR (DMSOd6, 300 MHz) δ=8.10 (d, 1H), 7.86 (d, 1H), 7.77 (dd, 1H), 7.66 (d, 1H), 7.33 (dd, 1H), 7.89 (d, 1H), 6.79 (s, 1H), 4.83 (s, 2H), 4.60 (t, 2H), 3.67 (s, 3H), 3.18 (t, 2H), 1.47 (s, 6H).
EXAMPLE 258
2-[[5-Chloro-1-[(2,3-dihydro-5-benzofuranyl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 257, the expected product is obtained in the form of a white solid (yield=94%).
M.p.=130-132° C.
EXAMPLE 259
2-Methyl-2-[[5-chloro-1-[(2-methyl-7-benzothiazolyl)sulfonyl]-1H-indol-2-yl]-methoxy]propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 147, the expected product is obtained in the form of a yellow oil (yield=78%).
1H NMR (DMSOd6, 250 MHz) δ=8.24 (dd, 1H), 7.95 (d, 1H), 7.84 (dd, 1H), 7.69 (m, 2H), 7.33 (dd, 1H), 6.87 (d, 1H), 4.81 (s, 2H), 3.62 (s, 3H), 2.85 (s, 3H), 1.34 (s, 6H).
EXAMPLE 260
2-Methyl-2-[[5-chloro-1-[(2-methyl-7-benzothiazolyl)sulfonyl]-1H-indol-2-yl]-methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 259, the expected product is obtained in the form of a white solid (yield=94%).
M.p.=128-130° C.
EXAMPLE 261
2-[[5-Chloro-1-[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 148, the expected product is obtained in the form of a colorless oil (yield 87%).
1H NMR (DMSOd6, 300 MHz) δ=8.02 (d, 1H), 7.88 (d, 2H), 7.67 (d, 1H), 7.46 (d, 2H), 7.36 (dd, 1H), 6.81 (s, 1H), 4.82 (s, 2H), 3.66 (s, 3H), 2.97 (hep, 1H), 1.45 (s, 6H), 1.15 (d, 6H).
EXAMPLE 262
2-[[5-Chloro-1-[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 261, the expected product is obtained in the form of a white solid (yield=88%).
M.p.=156-158° C.
EXAMPLE 263
2-[[5-Chloro-1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-1-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 149, the expected product is obtained in the form of a white solid (yield=85%).
M.p.=96-98° C.
EXAMPLE 264
2-[[5-Chloro-1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 263, the expected product is obtained in the form of a white solid (yield=98%).
M.p.=148-150° C.
EXAMPLE 265
2-[[5-Chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 150, the expected product is obtained in the form of a colorless oil (yield=94%).
1H NMR (DMSOd6, 300 MHz) δ=8.02 (d, 1H), 7.88 (d, 2H), 7.67 (d, 1H), 7.46 (d, 2H), 7.36 (dd, 1H), 6.81 (s, 1H), 4.82 (s, 2H), 3.66 (s, 3H), 2.97 (hep, 1H), 1.45 (s, 6H), 1.15 (d, 6H).
EXAMPLE 266
2-[[5-Chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 265, the expected product is obtained in the form of a pale yellow solid (yield=95%).
M.p.=60° C.
EXAMPLE 267
2-[[5-Chloro-1-[(3,5-dimethylphenyl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 151, the expected product is obtained in the form of a white solid (yield=94%).
M.p.=110-112° C.
EXAMPLE 268
2-[[5-Chloro-1-[(3,5-dimethylphenyl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 267, the expected product is obtained in the form of a white solid (yield=97%).
M.p.=162-164° C.
EXAMPLE 269
2-[[5-Chloro-1-[(2,5-dimethoxyphenyl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 152, the expected product is obtained in the form of a beige solid (yield=70%).
M.p.=132-134° C.
EXAMPLE 270
2-[[5-Chloro-1-[(2,5-dimethoxyphenyl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 269, the expected product is obtained in the form of a white solid (yield=96%).
M.p.=156-158° C.
EXAMPLE 271
2-[[5-Chloro-1-[(4-methoxyphenyl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 153, the expected product is obtained in the form of a white solid (yield=92%).
M.p.=96-98° C.
EXAMPLE 272
2-[[5-Chloro-1-[(4-methoxyphenyl)sulfonyl]-1H-indol-2-yl]methoxy]-2-methylpropanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 271, the expected product is obtained in the form of a white solid (yield=99%).
M.p.=150-152° C.
EXAMPLE 273
2-[([5-Chloro-1-[(2-methyl-6-benzothiazolyl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 154, the expected product is obtained in the form of a yellow oil (yield=78%).
1H NMR (DMSOd6, 250 MHz) δ=8.93 (s, 1H), 8.00 (m, 3H), 7.66 (d, 1H), 7.35 (dd, 1H), 6.85 (s, 1H), 5.03 (d, 1H), 4.92 (d, 1H), 4.24 (d, 1H), 4.13 (d, 2H), 2.83 (s, 3H), 1.32 (d, 3H), 1.19 (t, 3H).
EXAMPLE 274
2-[[5-Chloro-1-[(2-methyl-6-benzothiazolyl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 273, the expected product is obtained in the form of a white solid (yield=95%).
M.p.=106-108° C.
EXAMPLE 275
2-[[5-Chloro-1-[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]-1H-indol-2-yl]-methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 155, the expected product is obtained in the form of a yellow oil (yield=86%).
1H NMR (DMSOd6, 300 MHz) δ=7.98 (d, 1H), 7.68 (d, 1H), 7.46 (m, 2H), 7.35 (dd, 1H), 7.01 (d, 1H), 6.83 (s, 1H), 4.97 (d, 1H), 4.84 (d, 1H), 4.27 (m, 5H), 4.20 (q, 2H), 1.35 (d, 3H), 1.19 (t, 3H).
EXAMPLE 276
2-[[5-Chloro-1-[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]-1H-indol-2-yl]-methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 275, the expected product is obtained in the form of a yellow solid (yield=97%).
M.p.=70° C.
EXAMPLE 277
2-[[5-Chloro-1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 156, the expected product is obtained in the form of a colorless oil (yield=85%).
1H NMR (DMSOd6, 250 MHz) δ=8.01 (d, 1H), 7.66 (d, 1H), 7.34 (dd, 1H), 7.13 (dd, 1H), 6.99 (d, 1H), 6.78 (m, 2H), 4.98 (d, 1H), 4.85 (d, 1H), 4.23 (m, 3H), 4.18 (q, 2H), 3.24 (m, 2H), 2.80 (s, 3H), 1.34 (d, 3H), 1.19 (t, 3H).
EXAMPLE 278
2-[[5-Chloro-1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 277, the expected product is obtained in the form of a white solid (yield=98%).
M.p.=68° C.
EXAMPLE 279
2-[[5-Chloro-1-[(3,5-dimethyl-4-isoxazolyl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 157, the expected product is obtained in the form of a colorless oil (yield=91%).
1H NMR (DMSOd6, 300 MHz) δ=7.84 (d, 1H), 7.78 (d, 1H), 7.40 (dd, 1H), 6.92 (s, 1H), 4.91 (d, 1H), 4.77 (d, 1H), 4.12 (q, 1H), 4.08 (q, 2H), 2.63 (s, 3H), 2.03 (s, 3H), 1.18 (m, 6H).
EXAMPLE 280
2-[[5-Chloro-1-[(3,5-dimethyl-4-isoxazolyl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 279, the expected product is obtained in the form of a white solid (yield=92%).
M.p.=110-112° C.
EXAMPLE 281
2-[[5-Chloro-1-[(2,5-dimethoxyphenyl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 158, the expected product is obtained in the form of a beige solid (yield=88%).
M.p.=118-120° C.
EXAMPLE 282
2-[[5-Chloro-1-[(2,5-dimethoxyphenyl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 281, the expected product is obtained in the form of a white solid (yield=99%).
M.p.=196-198° C.
EXAMPLE 283
2-[[1-[(2-Methyl-6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]-methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 160, the expected product is obtained in the form of a yellow oil (yield=83%).
1H NMR (DMSOd6, 250 MHz) δ=8.98 (m, 1H), 8.26 (d, 1H), 8.04 (m, 3H), 7.65 (dd, 1H), 7.01 (s, 1H), 5.07 (d, 1H), 4.95 (d, 1H), 4.26 (q, 1H), 4.14 (q, 2H), 2.83 (s, 3H), 1.34 (d, 3H), 1.16 (t, 3H).
EXAMPLE 284
2-[[1-[(2-Methyl-6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]-methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 283, the expected product is obtained in the form of a white solid (yield=84%).
M.p.=146-148° C.
EXAMPLE 285
2-[[1-[(6-Benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 161, the expected product is obtained in the form of a yellow oil (yield 76%).
1H NMR (DMSOd6, 250 MHz) δ=9.67 (s, 1H), 9.13 (d, 1H), 8.21 (m, 2H), 8.14 (dd, 1H), 8.11 (m, 1H), 7.68 (dd, 1H), 7.01 (s, 1H), 5.08 (d, 1H), 4.96 (d, 1H), 4.26 (q, 1H), 4.11 (q, 2H), 1.31 (d, 3H), 1.16 (t, 3H).
EXAMPLE 286
2-[[1-[(6-benzothiazolyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 285, the expected product is obtained in the form of a pasty beige solid (yield=57%).
1H NMR (DMSOd6, 300 MHz) δ=9.67 (s, 1H), 9.15 (d, 1H), 8.24 (m, 2H), 8.11 (dd, 1H), 8.03 (s, 1H), 7.66 (dd, 1H), 7.02 (s, 1H), 5.10 (d, 1H), 4.94 (d, 1H), 4.18 (q, 1H), 1.32 (d, 3H).
EXAMPLE 287
2-[[1-[(2,3-Dihydro-1,4-benzodioxin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 162, the expected product is obtained in the form of a yellow oil (yield=84%).
1H NMR (DMSOd6, 250 MHz) δ=8.19 (d, 1H), 8.03 (s, 1H), 7.66 (dd, 1H), 7.53 (m, 2H), 7.04 (dd, 1H), 6.98 (s, 1H), 5.01 (d, 1H), 4.88 (d, 1H), 4.27 (m, 5H), 4.21 (q, 2H), 1.36 (d, 3H), 1.19 (t, 3H).
EXAMPLE 288
2-[[1-[(2,3-Dihydro-1,4-benzodioxin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 287, the expected product is obtained in the form of a yellow solid (yield=99%).
M.p.=70° C.
EXAMPLE 289
2-[[1-[(3,4-Dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 163, the expected product is obtained in the form of a yellow oil (yield=88%).
1H NMR (DMSOd6, 300 MHz) δ=8.22 (d, 1H), 8.02 (s, 1H), 7.65 (dd, 1H), 7.19 (dd, 1H), 7.04 (d, 1H), 6.96 (s, 1H), 6.78 (d, 1H), 5.03 (d, 1H), 4.89 (d, 1H), 4.24 (m, 3H), 4.14 (q, 2H), 3.24 (m, 2H), 2.80 (s, 3H), 1.36 (d, 3H), 1.19 (t, 3H).
EXAMPLE 290
2-[[1-[(3,4-Dihydro-4-methyl-2H-1,4-benzoxazin-7-yl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 289, the expected product is obtained in the form of a white solid (yield=87%).
M.p.=118-120° C.
EXAMPLE 291
2-[[1-[(2,5-Dimethoxyphenyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]-methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 164, the expected product is obtained in the form of a white solid (yield=89%).
M.p.=130-132° C.
EXAMPLE 292
2-[[1-[(2,5-Dimethoxyphenyl)sulfonyl]-5-(trifluoromethyl)-1H-indol-2-yl]-methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 291, the expected product is obtained in the form of a white solid (yield=97%).
M.p.=212-214° C.
EXAMPLE 293
(2S)-2-[[5-chloro-1-[(6-benzothiazolyl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid ethyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 166, the expected product is obtained in the form of a yellow oil (yield=77%).
1H NMR (DMSOd6, 300 MHz) δ=9.66 (s, 1H), 9.08 (d, 1H), 8.21 (d, 1H), 8.05 (m, 2H), 7.67 (d, 1H), 7.36 (dd, 1H), 6.86 (s, 1H), 5.03 (d, 1H), 4.93 (d, 1H), 4.23 (q, 1H), 4.10 (q, 2H), 1.31 (d, 3H), 1.17 (t, 3H).
EXAMPLE 294
(2S)-2-[[5-chloro-1-[(6-benzothiazolyl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 293, the expected product is obtained in the form of a white solid (yield=66%).
M.p.=82° C.
[α]D28=−41° (c=0.39; MeOH).
EXAMPLE 295
(2R)-2-[[5-chloro-1-[(6-benzothiazolyl)sulfonyl]-1H-indol-2-yl]methoxy]propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 168, the expected product is obtained in the form of a yellow oil (yield=80%).
1H NMR (DMSOd6, 300 MHz) δ=9.66 (s, 1H), 9.08 (d, 1H), 8.22 (d, 1H), 8.03 (m, 2H), 7.67 (d, 1H), 7.36 (dd, 1H), 6.86 (s, 1H), 5.03 (d, 1H), 4.92 (d, 1H), 4.27 (q, 1H), 3.66 (s, 3H), 1.32 (d, 3H).
EXAMPLE 296
5-Chloro-1-[(2-methyl-7-benzothiazolyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 169, the expected product is obtained in the form of a yellow solid (yield=76%).
M.p.=129° C.
EXAMPLE 297
5-Chloro-1-[(2-methyl-7-benzothiazolyl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 296, the expected product is obtained in the form of a white powder (yield=93%).
M.p.=177-181° C.
EXAMPLE 298
1-[(1-Acetyl-1H-indol-5-yl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 170, the expected product is obtained in the form of a white powder (yield=89%).
M.p.=127-131° C.
EXAMPLE 299
1-[(1H-indol-5-yl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 298, the expected product is obtained in the form of a white solid (yield=52%).
M.p.=213° C.
EXAMPLE 300
5-Chloro-1-[(2-methyl-7-benzothiazolyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 171, the expected product is obtained in the form of an amorphous solid (yield=70%).
1H NMR (DMSOd6, 300 MHz) δ=8.25 (dd, 1H), 7.93 (d, 1H), 7.76 (d, 1H), 7.68 (d, 1H), 7.63 (m, 1H), 7.30 (dd, 1H), 6.64 (s, 1H), 3.59 (s, 3H), 3.24 (t, 2H), 2.83 (s, 3H), 2.77 (t, 2H).
EXAMPLE 301
5-Chloro-1-[(2-methyl-7-benzothiazolyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 300, the expected product is obtained in the form of a white powder (yield=86%).
M.p.=188-189° C.
EXAMPLE 302
1-[(2-Amino-6-benzoxazolyl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 172, the expected product is obtained in the form of a beige solid (yield=50%).
M.p.=190-195° C.
EXAMPLE 303
1-[(2-Amino-6-benzoxazolyl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 302, the expected product is obtained in the form of a white solid (yield=53%).
M.p.=242-249° C.
EXAMPLE 304
5-Chloro-1-[(2,3-dihydro-5-benzofuranyl)sulfonyl]-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 173, the expected product is obtained in the form of an amorphous solid (yield=88%).
1H NMR (DMSOd6, 300 MHz) δ=8.02 (d, 1H), 7.70 (m, 1H), 7.63 (dd, 1H), 7.58 (d, 1H), 7.30 (dd, 1H), 6.89 (d, 1H), 6.56 (s, 1H), 4.60 (t, 2H), 3.62 (s, 3H), 3.28 (t, 2H), 3.18 (t, 2H), 2.81 (t, 2H).
EXAMPLE 305
5-Chloro-1-[(2,3-dihydro-5-benzofuranyl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 304, the expected product is obtained in the form of a white solid (yield=91%).
M.p.=170-171° C.
EXAMPLE 306
1-[(2-Amino-6-benzothiazolyl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 174, the expected product is obtained in the form of a yellow solid (yield=47%).
M.p.=217-222° C.
EXAMPLE 307
1-[(2-Amino-6-benzothiazolyl)sulfonyl]-5-chloro-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 306, the expected product is obtained in the form of a white powder (yield=45%).
M.p.=250-255° C.
EXAMPLE 308
2-[[[5-Chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methyl]thio]-2-methylpropanoic acid
By following a procedure analogous to Example 201 starting from the compound obtained according to Preparation 120 and 2-methyl-2-(2-propynylthio)propanoic acid, the expected product is obtained in the form of a beige solid (yield=14%).
M.p.=150-152° C.
EXAMPLE 309
2-[[[5-Chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methyl]thio]propanoic acid
By following a procedure analogous to Example 201 starting from the compound obtained according to Preparation 120 and 2-(2-propynylthio)propanoic acid, the expected product is obtained in the form of a white solid (yield=17%).
M.p.=138° C.
EXAMPLE 310
2-[[[1-(Phenylsulfonyl)-5-(trifluoromethyl)-1H-indol-2-yl]methyl]thio]-2-methylpropanoic acid
By following a procedure analogous to Example 201 starting from the compound obtained according to Preparation 121 and 2-methyl-2-(2-propynylthio)propanoic acid, the expected product is obtained in the form of a beige solid (yield=8%).
M.p.=90° C.
EXAMPLE 311
2-[[[1-(Phenylsulfonyl)-5-(trifluoromethyl)-1H-indol-2-yl]methyl]thio]propanoic acid
By following a procedure analogous to Example 201 starting from the compound obtained according to Preparation 121 and 2-(2-propynylthio)propanoic acid, the expected product is obtained in the form of a beige solid (yield=15%).
M.p.=120° C.
EXAMPLE 312
1-[(6-Benzothiazolyl)sulfonyl]-5-methyl-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 201 starting from the compound obtained according to Preparation 175 and the methyl ester of 5-hexynoic acid, the expected product is obtained in the form of a yellow powder (yield=47%).
M.p.=128-130° C.
EXAMPLE 313
1-[(6-Benzothiazolyl)sulfonyl]-5-methyl-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 312, the expected product is obtained in the form of a yellow powder (yield=70%).
M.p.=128° C.
EXAMPLE 314
1-(Phenylsulfonyl)-5-methyl-1H-indole-2-propanoic acid methyl ester
By following a procedure analogous to Example 201 starting from the compound obtained according to Preparation 176 and the methyl ester of 4-pentynoic acid, the expected product is obtained in the form of a beige solid (yield=13%).
M.p.=98-102° C.
EXAMPLE 315
1-(Phenylsulfonyl)-5-methyl-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 314, the expected product is obtained in the form of a white powder (yield=59%).
M.p.=176-182° C.
EXAMPLE 316
1-[(6-Benzothiazolyl)sulfonyl]-5-chloro-α,α-dimethyl-1H-indole-2-butanoic acid
By following a procedure analogous to Example 201 starting from the compound obtained according to Preparation 177 and 2,2-dimethyl-5-hexynoic acid, the expected product is obtained in the form of a yellow powder (yield=46%).
M.p.=151° C.
EXAMPLE 317
5-Chloro-α,α-dimethyl-1-(phenylsulfonyl)-1H-indole-2-butanoic acid
By following a procedure analogous to Example 201 starting from the compound obtained according to Preparation 120 and 2,2-dimethyl-5-hexynoic acid, the expected product is obtained in the form of a brown solid (yield=32%).
M.p.=242° C.
EXAMPLE 318
5-Chloro-1-[(2,3-dihydro-1H-indol-5-yl)sulfonyl]-1H-indole-2-propanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 158, the expected product is obtained in the form of a brown solid (yield=37%).
M.p.=157° C.
EXAMPLE 319
5-Chloro-1-[(1H-indol-5-yl)sulfonyl]-1H-indole-2-propanoic acid
A solution of 40 mg (0.1 mM) of the compound obtained according to Example 318 in 4 ml of toluene is prepared and a solution of 22 mg (0.1 mM) of DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) in 4 ml of toluene is added at the reflux temperature of the solvent. The reaction mixture is stirred for 12 hours at the reflux temperature of the solvent and then cooled, acidified by the addition of M hydrochloric acid solution and diluted with ethyl acetate. The organic phase is washed with sodium thiosulfate solution and then with water, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by HPLC using an acetonitrile/water gradient mixture as the eluent to give the expected product in the form of a beige solid (yield=28%).
M.p.=79° C.
EXAMPLE 320
5-Chloro-1-[[4-amino-3-(methylthio)phenyl]sulfonyl]-1H-indole-2-butanoic acid
A solution of 1 g (2.27 mM) of the compound obtained according to Example 117 in 16 ml of ethanol and 16 ml of 3.5 M aqueous potassium hydroxide solution is prepared. The mixture is stirred at room temperature for 5 hours, 0.9 ml of methyl iodide is then added and the reaction mixture is stirred again for 1 hour at room temperature. The medium is then diluted with 100 ml of water and acidified slowly with N hydrochloric acid solution. The precipitate formed is extracted with dichloromethane and the organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the expected product in the form of a crystalline white solid (yield=95%).
M.p.=158° C.
EXAMPLE 321
5-Chloro-1-[(4-fluoro-3-nitrophenyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
By following a procedure analogous to Example 215 starting from the compound obtained according to Preparation 178, the expected product is obtained in the form of a pale yellow powder (yield=96%).
M.p.=93° C.
EXAMPLE 322
1-[(4-Amino-3-nitrophenyl)sulfonyl]-5-chloro-1H-indole-2-butanoic acid methyl ester
A solution of 100 mg (0.22 mM) of the compound obtained according to Example 321 in 1 ml of dioxane is prepared and 0.77 ml of 32% aqueous ammonia is added. The mixture is stirred at room temperature for 30 min and then diluted with 8 ml of ethyl acetate, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the expected product in the form of a pale yellow powder (yield=95%).
M.p.=157° C.
EXAMPLE 323
5-Chloro-1-[(3,4-diaminophenyl)sulfonyl]-1H-indole-2-butanoic acid methyl ester
A suspension of 604 mg (1.33 mM) of the compound obtained according to Example 322 in 8 ml of acetic acid is prepared and 390 mg (7 mM) of iron powder are added, with stirring. The mixture is stirred at 60° C. for 1 hour and then diluted with water and ethyl acetate. The organic phase is separated off, filtered, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the expected product in the form of a pale yellow powder (yield=70%).
M.p.=158-160° C.
EXAMPLE 324
1-(1H-benzimidazol-5-ylsulfonyl)-5-chloro-1H-indole-2-butanoic acid methyl ester
A suspension of 498 mg (1.18 mM) of the compound obtained according to Example 323 in 1.5 ml of formic acid is prepared. The mixture is stirred at 60° C. for 2 hours and then diluted with water, neutralized with 10 ml of N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is separated off, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel using a toluene/isopropanol/aqueous ammonia mixture (85/15/1; v/v/v) as the eluent to give the expected product in the form of a beige foam (yield=83%).
1H NMR (DMSOd6, 300 MHz) δ=12.95 (s, 1H), 8.46 (s, 1H), 8.10 (m, 2H), 7.72 (d, 1H), 7.56 (m, 2H), 7.32 (dd, 1H), 7.19 (m, 2H), 6.58 (s, 1H), 3.58 (s, 3H), 3.05 (t, 2H), 2.45 (t, 2H), 1.99 (quin, 2H).
EXAMPLE 325
1-(1H-benzimidazol-5-ylsulfonyl)-5-chloro-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 324, the expected product is obtained in the form of a white powder (yield=66%).
M.p.=212° C.
EXAMPLE 326
5-Chloro-1-[(2,3-dihydro-1H-indol-5-yl)sulfonyl]-1H-indole-2-butanoic acid
By following a procedure analogous to Example 2 starting from the compound obtained according to Example 134, the expected product is obtained in the form of a beige solid (yield=19%).
M.p.=203° C.
The compounds according to the invention described above have been shown in the Tables below:
Table I collates compounds according to the invention in which X is a single bond and R3 and R4 are each a hydrogen atom.
Table II collates examples of compounds of formula I according to the invention in which X is an oxygen atom.
Table III collates examples of compounds of formula I according to the invention in which X is a sulfur atom.
Table IV collates the compounds in which X is a single bond and R3 or R4 is other than a hydrogen atom.
In these Tables, Ac represents an acetyl group.
TABLE I
Ex.
Ra
Rb
Ar
n
R
1
5-Cl
H
1
CH3
2
5-Cl
H
1
H
2a
5-Cl
H
1
Na
3
5-CF3
H
1
CH3
4
5-CF3
H
1
H
5
5-Br
H
1
CH3
6
5-Br
H
1
H
7
H
1
CH3
8
H
1
H
9
H
H
1
CH3
10
H
H
1
H
11
5-Cl
H
1
CH3
12
5-Cl
H
1
H
13
5-Cl
H
1
CH3
14
5-Cl
H
1
H
15
5-Cl
H
1
CH3
16
5-Cl
H
1
H
17
5-Cl
H
1
CH3
18
5-Cl
H
1
H
19
5-Cl
H
1
CH3
20
5-Cl
H
1
H
21
5-Cl
H
1
CH3
22
5-Cl
H
1
H
23
5-Cl
H
1
CH3
24
5-Cl
H
1
H
25
5-Cl
H
1
CH3
26
5-Cl
H
1
H
27
5-Cl
H
1
CH3
28
5-Cl
H
1
H
29
5-Cl
H
1
CH3
30
5-Cl
H
1
H
31
5-Cl
H
1
CH3
32
5-Cl
H
1
H
33
5-Cl
H
1
CH3
34
5-Cl
H
1
H
35
5-Cl
H
1
CH3
36
5-Cl
H
1
H
37
5-Cl
H
1
CH3
38
5-Cl
H
1
H
39
5-Cl
H
1
CH3
40
5-Cl
H
1
H
41
5-Cl
H
1
CH3
42
5-Cl
H
1
H
43
5-Cl
H
1
CH3
44
5-Cl
H
1
H
45
5-Cl
H
1
CH3
46
5-Cl
H
1
H
47
5-Cl
H
1
CH3
48
5-Cl
H
1
H
49
5-Cl
H
1
CH3
50
5-Cl
H
1
H
51
5-Cl
H
1
CH3
52
5-Cl
H
1
H
53
5-Cl
H
1
CH3
54
5-Cl
H
1
CH3
55
5-Cl
H
1
CH3
56
5-Cl
H
1
H
57
5-Cl
H
1
CH3
58
5-Cl
H
1
H
59
5-Cl
H
1
CH3
60
5-Cl
H
1
H
61
5-Cl
H
1
CH3
62
5-Cl
H
1
H
63
5-Cl
H
1
CH3
64
5-Cl
H
1
H
65
5-Cl
H
1
CH3
66
5-Cl
H
1
H
67
5-Cl
H
2
CH3
68
5-Cl
H
2
H
69
5-Cl
H
2
CH3
70
5-Cl
H
2
H
71
5-Cl
H
2
CH3
72
5-Cl
H
2
H
73
5-Cl
H
2
CH3
74
5-Cl
H
2
H
75
5-Cl
H
2
CH3
76
5-Cl
H
2
H
77
5-Cl
H
2
CH3
78
5-Cl
H
2
H
79
5-Cl
H
2
CH3
80
5-Cl
H
2
H
81
5-Cl
H
2
CH3
82
5-Cl
H
2
H
83
5-Cl
H
2
CH3
84
5-Cl
H
2
H
85
5-Cl
H
2
CH3
86
5-Cl
H
2
H
87
5-F
H
1
CH3
88
5-Cl
6-Cl
1
CH3
89
5-Cl
6-Cl
1
H
90
4-Cl
5-Cl
1
CH3
91
4-Cl
5-Cl
1
H
92
6-CF3
H
1
CH3
93
6-CF3
H
1
H
94
5-COCH3
H
1
CH3
95
5-COCH3
H
1
H
96
5-F
6-Cl
1
CH3
97
5-F
6-Cl
1
H
98
5-Cl
7-Cl
1
CH3
99
5-Cl
7-Cl
1
H
100
5-CN
H
1
CH3
101
5-CN
H
1
H
102
5-benzoyl
H
1
CH3
103
5-benzoyl
H
1
H
104
5-Cl
H
3
CH3
105
5-Cl
H
3
H
106
5-OCF3
H
1
CH3
107
5-OCF3
H
1
H
108
5-Cl
H
1
—CH(CH3)2
109
5-Cl
H
2
CH3
110
5-Cl
H
2
H
111
5-Cl
H
2
CH3
112
5-Cl
H
2
CH3
113
5-Cl
H
2
H
114
5-Cl
H
2
CH3
115
5-Cl
H
2
H
116
5-Cl
H
2
CH3
117
5-Cl
H
2
H
118
5-Cl
H
2
CH3
119
5-Cl
H
2
H
120
5-Cl
H
2
CH3
121
5-Cl
H
2
H
122
5-Cl
H
2
CH3
123
5-Cl
H
2
H
124
5-Cl
H
2
CH3
125
5-Cl
H
2
H
126
5-Cl
H
2
CH3
127
5-Cl
H
2
H
128
5-Cl
H
2
CH3
129
5-Cl
H
2
H
130
5-Cl
H
2
CH3
131
5-Cl
H
2
H
132
5-Cl
H
2
CH3
133
5-Cl
H
2
H
134
5-Cl
H
2
CH3
135
5-Cl
H
2
H
136
5-Cl
H
2
CH3
137
5-Cl
H
2
H
138
5-Cl
H
2
CH3
139
5-Cl
H
2
H
140
5-Cl
H
2
CH3
141
5-Cl
H
2
CH3
142
5-Cl
H
2
H
143
5-Cl
H
2
CH3
144
5-Cl
H
2
H
145
5-Cl
H
2
CH3
146
5-Cl
H
2
H
147
5-Cl
H
2
CH3
148
5-Cl
H
2
H
149
5-Cl
H
2
CH3
150
5-Cl
H
2
CH3
151
5-Cl
H
2
H
152
5-Cl
H
2
CH3
153
5-Cl
H
2
H
154
5-Cl
H
1
CH3
155
5-Cl
H
1
H
156
5-Cl
H
1
CH3
157
5-Cl
H
1
H
158
5-Cl
H
1
CH3
159
5-Cl
H
1
H
160
5-Cl
H
1
CH3
161
5-Cl
H
1
H
162
5-Cl
H
2
CH3
163
5-Cl
H
2
H
164
5-Cl
H
2
CH3
165
5-Cl
H
2
H
166
5-Cl
H
1
CH3
167
5-Cl
H
1
H
168
5-CF3
H
2
CH3
169
5-CF3
H
2
H
170
5-CF3
H
1
CH3
171
5-CF3
H
1
H
172
5-CF3
H
2
CH3
173
5-CF3
H
2
H
174
5-CF3
H
2
CH3
174
5-CF3
H
2
H
176
5-CF3
H
2
CH3
177
5-CF3
H
2
H
178
5-CF3
H
2
CH3
179
5-CF3
H
2
H
180
5-CF3
H
1
CH3
181
5-CF3
H
1
H
182
5-CF3
H
1
CH3
183
5-CF3
H
1
H
184
5-CF3
H
1
CH3
185
5-CF3
H
1
H
186
5-CF3
H
1
CH3
187
5-CF3
H
1
CH3
188
5-CF3
H
1
CH3
189
5-CF3
H
1
H
190
5-CF3
H
1
CH3
191
5-CF3
H
1
H
192
5-CF3
H
1
CH3
193
5-CF3
H
1
H
194
5-Cl
H
2
CH3
195
5-Cl
H
2
H
196
5-CF3
H
2
H
197
5-CF3
H
2
CH3
198
5-CF3
H
2
H
199
5-CF3
H
2
CH3
200
5-CF3
H
2
H
225
5-CF3
H
2
CH3
226
5-CF3
H
2
H
227
5-CF3
H
1
CH3
228
5-CF3
H
1
H
296
5-Cl
H
2
CH3
297
5-Cl
H
2
H
298
5-Cl
H
2
CH3
299
5-Cl
H
2
H
300
5-Cl
H
1
CH3
301
5-Cl
H
1
H
302
5-Cl
H
1
CH3
303
5-Cl
H
1
H
304
5-Cl
H
1
CH3
305
5-Cl
H
1
H
306
5-Cl
H
1
CH3
307
5-Cl
H
1
H
312
5-CH3
H
1
CH3
313
5-CH3
H
1
H
314
5-CH3
H
1
CH3
315
5-CH3
H
1
H
318
5-Cl
H
1
H
319
5-Cl
H
1
H
320
5-Cl
H
2
H
321
5-Cl
H
2
CH3
322
5-Cl
H
2
CH3
323
5-Cl
H
2
CH3
324
5-Cl
H
2
CH3
325
5-Cl
H
2
H
326
5-Cl
H
2
H
TABLE II
Ex.
Ra
n
R3
R4
Ar
R
201
5-Cl
1
CH3
H
C2H5
202
5-Cl
1
CH3
H
H
203
5-Cl
1
H
H
CH3
204
5-Cl
1
H
H
H
205
5-Cl
1
CH3
CH3
CH3
206
5-Cl
1
CH3
CH3
H
207
5-CF3
1
H
H
CH3
208
5-CF3
1
H
H
H
209
5-CF3
1
CH3
H
C2H5
210
5-CF3
1
CH3
H
H
211
5-CF3
1
CH3
CH3
CH3
212
5-CF3
1
CH3
CH3
H
213
5-Cl
2
H
H
C2H5
214
5-Cl
2
H
H
H
215
5-Cl
1
CH3
CH3
CH3
216
5-Cl
1
CH3
CH3
H
217
5-CF3
1
CH3
CH3
CH3
218
5-CF3
1
CH3
CH3
H
219
5-Cl
1
CH3
CH3
CH3
220
5-Cl
1
CH3
CH3
H
221
5-Cl
1
CH3
CH3
CH3
222
5-Cl
1
CH3
CH3
H
223
5-Cl
1
CH3
H
C2H5
224
5-Cl
1
CH3
H
H
229
5-CF3
1
CH3
CH3
CH3
230
5-CF3
1
CH3
CH3
H
231
5-CF3
1
CH3
CH3
CH3
232
5-CF3
1
CH3
CH3
H
233
5-CF3
1
CH3
CH3
CH3
234
5-CF3
1
CH3
CH3
H
235
5-CF3
1
CH3
CH3
CH3
236
5-CF3
1
CH3
CH3
H
237
5-CF3
1
CH3
CH3
CH3
238
5-CF3
1
CH3
CH3
H
239
5-CF3
1
CH3
CH3
CH3
240
5-CF3
1
CH3
CH3
H
241
5-CF3
1
CH3
CH3
CH3
242
5-CF3
1
CH3
CH3
H
243
5-CF3
1
CH3
CH3
CH3
244
5-CF3
1
CH3
CH3
H
245
5-CF3
1
CH3
CH3
CH3
246
5-CF3
1
CH3
CH3
H
247
5-CF3
1
CH3
CH3
CH3
248
5-CF3
1
CH3
CH3
H
249
5-CF3
1
CH3
CH3
CH3
250
5-CF3
1
CH3
CH3
H
251
5-Cl
1
CH3
CH3
CH3
252
5-Cl
1
CH3
CH3
H
253
5-Cl
1
CH3
CH3
CH3
254
5-Cl
1
CH3
CH3
H
255
5-Cl
1
CH3
CH3
CH3
256
5-Cl
1
CH3
CH3
H
257
5-Cl
1
CH3
CH3
CH3
258
5-Cl
1
CH3
CH3
H
259
5-Cl
1
CH3
CH3
CH3
260
5-Cl
1
CH3
CH3
H
261
5-Cl
1
CH3
CH3
CH3
262
5-Cl
1
CH3
CH3
H
263
5-Cl
1
CH3
CH3
CH3
264
5-Cl
1
CH3
CH3
H
265
5-Cl
1
CH3
CH3
CH3
266
5-Cl
1
CH3
CH3
H
267
5-Cl
1
CH3
CH3
CH3
268
5-Cl
1
CH3
CH3
H
269
5-Cl
1
CH3
CH3
CH3
270
5-Cl
1
CH3
CH3
H
271
5-Cl
1
CH3
CH3
CH3
272
5-Cl
1
CH3
CH3
H
273
5-Cl
1
CH3
H
C2H5
274
5-Cl
1
CH3
H
H
275
5-Cl
1
CH3
H
C2H5
276
5-Cl
1
CH3
H
H
277
5-Cl
1
CH3
H
C2H5
278
5-Cl
1
CH3
H
H
279
5-Cl
1
CH3
H
C2H5
280
5-Cl
1
CH3
H
H
281
5-Cl
1
CH3
H
C2H5
282
5-Cl
1
CH3
H
H
283
5-CF3
1
CH3
H
C2H5
284
5-CF3
1
CH3
H
H
285
5-CF3
1
CH3
H
C2H5
286
5-CF3
1
CH3
H
H
287
5-CF3
1
CH3
H
C2H5
288
5-CF3
1
CH3
H
H
289
5-CF3
1
CH3
H
C2H5
290
5-CF3
1
CH3
H
H
291
5-CF3
1
CH3
H
C2H5
292
5-CF3
1
CH3
H
H
293
5-Cl
1
CH3 (S)
H
C2H5
294
5-Cl
1
CH3 (S)
H
H
295
5-Cl
1
CH3 (R)
H
C2H5
TABLE III
Ex.
Ra
N
R3
R4
Ar
308
5-Cl
1
CH3
CH3
309
5-Cl
1
CH3
H
310
5-CF3
1
CH3
CH3
311
5-CF3
1
CH3
H
TABLE IV
Ex.
Ra
n
R3
R4
Ar
R
316
5-Cl
2
CH3
CH3
H
317
5-Cl
2
CH3
CH3
H
Pharmacological Activity
The compounds of the invention were subjected to biological tests in order to evaluate their potential for treating or preventing certain pathological conditions. The first step was to measure the ability of the compounds to behave as PPAR nuclear receptor activators.
A transactivation test is used as a primary screening test. Cos-7 cells are transfected with a plasmid expressing a chimera of a PPAR-Gal4 murine or human receptor (PPARα-Gal4, PPARδ-Gal4 or PPARγ-Gal4 receptor) and a 5Gal4pGL3 TK Luc reporter plasmid. The transfections are carried out with the aid of a chemical agent (Jet PEI).
The transfected cells are distributed over 384-well plates and left to stand for 24 hours.
After 24 hours the culture medium is changed. The test products are added (final concentration of between 3.10−5 and 3.10−10 M) to the culture medium. After incubation overnight, the expression of luciferase is measured after the addition of “SteadyGlo” according to the instructions provided by the manufacturer (Promega).
10−5 M fenofibric acid (PPARα agonist), 10−8 M GW501516 (PPARδ agonist) and 10−6M rosiglitazone (PPARγ agonist) are used as references.
The results are expressed as the induction rate (number of times) compared with the basal level in percentage activity of the appropriate reference (reference=100%). The effect concentration curves and the EC50 values are calculated using the Assay Explorer software (MDL).
In micromolar concentration, the compounds according to the invention have an induction rate ranging up to 154% (PPARα), 127% (PPARδ) and 100% (PPAR-γ). Some compounds according to the invention have an EC50 below 50 nM, especially the hPPARδ receptor.
A second series of tests was performed with the compounds according to the invention in order to confirm the activity deduced from their affinity for the aforementioned receptors. This test consists in measuring the β-oxidation on HuH7 cells of human hepatic origin and C2C12 cells of murine muscular origin after differentiation in myotubes.
The cells are inoculated into Petri dishes containing a central well. The products are added to the culture medium and incubated for 48 hours at different concentrations. After incubation for 22 hours, C14-radiolabeled oleate (1-C14 oleate) is added to the culture medium. The β-oxidation reaction is stopped 2 hours later by the addition of 40% perchloric acid.
The CO2 liberated during the oxidation of the oleate is trapped with KOH solution and then counted.
Each test is performed three times.
The results are expressed in % variation relative to the control dishes (dishes without compounds).
According to this test, the compounds according to the invention increase the β-oxidation up to +148% at a concentration of 10 μM on HuH7 cells. The β-oxidation is also increased by 82% in the presence of, for example, the compound according to Example 4 used at a concentration of 100 μM in a test on C2C12 cells.
Some compounds according to the invention were tested in a db/db mouse model in order to confirm their potential as active principles. The test protocol is as follows:
Homozygous C57BL/Ks-db male mice (db/db mice), 11 to 13 weeks old at the start of the studies, are divided up into groups of 9-10 animals. The products are administered orally once a day for 5 days. One group of mice receives the vehicle only (0.5 or 1% methyl cellulose solution). A blood sample is taken from the retro-orbital sinus before treatment and 4 hours after the last gavage.
After centrifugation, the serum is collected and the cholesterol, triglyceride and glucose levels are measured using a multiparameter analyzer with commercial kits.
The results are expressed in % variation on the final day relative to the control group.
As examples of the compounds according to the invention, the following comparative results are obtained:
Dose
Compound
(mg/kg)
Glucose
Triglycerides
Cholesterol
Fenofibrate
100
−9
−7
+32
Rosiglitazone
3
−41
−52
−30
Ex. 2
30
0
−7
+30
Ex. 4
30
−30
−12
+41
Ex. 155
30
−35
−41
+38
Ex. 163
30
−38
−35
−15
Ex. 202
30
−52
−48
+25
These results, which are in agreement with the modifications expected of PPARα and/or PPARδ nuclear receptor activators, confirm the value of the compounds according to the invention for use as active principles of drugs for preventing or treating hypertriglyceridemia and hypercholesterolemia and, more generally, for re-establishing normal parameters in the event of a perturbation of the lipid and carbohydrate metabolism. The compounds according to the invention are also useful in the treatment of endothelial dysfunction, inflammatory disease or neurodegeneration.
The invention further relates to the pharmaceutical compositions intended for the prevention or treatment of the aforesaid diseases when they contain at least one of the compounds of formula I according to the invention as the active principle.
These pharmaceutical compositions can be prepared in conventional manner using pharmaceutically acceptable excipients to give forms that can preferably be administered orally, e.g. tablets or capsules.
In practical terms, if the compound is administered orally, the daily dosage in humans will preferably be between 5 and 500 mg.
The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.
|
12039324
|
laboratories fournier s.a.
|
USA
|
B2
|
Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
|
Open
|
514/419
|
|
Mar 31st, 2022 02:21PM
|
Mar 31st, 2022 02:21PM
|
AbbVie
|
Health Care
|
Pharmaceuticals & Biotechnology
|
|
nyse:abbv
|
AbbVie
|
Apr 3rd, 2012 12:00AM
|
Mar 24th, 2006 12:00AM
|
https://www.uspto.gov?id=US08148407-20120403
|
Compounds derived from 5-thioxylose and their use in therapeutics
|
The invention relates to novel 5-thioxylose compounds, preferably derivatives of the 5-thioxylopyranose type, to the process for their preparation and to their use as active principles of drugs intended especially for the treatment or prevention of thrombosis or cardiac insufficiency.
|
8148407
|
1. A compound selected from the group consisting of:
a) compounds corresponding to formula I
wherein
the pentapyranosyl group is a free or acylated 5-thio-β-D-xylopyranosyl group;
R is a hydrogen atom or a C2-C6 acyl group;
R1 is a C1-C4 alkylsulfonyl group, a C2-C6 acyl group, a group CONR′R″ or a group
wherein
X is a single bond, an oxygen atom, a sulfoxy group, a group —CO— or a group —CHOH—;
Ra is a hydrogen atom, a halogen, a hydroxyl group, a C1-C4 alkyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a C1-C4 hydroxyalkyl group, a C2-C4 acyl group, a C1-C4 alkoxy group or a group NR′R″;
wherein R′ and R″ independently are each a hydrogen atom or a C1-C4 alkyl group optionally substituted by an aromatic ring, or together with the nitrogen atom to which they are attached form a ring having 5 or 6 carbon atoms;
Rb and Rc independently of one another are each a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a cyano group or a C1-C4 alkoxy group; and
R2 is a hydrogen atom, a C1-C4 alkyl group or a halogen atom;
b) acid addition salts of a); and
c) active metabolites of b) and c).
2. A compound according to claim 1, wherein R1 is a group corresponding to the formula:
wherein Ra, Rb and Rc are as defined in claim 1.
3. A compound according to claim 1, wherein R is a hydrogen atom.
4. A compound according to claim 1, wherein R is COCH3.
5. A process for producing a compound according to claim 1, said process comprising:
a) reacting a pyridinol corresponding to formula II
wherein
R1 is a C1-C4 alkylsulfonyl group, a C2-C6 acyl group, a group CONR′R″ or a group
wherein
X is a single bond, an oxygen atom, a sulfoxy group, a group —CO— or a group —CHOH—;
Ra is a hydrogen atom, a halogen, a C1-C4 alkyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a C1-C4 hydroxyalkyl group, a C2-C4 acyl group, a C1 -C4 alkoxy group or a group NR′R″;
wherein R′ and R″ independently are each a hydrogen atom or a C1-C4 alkyl group optionally substituted by an aromatic ring, or together with the nitrogen atom to which they are attached form a ring having 5 or 6 carbon atoms,
Rb and Rc independently of one another are each a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a cyano group or a C1-C4 alkoxy group, and
R2 is a hydrogen atom, a C1-C4 alkyl group or a halogen atom, with a 5-thioxylopyranose compound corresponding to formula III-D
wherein
Hal is a halogen, and
R is a C2-C6 acyl group, in an aprotic solvent, in the presence of a silver salt or a zinc salt, in an anhydrous medium, at a temperature between 25 and 110° C., for 1 to 10 hours, to yield a compound corresponding to formula I
wherein R, R1 and R2 have the meanings given above;
b) optionally reacting the compound of formula I obtained in a) with a solution of ammonia in methanol to yield a compound corresponding to formula Ia
wherein R1 and R2 have the meanings given above, and
c) optionally reacting the compound of formula I obtained in a) or the compound of formula Ia obtained in b) with an acid to yield a corresponding acid addition salt.
6. A process according to claim 5, wherein Hal is bromine.
7. A process for producing a compound according to claim 1, said process comprising:
a) reacting tetra-O-acetyl-5-thioxylopyranose corresponding to formula IV-D
wherein Ac is an acetyl group,
with a compound corresponding to formula II
wherein
R1 is a C1-C4 alkylsulfonyl group, a C2-C6 acyl group, a group CONR′R″ or a group
wherein
X is a single bond, an oxygen atom, a sulfoxy group, a group —CO— or a group —CHOH—,
Ra is a hydrogen atom, a halogen, a C1-C4 alkyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a C1-C4 hydroxyalkyl group, a C2-C4 acyl group, a C1-C4 alkoxy group or a group NR′R″,
wherein R′ and R″ independently are each a hydrogen atom or a C1-C4 alkyl group optionally substituted by an aromatic ring, or form, together with the nitrogen atom to which they are attached, a ring having 5 or 6 carbon atoms,
Rb and Rc independently of one another are each a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a cyano group or a C1-C4 alkoxy group, and
R2 is a hydrogen atom, a C1-C4 alkyl group or a halogen atom, in an aprotic solvent, in the presence of a Lewis acid catalyst, at a temperature between 20 and 60° C., for 1 to 2 hours, to yield a compound corresponding to formula Ib
wherein R1 and R2 have the meanings given above;
b) optionally reacting the compound of formula I obtained in a) with sodium methylate in methanol to yield a compound corresponding to formula Ia
wherein R1 and R2 have the meanings given above, and
c) optionally reacting the compound of formula Ib obtained in a) or the compound of formula Ia obtained in b) with an acid to yield a corresponding acid addition salt.
8. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier or adjuvant.
9. A method of treating or inhibiting thrombosis in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of a compound according to claim 1.
10. A method according to claim 9, wherein said thrombosis is venous thrombosis.
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10
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The present invention relates to novel 5-thioxylose compounds, preferably derivatives of the 5-thioxylopyranose type, to the process for their preparation and to their use as active substances of drugs intended especially for the treatment or prevention of thrombosis.
PRIOR ART
D-xylose derivatives have already been disclosed, e.g. in EP 051 023 B1, U.S. Pat. No. 4,877,808, EP 421 829 B1 or the publication J. Med. Chem., vol. 36 no. 7, pp 898-903. The compounds described in these documents are useful for reducing the risks of venous thrombosis in humans. The mechanism of action of these compounds seems to be an effect on the plasma glycosaminoglycans (J. Biol. Chem., vol. 270 no. 6, pp 2662-68; Thromb. Haemost., 1999, 81, pp 945-950).
SUBJECT OF THE INVENTION
A novel family of compounds derived from thioxylose have now been discovered which exhibit a good antithrombotic activity and can be synthesized efficiently.
DESCRIPTION
The novel compounds according to the invention are selected from:
a) the compounds of the formula
in which:
the pentapyranosyl group is a free or acylated 5-thio-β-D-xylopyranosyl group,
R is a hydrogen atom or a C2-C6 acyl group,
R1 is a C1-C4 alkylsulfonyl group, a C2-C6 acyl group, a group CONR′R″ or a group
in which:
X is a single bond, an oxygen atom, a sulfoxy group, a group —CO— or a group —CHOH—,
Ra is a hydrogen atom, a halogen, a hydroxyl group, a C1-C4 alkyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a C1-C4 hydroxyalkyl group, a C2-C4 acyl group, a C1-C4 alkoxy group or a group NR′R″,
Rb and Rc independently of one another are each a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a cyano group or a C1-C4 alkoxy group,
R2 is a hydrogen atom, a C1-C4 alkyl group or a halogen atom, and
R′ and R′″ independently are each a hydrogen atom or a C1-C4 alkyl group optionally substituted by an aromatic ring, or form, together with the nitrogen atom to which they are attached, a ring having 5 or 6 carbon atoms;
b) their addition salts; and
c) their active metabolites.
The invention further relates to the compounds of formula I for their use as pharmacologically active substances.
In particular, the invention relates to the use of at least one substance selected from the compounds of formula I and their non-toxic salts for the preparation of a drug that is useful in human or animal therapeutics and is intended for the prevention or treatment of thrombosis, especially venous thrombosis. As the compounds according to the invention are active by a mode of action involving glycosaminoglycans, they may be useful as active substances of a drug intended for the treatment or prevention of any other disease in which glycosaminoglycans are involved.
DETAILED DESCRIPTION
In formula I, C1-C4 alkyl group is understood as meaning a linear, branched or cyclic hydrocarbon chain having from 1 to 4 carbon atoms. Particular examples of C1-C4 alkyl groups are methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethyl-ethyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl or cyclopropylmethyl groups.
Alkyl group optionally substituted by an aromatic ring is understood as meaning e.g. a phenylmethyl (benzyl) or phenylethyl group.
Halogen is understood as meaning a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.
C2-C6 acyl group denotes an acetyl, propanoyl, butanoyl, pentanoyl or hexanoyl group or their homologs in which the chain can be branched.
C1-C4 alkoxy group is understood as meaning a linear, branched or cyclic hydrocarbon chain having from 1 to 4 carbon atoms and bonded via an oxygen atom. Examples of C1-C4 alkoxy groups which may be mentioned are methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy or cyclopropylmethoxy groups.
Addition salts are understood as meaning the addition salts obtained by reacting a compound of formula I with a mineral or organic acid. The pharmaceutically acceptable addition salts are preferred. The hydrates or solvates of the compounds of formula I or of the salts of the compounds of formula I also form an integral part of the invention.
Hydrochloric, hydrobromic, phosphoric and sulfuric acids are preferred among the mineral acids suitable for salifying a basic compound of formula I. Methanesulfonic, benzenesulfonic, toluenesulfonic, maleic, fumaric, oxalic, citric, tartaric, lactic and trifluoroacetic acids are preferred among the organic acids suitable for salifying a basic compound of formula I.
Active metabolites are understood as meaning the compounds which are produced in the biological medium from the compounds of formula I and which possess a pharmacological activity of the same nature as that of the compounds of formula I described in the present patent application. For example, the compounds of formula I in which R1 is an acyl group can metabolize by reduction of the ketone group to an alcohol group (—CHOH—) to give a novel compound (metabolite) which retains a pharmacological activity of the same nature as that of the compounds of formula I.
Very particularly preferred compounds according to the present invention are those in which R1 is a phenyl group optionally substituted by the groups Ra, Rb and Rc as defined above.
Other preferred compounds according to the present invention are those in which R is the hydrogen atom or the group —COCH3.
The compounds of formula I according to the invention can be prepared using the glycosylation methods known to those skilled in the art, especially:
a) HELFERICH's method described in the book “The Carbohydrate, Chemistry and Biochemistry”, 2nd edition, Academic Press, New York, London 1972, volume IA, pages 292-294, by condensing a peracetylated sugar with a hydroxylated aromatic heterocycle in the presence of a Lewis acid;
b) KOENIGS-KNORR's method (idem, pages 295-299), by condensing a halogenated acylose with a hydroxyl group of phenolic character in the presence of a proton acceptor such as mercuric cyanide, silver imidazolate or silver trifluoro-methylsulfonate;
c) SCHMIDT's method, by condensing an osyl trichloroacetimidate with a hydroxylated aromatic heterocycle in the presence of a Lewis acid such as trimethylsilyl trifluoromethanesulfonate or boron trifluoride etherate.
The compounds of formula I are preferably prepared by methods derived from the processes referred to above.
A first general process comprises carrying out the steps consisting in:
a) reacting a pyridinol of the formula
in which:
R1 is a C1-C4 alkylsulfonyl group, a C2-C6 acyl group, a group CONR′R″ or a group
in which:
X is a single bond, an oxygen atom, a sulfoxy group, a group —CO— or a group —CHOH—,
Ra is a hydrogen atom, a halogen, a C1-C4 alkyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a C1-C4 hydroxyalkyl group, a C2-C4 acyl group, a C1-C4 alkoxy group or a group NR′R″,
Rb and Rc independently of one another are each a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a cyano group or a C1-C4 alkoxy group,
R2 is a hydrogen atom, a C1-C4 alkyl group or a halogen atom, and
R′ and R″ independently are each a hydrogen atom or a C1-C4 alkyl group optionally substituted by an aromatic ring, or form, together with the nitrogen atom to which they are attached, a ring having 5 or 6 carbon atoms,
with a 5-thioxylopyranose derivative of the formula
in which Hal is a halogen, preferably bromine, and R is a C2-C6 acyl group, preferably the acetyl group, in an aprotic solvent such as acetonitrile or toluene, in the presence of a silver salt, especially silver oxide or imidazolate, or a zinc salt (especially the oxide or chloride), in an anhydrous medium, at a temperature between 25 and 110° C., for 1 to 10 hours, to give the compound of the formula
in which R, R1 and R2 are as defined in the starting compounds;
b) if necessary, reacting the compound of formula I obtained above with a solution of ammonia in methanol to effect deacylation and thus replace the acyl group with hydrogen atoms to give the compound of the formula
in which R1 and R2 are as defined above; and
c) if necessary, reacting one of the compounds I or la obtained above with an acid, by methods known to those skilled in the art, to give the corresponding addition salt.
As a variant of step b) described above, the replacement of the acyl group with a hydrogen atom can be effected by reaction with a metal alcoholate, preferably a catalytic amount of sodium methylate in methanol, at a temperature between 0 and 30° C., for 0.5 to 2 hours, to give the compound of formula Ia from the compound of formula I in which R is a C2-C6 acyl group.
In a second process, the compounds of formula I can be obtained by reacting tetra-O-acetyl-5-thioxylopyranose of the formula
in which Ac is the acetyl group, with a compound of the formula
in which:
R1 is a C1-C4 alkylsulfonyl group, a C2-C6 acyl group, a group CONR′R″ or a group
in which:
X is a single bond, an oxygen atom, a sulfoxy group, a group —CO— or a group —CHOH—,
Ra is a hydrogen atom, a halogen, a C1-C4 alkyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a C1-C4 hydroxyalkyl group, a C2-C4 acyl group, a C1-C4 alkoxy group or a group NR′R″,
Rb and Rc independently of one another are each a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a cyano group or a C1-C4 alkoxy group,
R2 is a hydrogen atom, a C1-C4 alkyl group or a halogen atom, and
R′ and R″ independently are each a hydrogen atom or a C1-C4 alkyl group optionally substituted by an aromatic ring, or form, together with the nitrogen atom to which they are attached, a ring having 5 or 6 carbon atoms,
in an aprotic solvent such as dichloromethane, in the presence of a catalyst of the Lewis acid type, e.g. tin tetrachloride, at a temperature between 20 and 60° C., for 1 to 2 hours, to give the compound of the formula
in which R1 and R2 are as defined in the starting compounds.
The compound of formula Ib can then be reacted according to the protocol described in the previous process to give the unsubstituted pyranosyl compound and/or a salt with an acid.
In a third process, the compounds of formula I can be obtained by reacting a thioxylose derivative of the formula
in which Ac is the acetyl group,
with a compound of the formula
in which:
R1 is a C1-C4 alkylsulfonyl group, a C2-C6 acyl group, a group CONR′R″ or a group
in which:
X is a single bond, an oxygen atom, a sulfoxy group, a group —CO— or a group —CHOH—,
Ra is a hydrogen atom, a halogen, a C1-C4 alkyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a C1-C4 hydroxyalkyl group, a C2-C4 acyl group, a C1-C4 alkoxy group or a group NR′R″,
Rb and Rc independently of one another are each a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a cyano group or a C1-C4 alkoxy group,
R2 is a hydrogen atom, a C1-C4 alkyl group or a halogen atom, and
R′ and R″ independently are each a hydrogen atom or a C1-C4 alkyl group optionally substituted by an aromatic ring, or form, together with the nitrogen atom to which they are attached, a ring having 5 or 6 carbon atoms, in an aprotic solvent such as dichloromethane, in the presence of a catalyst such as trimethylsilyl trifluoromethanesulfonate, at a temperature between −25° C. and room temperature, for 1 to 5 hours, to give the thioxylopyranoside of the formula
in which R1 and R2 are as defined in the starting compounds.
The resulting compound of formula Ib can then be reacted as above to give the unsubstituted pyranosyl compounds and/or the acid salts.
The compounds of formula I according to the invention in which R1 is a group
in which X is a single bond can also be prepared from halogenated glycosylated products by means of a Suzuki coupling reaction between two aromatic rings.
One general process comprises carrying out the steps consisting in:
a) reacting a compound of the formula
in which Hal is a halogen atom, preferably bromine or iodine, R2 is a hydrogen atom, a halogen atom (other than bromine or iodine) or a C1-C4 alkyl group and R is a hydrogen atom or a C2-C6 acyl group,
with a phenylboronic acid derivative or an alkyl phenylboronate of the formula
in which:
Ra is a hydrogen atom, a halogen, a hydroxyl group, a C1-C4 alkyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a C1-C4 hydroxy-alkyl group, a C2-C4 acyl group, a C1-C4 alkoxy group or a group NR′R″,
Rb and Rc independently of one another are each a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a cyano group or a C1-C4 alkoxy group,
R′ and R″ independently are each a hydrogen atom or a C1-C4 alkyl group optionally substituted by an aromatic ring, or form, together with the nitrogen atom to which they are attached, a ring having 5 or 6 carbon atoms, and
R′″ is a hydrogen atom or a C1-C4 alkyl group,
in the presence of a palladium catalyst such as [1,1-bisdiphenylphosphinoferrocene]dichloropalladium dichloromethane, a palladium catalyst immobilized on resin, or Herrmann's catalyst, in the presence of a polar protic solvent such as methanol, and in the presence of cesium fluoride or sodium carbonate or other mineral bases to which lithium chloride has optionally been added, at a temperature between 70° C. and 150° C., for 5 minutes to 72 hours, with the aid of microwaves or a conventional mode of heating, to give the compound of the formula
in which:
Ra, Rb, Rc, R and R2 are as defined in the starting materials.
For compounds of this type, another similar process consists in reacting a glycosylated pyridinylboronate of the formula
with an aryl halide of the formula
under the same conditions as above, to give the compound of the formula
in which:
Ra, Rb, Rc, R and R2 are as defined in the starting materials.
In general terms it is preferable to use 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide or tetra-O-acetyl-5-thio-α-D-xylopyranose when preparing a β-D-5-thioxylopyranose derivative.
The glycosylation reactions described above most often give rise to a mixture of the isomers of α and β configuration and it is generally necessary to optimize the operating conditions to obtain proportions that favor the isomer of P configuration. For this same reason it may also be necessary to carry out purifications, either by recrystallization or by chromatography, in order to obtain the pure β isomer.
The Examples which follow are intended to illustrate the invention and cannot in any case limit its scope. The melting points were measured on a Koffler bench or in a capillary and the nuclear magnetic resonance spectral values are characterized by the chemical shift calculated relative to TMS, by the number of protons associated with the signal and by the shape of the signal (s for singlet, d for doublet, t for triplet, q for quadruplet, m for multiplet). The operating frequency and the solvent used are indicated for each compound.
The following abbreviations have been used:
mM denotes millimol (10−3 mol)
DMSO denotes dimethyl sulfoxide
THF denotes tetrahydrofuran
CHCl3 denotes chloroform
DME denotes dimethoxyethane
Preparation 1
(4-bromophenyl)(3-hydroxy-2-pyridinyl)methanone
48.5 g (205.5 mM) of 1,4-dibromobenzene are added dropwise to a mixture containing one crystal of iodine and 5 g (205.5 mM) of magnesium metal covered with 150 ml of THF. The mixture is stirred at the reflux temperature of the solvent for 2 hours and then cooled to 10° C. 12.34 g (102.7 mM) of 2-cyano-3-pyridinol are then added dropwise. The reaction medium is heated at the reflux temperature of the solvent for 3 hours, then stirred for 18 h at room temperature and then treated with 300 ml of 0.5 N sulfuric acid. The solvents are driven off under reduced pressure and the residual aqueous phase is brought to pH 4 by adding a necessary and sufficient amount of 2 N sodium hydroxide solution. The neutralized mixture is extracted with dichloromethane and the organic phase is dried over magnesium sulfate. After evaporation of the solvent, the expected product is obtained in the form of a yellow solid with a yield of 35%.
M.p.=94-95° C.
Preparation 2
4-[(3-hydroxy-2-pyridinyl)carbonyl]benzonitrile
10 g (35.96 mM) of (4-bromophenyl)(3-hydroxy-2-pyridinyl)methanone are mixed with 6.44 g (71.92 mM) of cuprous cyanide in 90 ml of dimethylformamide. The mixture is refluxed for 21 h. A solution of 19.25 g of ferric chloride in 42.5 ml of water and 6.7 ml of concentrated hydrochloric acid is prepared and added to the cooled reaction medium and the resulting mixture is then heated at 90° C. for 30 minutes. After cooling, ethyl acetate and water are added and the mixture is filtered on Celite. The product is then extracted with ethyl acetate and the organic phase is washed with saturated sodium chloride solution. The solvent is evaporated off under reduced pressure to give the desired product in the form of a yellow solid with a yield of 45%.
M.p.=145-146° C.
Preparation 3
(5-hydroxy-2-pyridinyl) [4-(trifluoromethyl)phenyl]methanone
A solution of 23.4 g (104 mM) of 1-bromo-4-trifluoromethylbenzene in 100 ml of THF is added dropwise to 2.53 g (104 mM) of magnesium metal and one crystal of iodine covered with 100 ml of THF. The mixture is stirred at the reflux temperature of the solvent for 2 hours and then cooled to 10° C. A solution of 5 g (42 mM) of 2-cyano-5-pyridinol in 80 ml of THF is then added dropwise. The mixture is refluxed for 2 hours and then stirred for 18 h at room temperature. It is treated with 120 ml of 0.5 N sulfuric acid and the solvents are evaporated off under reduced pressure. The medium is brought to neutral pH by washing with saturated sodium bicarbonate solution, extraction is carried out with ethyl acetate and the extract is dried over magnesium sulfate. After purification by chromatography on silica gel (eluent: toluene/ethyl acetate 8/2, then pure ethyl acetate and finally ethyl acetate/aqueous ammonia 95/5; v/v), the expected product is obtained in the form of a pale pink solid with a yield of 66%.
M.p. >260° C.
Preparation 4
4-(5-methoxy-2-pyridinyl)benzonitrile
A mixture of 3.1 g (13.2 mM) of 2-iodo-5-methoxypyridine, 2.9 g (19.8 mM) of 4-cyanophenylboronic acid, 1.7 g (40 mM) of lithium chloride, 0.6 g (0.52 mM) of tetrakis(triphenylphosphine)palladium, 30 ml of methanol and 30 ml of toluene is prepared and 20 ml (40 mM) of 2 M sodium carbonate are added. The reaction mixture is heated at the reflux temperature of the solvent for 72 hours. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with N sodium hydroxide solution, with water and with saturated sodium chloride solution and then dried over magnesium sulfate. After evaporation of the solvents, the crude product is purified by chromatography on silica gel using dichloromethane as the eluent to give the expected product in the form of a pale yellow solid with a yield of 66%.
M.p.=93-95° C.
Preparation 5
4-(5-hydroxy-2-pyridinyl)benzonitrile
A mixture of 1.82 g (8.65 mM) of the compound obtained according to Preparation 4 and 6 g (52 mM) of pyridinium hydrochloride is heated at 160° C. for 3 h 30 min. It is then cooled to room temperature, taken up with 100 ml of water, adjusted to pH 7 and extracted with ethyl acetate. The organic phase is washed with water and then with saturated sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvents, the product is purified by chromatography on a silica column (eluent: dichloromethane/ethanol 99/1; v/v) to give the expected product in the form of a white powder with a yield of 53%.
M.p.=210° C.
Preparation 6
4-(3-methoxy-2-pyridinyl)benzonitrile
By following a procedure analogous to Preparation 4 starting from 2-bromo-3-methoxypyridine, 4-(3-methoxy-2-pyridinyl)benzonitrile is obtained in the form of a white solid with a yield of 85%.
1H NMR (300 MHz; DMSO) δ=8.34 (dd, 1H); 8.07 (d, 2H); 7.72 (d, 2H); 7.30 (m, 2H); 3.90 (s, 3H).
Preparation 7
4-(3-hydroxy-2-pyridinyl)benzonitrile
By following a procedure analogous to Preparation 5 starting from 4-(3-methoxy-2-pyridinyl)benzonitrile, 4-(3-hydroxy-2-pyridinyl)benzonitrile is obtained in the form of a light beige solid with a yield of 65%.
M.p.=245-246° C.
Preparation 8
4-(5-methoxy-3-pyridinyl)benzonitrile
1.93 g (10.3 mM) of 3-bromo-5-methoxypyridine and 1.85 g (12.36 mM) of 4-cyanophenylboronic acid are mixed with 40 ml of toluene and 40 ml of methanol. 0.6 g (0.5 mM) of tetrakis(triphenylphosphine)palladium and 1.3 g (30.9 mM) of lithium chloride are added. 26 ml of 1 M sodium carbonate solution are then added. The mixture is refluxed for 5 hours and, after cooling, water and ethyl acetate are added to the reaction medium. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a dichloromethane/ethyl acetate mixture (94/6; v/v) as the eluent to give the expected product in the form of a beige solid with a yield of 89%.
1H NMR (300 MHz; DMSO) δ=8.56 (m, 1H); 8.36 (m, 1H); 7.98 (m, 4H); 7.73 (m, 1H); 3.92 (s, 3H).
Preparation 9
4-(5-hydroxy-3-pyridinyl)benzonitrile
A mixture of 1.9 g (9.02 mM) of 4-(5-methoxy-3-pyridinyl)benzonitrile and 6.39 g (54.2 mM) of pyridinium hydrochloride is heated at 160° C. for 5 hours. After cooling and the addition of water, the pH is adjusted to 5 with concentrated sodium hydroxide solution. The mixture is extracted with ethyl acetate and the extract is dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate 92/8; v/v, then dichloromethane/methanol 9/1; v/v) to give the expected product in the form of a beige solid with a yield of 76%.
M.p.=241-243° C.
Preparation 10
4-[(5-hydroxy-2-pyridinyl)thio]benzonitrile
0.25 g (1.31 mM) of copper(I) iodide, 7.26 g (52.5 mM) of potassium carbonate and 5.8 g (26.25 mM) of 6-iodo-3-pyridinol are introduced into a tube under an argon atmosphere. 30 ml of isopropanol, 5 g of 1,2-dimethoxyethane and 3.55 g (26.25 mM) of 4-mercaptobenzonitrile are then added. The tube is sealed and heated at 80° C. for 24 hours. When the mixture has returned to room temperature, it is diluted with 120 ml of ethyl acetate and filtered, the solid on the filter is washed with ethyl acetate and the organic phases are concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: cyclohexanol/ethyl acetate 55/45; v/v) to give the expected product in the form of a beige powder with a yield of 53%.
M.p.=180-181° C.
Preparation 11
4-[(5-hydroxy-2-pyridinyl)sulfonyl]benzonitrile
3.15 g (13.80 mM) of the product obtained according to Preparation 10 are dissolved in 45 ml of acetic acid. 7 ml of hydrogen peroxide are added. The reaction mixture is stirred for six days at room temperature. The precipitate formed is filtered off, washed with water and with petroleum ether and dried to give a first crop of the expected product. The filtrate is brought to pH 5 with dilute sodium hydroxide solution and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: toluene/ethyl acetate 6/4; v/v) to give the expected product in the form of a white powder with an overall yield of 91%.
M.p.=225-226° C.
Preparation 12
2-(methylsulfonyl)-3-pyridinol
A solution of 0.423 g (3 mM) of 2-methylthio-3-pyridinol in 11 ml of ethanol is prepared and a solution of 1.855 g (4.8 mM) of the magnesium salt of monoperoxyphthalic acid in 30 ml of water is added dropwise. The reaction mixture is stirred for 8 hours at room temperature and concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a cyclohexane/acetone mixture (80/20; v/v) as the eluent to give the desired product in the form of a white solid with a yield of 83%.
M.p.=115° C.
Preparation 13
6-(methylthio)-3-pyridinol
A solution of 5.5 ml of concentrated sulfuric acid and 8 ml of water is added to 1.9 g (13.55 mM) of 6-(methylthio)-3-pyridinamine. The reaction medium is brought to −6° C. and a solution of 1.59 g (23.03 mM) of sodium nitrite in 3 ml of water is added dropwise without exceeding 0° C. The mixture is stirred for 1 hour 30 min between 0° C. and −4° C. and then refluxed for 1 hour. The cooled reaction medium is poured in the presence of sodium bicarbonate and the mixture is then extracted with ethyl acetate. The organic phase is concentrated under reduced pressure and the residue is then chromatographed on silica gel (dichloromethane/ethyl acetate, 90/10; v/v) to give the expected product in the form of a white powder with a yield of 60%.
M.p.=133° C.
Preparation 14
6-(methylsulfonyl)-3-pyridinol
By following a procedure analogous to Preparation 12 starting from 6-(methylthio)-3-pyridinol, 6-(methylsulfonyl)-3-pyridinol is obtained in the form of a white powder with a yield of 91%.
M.p.=187° C.
Preparation 15
3-methoxy-5-phenoxypyridine
A solution of 0.9 g (3.6 mM) of 3-bromo-5-phenoxypyridine in 2 ml of methanol is prepared in a microwave tube. 8 ml (8 mM) of a 1 M solution of sodium methylate in methanol and 0.252 g (4 mM) of copper powder are added. The tube is closed and the reaction mixture is heated by microwaves at 150° C. for one hour and then filtered and concentrated under reduced pressure. The concentration residue is taken up with water and extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product is chromatographed on silica gel using a toluene/ethyl acetate mixture (95/5; v/v) as the eluent to give the expected product in the form of a colorless oil with a quantitative yield.
1H NMR (DMSO, 250 MHz) δ: 8.12 (d, 1H); 7.92 (d, 1H); 7.43 (m, 2H); 7.19 (m, 1H); 7.09 (m, 3H); 3.81 (s, 3H).
Preparation 16
5-phenoxy-3-pyridinol
A mixture of 0.6 g (3.37 mM) of 3-methoxy-5-phenoxypyridine and 1.15 g (10 mM) of pyridinium hydrochloride is prepared. It is heated by microwaves for 40 minutes at 150° C. and then cooled, taken up with methanol and brought to pH 7 with 1 N sodium hydroxide solution. After concentration under reduced pressure, the residue obtained is purified by chromatography on silica gel using a toluene/isopropanol mixture (95/5; v/v) as the eluent to give the desired product in the form of an off-white solid with a yield of 54%.
M.p.=107° C.
Preparation 17
2-chloro-3-fluoro-5-(phenylmethoxy)pyridine
0.5 g (3.38 mM) of 6-chloro-5-fluoro-3-pyridinol, 10 ml of dimethyl-formamide and 0.843 g (6.08 mM) of potassium carbonate are mixed. 0.8 ml (6.76 mM) of benzyl bromide is added and the mixture is heated at 80° C. for one hour. After hydrolysis in 100 ml of water, the mixture is extracted with ethyl acetate and the organic phases are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: pure toluene) to give the expected product in the form of a white solid with a quantitative yield.
M.p=48-52° C.
Preparation 18
2-phenyl-3-fluoro-5-(phenylmethoxy)pyridine
6.8 g (28.6 mM) of 2-chloro-3-fluoro-5-(phenylmethoxy)pyridine, 110 ml of DME and 4.18 g (34 mM) of phenylboronic acid are mixed. 6.64 g (156 mM) of lithium chloride and 1.65 g (1.4 mM) of tetrakis(triphenylphosphine)palladium are added. Finally, 38 ml (76 mM) of 2 M potassium carbonate solution are added and the mixture is refluxed for 18 hours. After hydrolysis in 250 ml of water, the mixture is extracted with ethyl acetate and the organic phases are washed with water and then with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (95/5, then 90/10; v/v) as the eluent to give the desired product in the form of a white solid with a yield of 84%.
M.p.=105-106° C.
Preparation 19
5-fluoro-6-phenyl-3-pyridinol
6.55 g (29.7 mM) of 2-phenyl-3-fluoro-5-(phenylmethoxy)pyridine are added to 160 ml of methanol, 30 ml of ethyl acetate and 30 ml of acetic acid. 0.33 g of 10% palladium-on-charcoal is added. The mixture is stirred under a hydrogen atmosphere for 3 hours. The catalyst is filtered off and the solvents are concentrated to give a white solid, which is taken up with 1 N sodium hydroxide solution. The aqueous phase obtained is washed with dichloromethane and then acidified to pH 5 with 1 N hydrochloric acid solution. The white precipitate obtained is filtered off and washed with water. After drying, the desired product is obtained in the form of a white solid with a yield of 77%.
M.p.=150-151° C.
Preparation 20
5-bromo-2-fluoro-3-pyridinol
A solution of 1.36 g (6.18 mM) of 5-bromo-2-fluoro-3-pyridineboronic acid in a mixture of 9.5 ml of ethanol, 2.3 ml of acetic acid and 1.3 ml of ethyl acetate is prepared. 2.2 ml of 30% hydrogen peroxide are added to the solution. The reaction mixture is stirred at a temperature of 35° C. for 3 hours and then cooled and extracted with ethyl ether. The organic phases are washed with a solution of ferrous ammonium sulfate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solid residue is purified by chromatography on silica gel using a toluene/ethyl acetate mixture (9/1; v/v) as the eluent to give the desired product in the form of a white solid with a yield of 62%.
M.p.=146° C.
Preparation 21
4-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 4-iodo-3-pyridinol, 4-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=31%).
[α]D24=−63° (c=0.20; DMSO).
M.p.=176° C.
Preparation 22
5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 5-bromo-2-fluoro-3-pyridinol, 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=39%).
M.p.=120-122° C.
Preparation 23
5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 5-bromo-3-pyridinol, 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a light brown powder (yield=61%).
M.p.=174° C.
[α]D20=−20° (c=0.20; DMSO).
Preparation 24
2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 2-chloro-4-methyl-3-pyridinol, 2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=30%).
M.p.=144° C.
[α]D30=+ 45° (c=0.37; DMSO).
Preparation 25
2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 2-bromo-4-pyridinol, 2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=37%).
M.p. 162° C.
[α]D29=−11° (c=0.48; DMSO).
Preparation 26
6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 6-bromo-3-pyridinol, 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a beige powder (yield=43%).
M.p.=145° C.
[α]D29=−20° (c=0.52; DMSO).
Preparation 27
4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 4-bromo-3-pyridinol, 4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a yellow powder (yield=38%).
M.p.=153° C.
[α]D30=−69° (c=0.31; DMSO).
Preparation 28
2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 2-bromo-3-pyridinol, 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=41%).
M.p.=156° C.
[α]D24=−78° (c=0.40; CH3OH).
Preparation 29
2-iodo-6-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 2-iodo-6-methyl-3-pyridinol, 2-iodo-6-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=81%).
M.p.=187° C.
[α]D30=−88° (c=0.28; DMSO).
Preparation 30
5-methylthio-3-pyridinol
1.284 g (8.2 mM) of 3-methoxy-5-methylthiopyridine and 2.87 g (24.8 mM) of pyridinium hydrochloride are heated at 150° C. for 2 hours in a reactor adapted for microwaves. A saturated aqueous solution of ammonium chloride is added to the cooled reaction medium and the pH is adjusted to neutral with 1 N hydrochloric acid solution. The precipitate formed is filtered off, the filtrate is then extracted with ether and the organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel using a dichloromethane/methanol mixture (99/1, then 80/20; v/v) as the eluent to give the expected product with a yield of 47%.
M.p.=179° C.
Preparation 31
5-methylsulfonyl-3-pyridinol
A solution of 4.018 g (10.39 mM) of the magnesium salt of peroxyphthalic acid in 120 ml of water is added dropwise to a solution of 0.916 g (6.49 mM) of the product obtained according to Preparation 30 in 50 ml of ethanol. The reaction mixture is stirred at 40° C. for 1 hour and then concentrated under reduced pressure. The residue is taken up in a dichloromethane/methanol mixture (10/1; v/v) and filtered. The filtrate is concentrated and then purified by chromatography on silica gel using a toluene/acetone mixture (90/10; v/v) as the eluent to give the expected product in the form of a white solid mixed with phthalic acid, and the product is used without further purification in the synthesis of Example 114.
Preparation 32
5-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
1.34 g (3 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-α-D-xylo-pyranoside, 10 ml of dioxane, 0.057 g (0.3 mM) of copper(I) iodide, 0.899 g (6 mM) of sodium iodide and 0.085 g (0.6 mM) of (1R,2R)—N,N′-dimethyl-1,2-cyclohexanediamine are mixed under an argon atmosphere in a reactor adapted for microwaves and the mixture is heated for 3 h 30 min at 130° C. 100 ml of water are added to the cooled reaction mixture and extraction is then carried out with ethyl acetate. The organic phase is washed with 1 N sodium thiosulfate solution and with water, dried over sodium sulfate and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a toluene/acetone mixture (1/1; v/v) as the eluent to give the expected product in the form of a white solid with a yield of 85%.
M.p.=148-150° C.
[α]D29=−7° (c=0.33; DMSO).
Preparation 33
2-iodo-5-triisopropylsilyloxypyridine
5 g (22.6 mM) of 5-hydroxy-2-iodopyridine and 6.42 ml (30.09 mM) of triisopropylsilyl chloride in 35 ml of acetonitrile are stirred at room temperature for 10 minutes. After the addition of 4.62 g (67.87 mM) of imidazole, stirring is maintained for 4 h 20 min at room temperature. The acetonitrile is evaporated off and the reaction mixture is taken up with three 150 ml portions of pentane. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is passed through a silica plug using petroleum ether as the eluent to give the desired product in the form of a light yellow oil with a yield of 98%.
1H NMR (250 MHz; DMSO) δ=8.04 (dd, 1H); 7.69 (dd, 1H); 7.08 (dd, 1H); 1.25 (m, 3H); 1.00 (m, 18H).
Preparation 34
5-hydroxy-N-(phenylmethyl)-2-pyridinecarboxamide
3 g (7.95 mM) of the product obtained according to Preparation 33, 3 ml (27.44 mM) of benzylamine, 2.1 g (7.95 mM) of molybdenum hexacarbonyl, 2.25 ml (14.93 mM) of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) and 0.373 g (0.4 mM) of trans-di-μ-acetatobis[2-(di-O-tolylphosphino)benzyl]dipalladium(II) (Herrmann's catalyst) are mixed under an argon atmosphere in a reactor adapted for microwaves. The mixture is heated at 150° C. for 15 minutes by microwaves. After cooling, the reaction medium is filtered and concentrated under reduced pressure. The evaporation residue is taken up in methylene chloride and 5 N sodium hydroxide solution. The combined aqueous phases are neutralized in the cold with concentrated hydrochloric acid solution (10 N) and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using pure dichloromethane and then a dichloromethane/methanol mixture (9/1; v/v) as the eluent to give the expected product in the form of an orange solid with a yield of 35%.
1H NMR (250 MHz; DMSO) δ=10.3 (broad, 1H); 9.00 (t, 1H); 8.14 (dd, 1H); 7.90 (dd, 1H); 7.25 (m, 6H); 4.46 (d, 2H).
Preparation 35
5-acetyl-3-pyridinol
A solution of 1.8 g (14.98 mM) of 5-hydroxy-3-pyridinecarbonitrile in 120 ml of THF is added dropwise to a 1.6 M solution of methyllithium in ether (18.7 ml, 29.92 mM), cooled to 0° C. After stirring for 15 minutes, the reaction medium is allowed to warm up to room temperature and stirring is continued for 2 hours. 50 ml of 0.5 N sulfuric acid solution are added to the reaction medium and the pH of the medium is then brought to 6 by adding concentrated hydrochloric acid solution (10 N). The aqueous phase is saturated with sodium chloride and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product obtained is then washed with ether and filtered off to give the desired product in the form of a yellow powder with a yield of 75%.
M.p.=186° C.
EXAMPLE 1
6-acetyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
1.29 g (9.47 mM) of zinc chloride are melted and left to cool to room temperature. 4 g of 13× molecular sieve, 50 ml of acetonitrile, 3.1 g (8.7 mM) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.4 g (8 mM) of silver imidazolate and 1 g (7.3 mM) of 6-acetyl-3-pyridinol are added. The mixture is stirred for 3 hours at 65° C. After filtration, the material on the filter is rinsed with ethyl acetate and the volatile solvents are evaporated off under reduced pressure. The product is purified by chromatography on silica gel using a toluene/isopropanol mixture (98/2; v/v) as the eluent. The purified product is crystallized from isopropyl alcohol to give the expected product in the form of a white solid with a yield of 15%.
M.p.=149° C.
[α]D22=−24° (c=0.1; DMSO).
EXAMPLE 2
6-acetyl-3-pyridinyl 5-thio-β-D-xylopyranoside
0.1 g (0.24 mM) of the product obtained according to Example 1, 5 ml of methanol and a few drops of an 8% solution of sodium methylate in methanol are mixed. The mixture is stirred for 30 minutes at room temperature. The precipitate obtained is filtered off and dried under reduced pressure to give the expected product in the form of white flakes with a yield of 48%.
M.p.=178-179° C.
[α]D24=−76° (c=0.09; DMSO).
EXAMPLE 3
2-acetyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
A mixture of 2.34 g (17.5 mM) of 2-acetyl-3-pyridinol, 8.4 g (19.2 mM) of 5-thio-α-D-xylopyranosyl trichloroacetimidate and 80 ml of dichloromethane is cooled to −20° C. and 316 μl (1.75 mM) of trimethylsilyl trifluoromethanesulfonate are added. The mixture is stirred for 30 minutes at 0° C. and for 4 hours at room temperature. The organic phase is washed with N sodium hydroxide solution and then with water until the pH is neutral. It is dried over magnesium sulfate and the solvent is driven off under reduced pressure. The product is purified by chromatography on a silica column using a cyclohexane/ethyl acetate mixture (6/4; v/v) as the eluent to give the expected product in the form of a yellow solid with a yield of 40%.
M.p.=168° C.
[α]D23=90° (c=0.25; CH2Cl2).
EXAMPLE 4
2-acetyl-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 3,2-acetyl-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=82%).
M.p.=123° C.
[α]D23=−101° (c=0.44; CH3OH).
EXAMPLE 5
[(4-cyanobenzoyl)-3-pyridinyl]2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 1 starting from the pyridinol obtained according to Preparation 2, the expected compound is obtained in the form of a white powder (yield=5%).
[+]D26=−35.7° (c=0.11; DMSO).
EXAMPLE 6
[2-(4-cyanobenzoyl)-3-pyridinyl]5-thio-β-D-xylopyranoside
0.23 g (0.46 mM) of the product obtained according to Example 5 is stirred at room temperature for 2 h 30 min with 15 ml of a 7 M solution of ammonia in methanol. The reaction mixture is concentrated under reduced pressure and the crude product obtained is purified by chromatography on silica gel using a dichloromethane/methanol mixture (99/1; v/v) as the eluent. The oil obtained is taken up in solution in 8 ml of hot water and then lyophilized to give the desired product in the form of a yellow powder with a yield of 64%.
M.p.=112° C.
[α]D32=−89.5° (c=0.12; DMSO).
EXAMPLE 7
[6-[4-(trifluoromethyl)benzoyl]-3-pyridinyl]2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 3, the expected compound is obtained in the form of white crystals (yield=22%).
[α]D26=−10.1° (c=0.25; DMSO).
M.p.=158-160° C.
EXAMPLE 8
[6-[4-(trifluoromethyl)benzoyl]-3-pyridinyl]5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 7, the expected compound is obtained in the form of a white solid (yield=29%).
M.p.=129-132° C.
[+]D26=−293.2° (c=0.12; DMSO).
EXAMPLE 9
[6-(4-cyanophenyl)-3-pyridinyl]2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 5, the expected product is obtained in the form of a white powder (yield=26%).
[α]D23=+26° (c=0.42; DMSO).
M.p.=197-198° C.
EXAMPLE 10
[6-(4-cyanophenyl)-3-pyridinyl]5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained according to Example 9, the expected product is obtained in the form of a white powder (yield=81%).
[α]D23=−32° (c=0.42; DMSO).
M.p.=213-214° C.
EXAMPLE 11
[2-(4-cyanophenyl)-3-pyridinyl]2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 7, the expected product is obtained in the form of an amorphous solid (yield=10%).
[α]D26=−91.2° (c=0.28; DMSO).
M.p.=120° C.
EXAMPLE 12
[2-(4-cyanophenyl)-3-pyridinyl]5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained according to Example 11, the expected product is obtained in the form of a white powder (yield=100%).
[α]D32=−26° (c=0.50; DMSO).
M.p.=180° C.
EXAMPLE 13
5-phenyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 1 starting from 5-phenyl-3-pyridinol, the expected product is obtained in the form of a white solid (yield=25%).
[α]D25=−9° (c=0.20; DMSO).
M.p.=181° C.
EXAMPLE 14
5-phenyl-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 13, the expected product is obtained in the form of a white solid (yield=54%).
M.p.=169° C.
[α]D26=−66° (c=0.22; DMSO).
EXAMPLE 15
[5-(4-cyanophenyl)-3-pyridinyl]2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 1 starting from 5-(4-cyanophenyl)-3-pyridinol, the expected product is obtained in the form of a white powder (yield=27%).
[α]D23=+10° (c=0.39; DMSO).
M.p.=116-117° C.
EXAMPLE 16
[2-(4-cyanophenyl)-3-pyridinyl]5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained according to Example 15, the expected product is obtained in the form of a white powder (yield=72%).
[α]D23=−40° (c=0.36; DMSO).
M.p.=202-203° C.
EXAMPLE 17
6-[(4-cyanophenyl)sulfonyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 1 starting from 6-[(4-cyanophenyl)sulfonyl]-3-pyridinol, the expected product is obtained in the form of a white powder (yield=20%).
[α]D29=−19.8° (c=0.24; DMSO).
M.p.=179-180° C.
EXAMPLE 18
6-[(4-cyanophenyl)sulfonyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 17, the expected product is obtained in the form of a flaky white powder (yield=65%).
[α]D26=−27° (c=0.16; DMSO).
M.p.=179° C.
EXAMPLE 19
2-(methylsulfonyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 12, the expected product is obtained in the form of a white powder (yield=53%).
M.p.=172-173° C.
EXAMPLE 20
2-(methylsulfonyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 19, the expected product is obtained in the form of white flakes (yield=84%).
[α]D28=−70° (c=0.45; H2O).
M.p.=81-105° C.
EXAMPLE 21
6-(methylsulfonyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 1 starting from the compound obtained according to Preparation 14, the expected product is obtained in the form of a white powder (yield=51%).
[α]D21=−116° (c=0.46; CHCl3).
M.p.=178° C.
EXAMPLE 22
6-(methylsulfonyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the 6-(methylsulfonyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained in Example 21, the expected product is obtained in the form of a white powder (yield=98%).
[α]D24=−61°(c=0.43; DMSO).
M.p.=95-114° C.
EXAMPLE 23
2-phenyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
0.1 g (0.24 mM) of 2-chloro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 30 ml of DME, 0.037 g (0.29 mM) of phenylboronic acid, 0.102 g (0.66 mM) of cesium fluoride and 0.021 g (0.024 mM) of [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) dichloromethane are mixed. The mixture is heated for 2 hours at 120° C. under an inert atmosphere in a microwave oven. The reaction medium is then filtered on a Whatman filter, the material on the filter is rinsed with ethyl acetate and the filtrate is extracted. The pH is neutralized with ammonium chloride solution. The organic phase is dried over sodium sulfate and the product is concentrated under reduced pressure. It is purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate 99/1; v/v) to give the expected product in the form of a white powder with a yield of 90%.
M.p.=69-101° C.
[α]D23=−44° (c=0.12; CHCl3).
EXAMPLE 24
2-phenyl-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 23,2-phenyl-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=89%).
M.p.=89-108° C.
[α]D25=−28° (c=0.2; CH3OH).
EXAMPLE 25
5-phenoxy-3-pyridinyl 2,3,4-tri-O-acetyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 1 starting from 5-phenoxy-3-pyridinol, 5-phenoxy-3-pyridinyl 2,3,4-tri-O-acetyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=25%).
[α]D25=−18° (c=0.26; DMSO). M.p.=178° C.
EXAMPLE 26
5-phenoxy-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the product obtained in Example 25,5-phenoxy-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=78%).
M.p.=226° C.
[α]D26=−83° (c=0.27; DMSO).
EXAMPLE 27
4-(4-cyanophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
A solution of 0.55 g (1.11 mM) of 4-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside in 3 ml of DME is prepared and a solution of 0.176 g (1.66 mM) of sodium carbonate in 2.5 ml of water, 0.091 g (0.11 mM) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane and 0.326 g (2.2 mM) of 4-cyanophenylboronic acid are added. The reaction mixture is heated by microwaves at 90° C. for 8 minutes and cooled, water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with 1 M sodium carbonate solution and then with water until the pH is neutral, dried over magnesium sulfate and concentrated under reduced pressure. The product is purified by chromatography on a silica column (eluent: dichloromethane/acetone 80/20; v/v) to give the expected product in the form of an ecru solid with a yield of 63%.
M.p.=212° C.
[α]D21=−113° (c=0.30; DMSO).
EXAMPLE 28
4-(4-cyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the product obtained in Example 27, 4-(4-cyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=90%).
M.p.=238° C.
[α]D20=−97° (c=0.20; DMSO).
EXAMPLE 29
5-[[(phenylmethyl)amino]carbonyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
0.5 g (1.115 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 0.37 ml (3.346 mM) of benzylamine, 0.294 g (1.115 mM) of molybdenum hexacarbonyl, 0.042 g (0.056 mM) of Herrmann's catalyst and 0.5 ml (3.346 mM) of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) are mixed in 3 ml of THF. The mixture is heated at 150° C. for 15 minutes by microwaves. The reaction mixture is filtered, the filtrate is taken up in 20 ml of ethyl acetate and the organic phase is washed with 1 N sodium hydroxide solution, dried over magnesium sulfate and concentrated under reduced pressure to give the expected product in the form of a pale yellow solid with a yield of 0.7%.
1H NMR (300 MHz; DMSO) δ=9.21 (t, 1H); 8.71 (d, 1H); 8.52 (d, 1H); 7.96 (t, 1H); 7.34 (m, 5H); 5.57 (d, 1H); 5.32 (d, 1H); 5.15 (d, 1H); 5.05 (d, 1H); 4.50 (d, 2H); 3.61 (m, 1H); 3.49 (m, 1H); 3.14 (m, 1H); 2.64 (m, 2H).
EXAMPLE 30
5-fluoro-6-phenyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
2.76 g (19.75 mM) of zinc chloride are melted and cooled under an inert atmosphere and 18 ml of toluene, 18 ml of acetonitrile, 3.16 g of 4 Å molecular sieve and 1.5 g (7.9 mM) of 5-fluoro-6-phenyl-3-pyridinol are then added. This mixture is heated for 5 min at 90° C. and then cooled to room temperature. 2.81 ml (19.75 mM) of triethylamine and 3.16 g (8.69 mM) of 2,3,4-tri-O-acetyl-5-thio-(X-D-xylopyranosyl bromide are then added. The mixture is stirred at 90° C. for 20 minutes and the reaction is then stopped by cooling and by adding 90 ml of 0.5 N sodium hydroxide solution. The reaction medium is filtered to remove the mineral salts, which are washed with ethyl acetate. The combined organic phases are washed with ammonium chloride solution to adjust the pH to 7-8, dried over magnesium sulfate and concentrated under reduced pressure. The product is crystallized from ethyl ether to give the desired product in the form of a beige solid with a yield of 47%.
M.p.=160-162° C.
[α]D23=−58° (c=0.58; CHCl3).
EXAMPLE 31
5-fluoro-6-phenyl-3-pyridinyl 5-thio-β-D-xylopyranoside
1.72 g (3.71 mM) of the product obtained in Example 30 are mixed with 35 ml of methanol. 0.05 ml of a 7 M solution of sodium methylate in methanol is added. The mixture is stirred for 30 minutes at 30° C. The reaction is stopped by adding about 1 g of IR 120 resin. The reaction medium is filtered, the material on the filter is rinsed with methanol and the organic phases are concentrated. The product is recrystallized from ethanol to give the desired product in the form of a white solid with a yield of 61%.
M.p.=174-176° C.
[α]D23=53° (c=0.57; CH3OH).
EXAMPLE 32
5-(4-cyanophenyl)-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(4-cyano-phenyl)-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=69%).
M.p.=132-133° C.
[α]D19=−1.3° (c=0.60; CH3OH).
EXAMPLE 33
5-(4-cyanophenyl)-2-fluoro-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the product obtained in Example 32, 5-(4-cyanophenyl)-2-fluoro-3-pyridinyl 5-thio-β-D-xylo-pyranoside is obtained in the form of a beige solid (yield=73%).
M.p.=220° C.
[α]D19=−62° (c=0.50; CfH3OH).
EXAMPLE 34
4-[4-(trifluoromethyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-(trifluoromethyl)-phenylboronic acid, 4-[4-(trifluoromethyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=31%).
M.p. 168° C.
[α]D22−63° (c=0.36; DMSO).
EXAMPLE 35
4-(4-trifluoromethylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 34, 4-(4-trifluoromethylphenyl)-3-pyridinyl 5-thio-β-D-xylo-pyranoside is obtained in the form of a white solid (yield=86%).
M.p.=204° C.
[α]D222 −70° (c=0.32; DMSO).
EXAMPLE 36
5-(4-trifluoromethoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
0.5 g (1.11 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 0.275 g (1.33 mM) of 4-(trifluoromethoxy)phenylboronic acid, 0.373 g (2.45 mM) of cesium fluoride and 0.24 g of tetrakis(triphenylphosphine)palladium catalyst grafted onto polystyrene resin are mixed in 3.5 ml of DME and 5 ml of methanol. The reaction mixture is heated at 110° C. for 20 minutes by microwaves. It is filtered and then concentrated under reduced pressure. The crude product is purified by chromatography on a silica column (eluent: dichloromethane/methanol 90/10; v/v) to give the expected product in the form of a white solid with a yield of 68%.
M.p.=199-202° C.
[α]D25=−67.6° (c=0.10; DMSO).
EXAMPLE 37
5-(3-acetylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 36 starting from 3-acetyl-phenylboronic acid, 5-(3-acetylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=63%).
M.p.=159-163° C.
[α]D25=−96.7° (c=0.12; DMSO).
EXAMPLE 38
5-(4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 36 starting from 4-fluoro-phenylboronic acid, 5-(4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=41%).
M.p. 208-209° C.
[α]D25=−83.6° (c=0.13; DMSO).
EXAMPLE 39
2-(1-piperidinylcarbonyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 1 starting from 2-(1-piperidinylcarbonyl)-3-pyridinol, the expected compound is obtained in the form of white crystals (yield=35%).
M.p.=89-92° C.
[α]D25=−105.6° (c=0.10; DMSO).
EXAMPLE 40
2-(1-piperidinylcarbonyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 39, the expected compound is obtained in the form of a white solid (yield=38%).
M.p.=81-92° C.
[α]D19=−101.6° (c=0.10; DMSO).
EXAMPLE 41
2-(dimethylaminocarbonyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 1 starting from 2-(dimethylaminocarbonyl)-3-pyridinol, the expected compound is obtained in the form of a white solid (yield=5%).
M.p.=85-89° C.
[α]D19=−69.3° (c=0.10; DMSO).
EXAMPLE 42
2-(dimethylaminocarbonyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 41, 2-(dimethylaminocarbonyl)-3-pyridinyl 5-thio-β-D-xylo-pyranoside is obtained in the form of a white solid (yield=18%).
M.p.=80-85° C.
[α]D21=−31° (c=0.17; DMSO).
EXAMPLE 43
5-(4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
1 g (2.23 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 0.4 g (2.67 mM) of 4-methoxyphenylboronic acid, 1.6 g (4.46 mM) of carbonate resin and 0.02 g (0.004 mM) of [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane are mixed in 7 ml of DME and 5 ml of methanol. The reaction mixture is heated for 20 minutes at 110° C. by microwaves. It is filtered, the material on the filter is rinsed with methanol and the organic phases are concentrated. The product is purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate 98/2, then 70/30; v/v) to give the expected product in the form of a cream-colored powder with a yield of 80%.
M.p.=156° C.
[α]D25=−11.1° (c=0.42; DMSO).
EXAMPLE 44
5-(4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 43, 5-(4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylo-pyranoside is obtained in the form of a gray powder (yield=85%).
M.p.=216° C.
[α]D20=−90.9° (c=0.11; DMSO).
EXAMPLE 45
5-(4-hydroxymethylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 4-(hydroxymethyl)phenylboronic acid, 5-(4-hydroxymethylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of brown crystals (yield=59%).
M.p.=132-133° C.
[+]D21=−5.3° (c=0.24; DMSO).
EXAMPLE 46
5-(4-hydroxymethylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 45, 5-(4-hydroxymethylphenyl)-3-pyridinyl 5-thio-β-D-xylo-pyranoside is obtained in the form of a pale pink powder (yield=65%).
M.p.=153° C.
[α]D25=−67.5° (c=0.20; DMSO).
EXAMPLE 47
5-[4-(1-piperidinyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 4-(1-piperidinyl)phenylboronic acid, the expected compound is obtained in the form of a white solid (yield=15%).
M.p.=196° C.
[α]D20=0° (c=0.17; DMSO).
EXAMPLE 48
5-[4-(1-piperidinyl)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 47, 5-[4-(1-piperidinyl)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a grayish powder (yield=74%).
M.p.=196° C.
[α]D26=−52.5° (c=0.11; DMSO).
EXAMPLE 49
5-[4-(dimethylamino)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 4-(dimethylamino)phenylboronic acid, the expected compound is obtained in the form of a beige powder (yield=25%).
[α]D22=+16° (c 0.33; DMSO).
M.p.=198-199° C.
EXAMPLE 50
5-[4-(dimethylamino)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 49, 5-[4-(dimethylamino)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder with a yield of 74%.
M.p.=240° C.
[α]D23=−40° (c=0.40; DMSO).
EXAMPLE 51
5-(4-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 43 starting from 4-methyl-phenylboronic acid, 5-(4-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of beige crystals (yield=80%).
M.p.=160-162° C.
[α]D22=−5° (c=0.44; DMSO).
EXAMPLE 52
5-(4-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 51, 5-(4-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a beige powder with a yield of 80%.
M.p.=228° C.
[α]D22=−73° (c=0.41; DMSO).
EXAMPLE 53
5-[4-(trifluoromethyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside and 5-[4-(trifluoromethyl)phenyl]-3-pyridinyl 5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 36 starting from 4-(tri-fluoromethyl)phenylboronic acid, 5-[4-(trifluoromethyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=19%, m.p.=163-164° C., [α]D22=−14° (c=+0.44; DMSO)) and 5-[4-(trifluoromethyl)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=17%, m.p.=218-219° C., [α]D22=−62° (c=0.43; DMSO)).
EXAMPLE 54
5-(3-cyanophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 27 starting from the 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 23 and 3-cyanophenylboronic acid, 5-(3-cyanophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=59%).
M.p.=130-131° C.
[α]D30=−21° (c=0.10; DMSO).
EXAMPLE 55
5-(3-cyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 54, 5-(3-cyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=67%).
M.p.=172° C.
[α]D28=−87° (c=0.11; DMSO).
EXAMPLE 56
4-(4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 27 starting from the 4-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 21 and 4-fluorophenylboronic acid, 4-(4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=47%).
M.p.=111° C.
[α]D30=−49° (c=0.30; DMSO).
EXAMPLE 57
4-(4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the product obtained in Example 56, 4-(4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid with a yield of 62%.
M.p. 219° C.
[α]D30=−70° (c=0.32; DMSO).
EXAMPLE 58
5-(4-fluoro-3-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluoro-3-methyl-phenylboronic acid, 5-(4-fluoro-3-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=48%).
M.p.=161° C.
[α]D33=−16° (c=0.27; DMSO).
EXAMPLE 59
5-(4-fluoro-3-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 58, 5-(4-fluoro-3-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=76%).
M.p.=197° C.
[α]D34=−75° (c=0.20; DMSO).
EXAMPLE 60
5-(4-fluoro-2-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluoro-2-methyl-phenylboronic acid, 5-(4-fluoro-2-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=72%).
M.p.=120° C.
[α]D34=−20° (c=0.25; DMSO).
EXAMPLE 61
5-(4-fluoro-2-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 60, 5-(4-fluoro-2-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=71%).
M.p.=217° C.
[α]D34=−75° (c=0.20; DMSO).
EXAMPLE 62
5-(3-cyano-4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-cyano-4-fluoro-phenylboronic acid, 5-(3-cyano-4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=66%).
M.p.=178° C.
[α]D32=−13° (c=0.13; DMSO).
EXAMPLE 63
5-(3-cyano-4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 62, 5-(3-cyano-4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=59%).
M.p.=197° C.
[α]D29=−118° (c=0.11; DMSO).
EXAMPLE 64
5-(3-chloro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-chloro-4-methoxy-phenylboronic acid, 5-(3-chloro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=66%).
M.p.=155° C.
[α]D32=7° (c=0.30; DMSO).
EXAMPLE 65
5-(3-chloro-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 64, 5-(3-chloro-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of an ecru solid (yield=60%).
M.p.=165° C.
[α]D32=40° (c=0.34; DMSO).
EXAMPLE 66
5-(3-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-methoxyphenyl-boronic acid, 5-(3-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside is obtained in the form of a white powder (yield=77%).
M.p.=112-115° C.
[α]D32=+1° (c=0.12; DMSO).
EXAMPLE 67
5-(3-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 66, 5-(3-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=95%).
M.p.=200° C. (recrystallized from methanol).
[α]D28=−72° (c=0.32; DMSO).
EXAMPLE 68
5-[4-(1-methylethoxy)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-methylethoxy-phenylboronic acid, 5-[4-(1-methylethoxy)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=55%).
M.p. 135° C.
[α]D28=−3° (c=0.35; DMSO).
EXAMPLE 69
5-[4-(1-methylethoxy)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 68, 5-[4-(1-methylethoxy)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a cottony white solid (yield=20%).
M.p.=158° C.
[α]D29=−65° (c=0.42; DMSO).
EXAMPLE 70
5-(3,4-dimethoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3,4-dimethoxyphenylboronic acid, 5-(3,4-dimethoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=73%).
M.p.=145° C.
[α]D32=−8° (c=0.27; DMSO).
EXAMPLE 71
5-(3,4-dimethoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 70, 5-(3,4-dimethoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=76%).
M.p.=211° C.
[α]D29=−41° (c=0.35; DMSO).
EXAMPLE 72
2-(4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 27 starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluorophenylboronic acid, 2-(4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=64%).
M.p.=149° C.
[α]D27=−91° (c=0.30; DMSO).
EXAMPLE 73
2-(4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 72, 2-(4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=88%).
M.p. 110° C.
[α]D28=−56° (c=0.14; DMSO).
EXAMPLE 74
2-(4-methoxyphenyl)-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from the 2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 24 and 4-methoxyphenylboronic acid, 2-(4-methoxy-phenyl)-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained and is used directly for the deacetylation step.
EXAMPLE 75
2-(4-methoxyphenyl)-4-methyl-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 74, 2-(4-methoxyphenyl)-4-methyl-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a cottony white solid (yield=62%).
M.p.=101° C.
[α]D31=+14° (c=0.14; DMSO).
EXAMPLE 76
2-(4-methoxyphenyl)-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 27 starting from the 2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 25 and 4-methoxyphenylboronic acid, 2-(4-methoxyphenyl)-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a beige solid (yield=53%).
M.p.=113-114° C.
[β]D27=−9° (c=0.12; DMSO).
EXAMPLE 77
2-(4-methoxyphenyl)-4-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 76, 2-(4-methoxyphenyl)-4-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=33%).
M.p.=150-154° C.
[α]D27=−44° (c=0.11; DMSO).
EXAMPLE 78
5-[3-fluoro-4-(1-methylethoxy)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-fluoro-4-(1-methyl-ethoxy)phenylboronic acid, 5-[3-fluoro-4-(1-methylethoxy)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=82%).
M.p.=65° C.
[α]D29=+3° (c=0.22; DMSO).
EXAMPLE 79
5-[3-fluoro-4-(1-methylethoxy)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 78, 5-[3-fluoro-4-(1-methylethoxyphenyl)]-3-pyridinyl 5-thio-α-D-xylopyranoside is obtained in the form of a white solid (yield=67%).
M.p.=181° C.
[α]D30=−62° (c=0.38; DMSO).
EXAMPLE 80
5-(2,6-difluoro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 2,6-difluoro-4-methoxyphenylboronic acid, 5-(2,6-difluoro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=30%).
M.p.=62° C.
[α]D30=−4° (c=0.18; DMSO).
EXAMPLE 81
5-(2,6-difluoro-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 80, 5-(2,6-difluoro-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=59%).
M.p. 200° C.
[α]D30=−59° (c=0.36; DMSO).
EXAMPLE 82
5-(3,5-dimethyl-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3,5-dimethyl-4-methoxyphenylboronic acid, 5-(3,5-dimethyl-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=52%).
M.p.=146° C.
[α]D29=0° (c=0.22; DMSO).
EXAMPLE 83
5-(3,5-dimethyl-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 82, 5-(3,5-dimethyl-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=72%).
M.p.=173° C.
[α]D=−63° (c=0.23; DMSO).
EXAMPLE 84
5-(2,4-difluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 2,4-difluorophenyl-boronic acid, 5-(2,4-difluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of an off-white foam (yield=87%).
M.p.=121° C.
[α]D27=−9° (c=0.25; DMSO).
EXAMPLE 85
5-(2,4-difluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 84, 5-(2,4-difluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=79%).
M.p.=221° C.
[α]D27=−62° (c=0.66; DMSO).
EXAMPLE 86
5-(4-fluoro-2-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluoro-2-methoxy-phenylboronic acid, 5-(4-fluoro-2-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of an off-white foam (yield=92%).
M.p.=121° C.
[α]D27=−11° (c=0.23; DMSO).
EXAMPLE 87
5-(4-fluoro-2-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 86, 5-(4-fluoro-2-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=71%).
M.p.=218-228° C. (recrystallized from methanol).
[α]D27=+64° (c=0.54; DMSO).
EXAMPLE 88
5-(2-chloro-4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 2-chloro-4-fluoro-phenylboronic acid, 5-(2-chloro-4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of an off-white foam (yield 81%).
M.p.=115° C.
[α]D27=−11° (c=0.38; DMSO).
EXAMPLE 89
5-(2-chloro-4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 88, 5-(2-chloro-4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=78%).
M.p.=208-211° C.
[α]D27=−58° (c=0.49; DMSO).
EXAMPLE 90
5-(4-cyano-3-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-fluoro-4-cyano-phenylboronic acid, 5-(4-cyano-3-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a cream-colored solid (yield=65%).
M.p.=223° C.
[α]D26=−20° (c=0.23; DMSO).
EXAMPLE 91
5-(4-cyano-3-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 90, 5-(4-cyano-3-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=75%).
M.p.=214° C.
[α]D21=−51° (c=0.16; DMSO).
EXAMPLE 92
6-(4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 4-methoxyphenylboronic acid and the 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 26, 6-(4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a whitish powder (yield=28%).
M.p.=208° C. (crystallized from ethyl acetate).
[α]D29=+12° (c=0.25; DMSO).
EXAMPLE 93
6-(4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 92, 6-(4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=74%).
M.p.=164° C.
[α]D29=−37° (c=0.23; DMSO).
EXAMPLE 94
6-[4-(hydroxymethyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 4-(hydroxymethyl)phenylboronic acid and the 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 26, 6-[4-(hydroxymethyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=29%).
M.p.=157° C.
[α]D29=+12° (c=0.42; DMSO).
EXAMPLE 95
6-[4-(hydroxymethyl)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 94, 6-[4-(hydroxymethyl)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=68%).
M.p.=215° C. (crystallized from water).
[α]D28=−18° (c=0.17; DMSO).
EXAMPLE 96
6-[4-(trifluoromethyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 4-(trifluoromethyl)phenylboronic acid and the 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 26, 6-[4-(trifluoromethyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=25%).
M.p.=178-180° C.
[α]D23=+7° (c=0.34; DMSO).
EXAMPLE 97
6-[4-(trifluoromethyl)phenyl]-3-pyridinyl 5-thio-α-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 96, 6-[4-(trifluoromethyl)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=90%).
M.p.=194-195° C. (crystallized from methanol).
[α]D28=−41° (c=0.34; DMSO).
EXAMPLE 98
6-(4-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranoside
By following a procedure analogous to Example 43 starting from 4-methyl-phenylboronic acid and the 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 26, 6-(4-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=25%).
M.p.=150-152° C.
[α]D31=+10° (c=0.32; DMSO).
EXAMPLE 99
6-(4-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 98, 6-(4-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=84%).
M.p.=191° C.
[α]D30=48° (c=0.33; DMSO).
EXAMPLE 100
4-(4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 4-methoxyphenylboronic acid and the 4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 27, 4-(4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=29%).
M.p. 193° C. (crystallized from 2-propanol).
[α]D30=93° (c=0.26; DMSO).
EXAMPLE 101
4-(4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 100, 4-(4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a pink powder (yield=66%).
M.p.=228° C. (crystallized from methanol).
[α]D32=−80° (c=0.54; DMSO).
EXAMPLE 102
5-(3-fluoro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 3-fluoro-4-methoxyphenylboronic acid, 5-(3-fluoro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a pale pink powder (yield=64%).
M.p.=150-152° C.
[α]D31=+5° (c=0.16; DMSO).
EXAMPLE 103
5-(3-fluoro-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 102, 5-(3-fluoro-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=80%).
M.p.=200° C. (crystallized from methanol).
[α]D28=−3° (c=0.48; DMSO).
EXAMPLE 104
5-(4-methoxy-2-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 4-methoxy-2-methylphenylboronic acid, 5-(4-methoxy-2-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=32%).
M.p.=283° C. (crystallized from 2-propanol).
[α]D29=−6° (c=0.35; DMSO).
EXAMPLE 105
5-(4-methoxy-2-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 104, 5-(4-methoxy-2-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a gray powder (yield=68%).
M.p.=231° C. (crystallized from water).
[α]D29=−57° (c=0.32; DMSO).
EXAMPLE 106
5-(3-fluoro-4-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 3-fluoro-4-methylphenylboronic acid, 5-(3-fluoro-4-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a pink powder (yield=31%).
M.p.=159° C.
[α]D27=−14° (c=0.19; DMSO).
EXAMPLE 107
5-(3-fluoro-4-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 106, 5-(3-fluoro-4-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of gray crystals (yield=25%).
M.p.=213° C. (crystallized from 2-propanol).
[α]D30=−22° (c=0.17; DMSO).
EXAMPLE 108
5-(3,4-dimethylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 3,4-dimethylphenylboronic acid, 5-(3,4-dimethylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=50%).
M.p.=131° C.
[α]D27=−5° (c=0.15; DMSO).
EXAMPLE 109
5-(3,4-dimethylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 108, 5-(3,4-dimethylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=31%).
M.p. 184° C.
[α]D28=−57° (c=0.22; DMSO).
EXAMPLE 110
5-(2-chloro-4-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 2-chloro-4-methylphenylboronic acid, 5-(2-chloro-4-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a beige powder (yield=50%).
M.p.=162° C.
[α]D30=−8° (c=0.27; DMSO).
EXAMPLE 111
5-(2-chloro-4-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 110, 5-(2-chloro-4-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=58%).
M.p.=207° C.
[α]D30=−48° (c=0.15; DMSO).
EXAMPLE 112
5-(2-chloro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from 2-chloro-4-methoxyphenylboronic acid, 5-(2-chloro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=32%).
M.p.=126° C.
[α]D30=−11° (c=0.41; DMSO).
EXAMPLE 113
5-(2-chloro-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 112, 5-(2-chloro-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of beige needles (yield=53%).
M.p.=218° C. (crystallized from an ethanol/water mixture).
[α]D26=−43° (c=0.16; DMSO).
EXAMPLE 114
5-methylsulfonyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from the 5-methylsulfonyl-3-pyridinol obtained according to Preparation 31,5-methylsulfonyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a cream-colored powder (yield=18%).
M.p.=193° C.
[α]D29=+162° (c=0.50; CHCl3).
EXAMPLE 115
5-methylsulfonyl-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 114, 5-methylsulfonyl-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white flakes (yield=90%).
M.p.=183° C.
[α]D29=+248° (c=0.30; H2O).
EXAMPLE 116
6-{[(phenylmethyl)amino]carbonyl}-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranosyl bromide and the 5-hydroxy-N-(phenylmethyl)-2-pyridinecarboxamide obtained according to Preparation 34, 6-{[(phenyl-methyl)amino]carbonyl}-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a beige solid (yield=31%).
M.p.=177-178° C.
[α]D30=−13° (c=0.17; DMSO).
EXAMPLE 117
6-{[(phenylmethyl)amino]carbonyl}-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 116, 6-{[(phenylmethyl)amino]carbonyl}-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of yellow crystals (yield=86%).
M.p. 89-91° C.
[α]D30=−52° (c=0.15; DMSO).
EXAMPLE 118
5-acetyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from the 5-acetyl-3-pyridinol obtained according to Preparation 35,5-acetyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a light yellow powder (yield=20%).
M.p.=157° C.
[α]D27=−7° (c=0.21; DMSO).
EXAMPLE 119
5-acetyl-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 118, 5-acetyl-3-pyridinyl 5-thio-β-D-xylo-pyranoside is obtained in the form of pink needles (yield=50%).
M.p.=209° C.
[α]D27=−93° (c=0.19; DMSO).
EXAMPLE 120
4-acetyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 30 starting from 4-acetyl-3-pyridinol, 4-acetyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained and is used directly in the deacetylation step without intermediate purification.
EXAMPLE 121
4-acetyl-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 120, 4-acetyl-3-pyridinyl 5-thio-β-D-xylo-pyranoside is obtained in the form of a yellow powder (yield=23%).
M.p.=163° C. (crystallized from 2-propanol).
[α]D29=−83° (c=0.23; DMSO).
EXAMPLE 122
2-(4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
A mixture of 0.8 g (1.8 mM) of the 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 28, 0.325 g (2.14 mM) of 4-methoxyphenylboronic acid, 0.8 g (0.08 mM) of Suzuki's catalyst supported on resin (Argonaut, PSPPh3Pd resin), 1.16 g (3.56 mM) of cesium carbonate, 5 ml of DME and 4 ml of methanol is placed in a reactor adapted for microwaves. The mixture is heated at 120° C. for 30 minutes by microwaves. After filtration, rinsing with methanol and evaporation of the solvents, the residue obtained is chromatographed directly on silica gel using firstly pure dichloro-methane and then a dichloromethane/methanol mixture (9/1; v/v) as the eluent. The foam obtained is crystallized from ether to give the expected product in the form of a white powder (yield=65%).
M.p.=137° C.
[α]D33=−79° (c=0.17; DMSO).
EXAMPLE 123
5-(3-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 3-fluoro-phenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 5-(3-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=67%).
M.p.=182-184° C.
[α]D28=−55° (c=0.11; DMSO).
EXAMPLE 124
6-(3-acetylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 3-acetyl-phenylboronic acid and the 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 26, 6-(3-acetylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=44%).
M.p.=159-163° C. (crystallized from water).
[α]D31=−38° (c=0.10; DMSO).
EXAMPLE 125
6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 4-(trifluoromethoxy)phenylboronic acid and the 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 26, 6-[4-(trifluoromethoxy)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=31%).
M.p.=184-186° C. (crystallized from water).
[α]31=−34° (c=0.10; DMSO).
EXAMPLE 126
5-(2-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 2-fluoro-phenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 5-(2-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=51%).
M.p.=206-208° C.
[α]D32=−63° (c=0.17; DMSO).
EXAMPLE 127
2-[4-(trifluoromethoxy)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 4-(trifluoromethoxy)phenylboronic acid and the 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 28, 2-[4-(trifluoromethoxy)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=33%).
M.p.=114-119° C. (crystallized from water).
[α]D30=−38° (c=0.15; DMSO).
EXAMPLE 128
2-(3-acetylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 3-acetyl-phenylboronic acid and the 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 28, 2-(3-acetylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=44%).
M.p. 128-133° C. (crystallized from water).
[α]D30117° (c=0.10; DMSO).
EXAMPLE 129
6-(4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 4-fluoro-phenylboronic acid and the 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 26, 6-(4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=46%).
M.p.=180-183° C.
[α]D28=−50° (c=0.10; DMSO).
EXAMPLE 130
5-(2-cyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 2-cyano-phenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 5-(2-cyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=67%).
M.p.=177-179° C.
[α]D28=−74° (c=0.15; DMSO).
EXAMPLE 131
5-(3-chloro-4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 3-chloro-4-fluorophenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(3-chloro-4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=59%).
M.p.=200-201° C.
[α]D28=74° (c=0.18; DMSO).
EXAMPLE 132
5-(3,4-difluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 3,4-difluorophenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(3,4-difluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a beige powder (yield=44%).
M.p.=198-203° C.
[α]D30=0° (c=0.18; DMSO).
EXAMPLE 133
5-(2-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 2-methoxyphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(2-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a beige powder (yield=69%).
M.p.=209-211° C.
[α]D29=−94° (c=0.14; DMSO).
EXAMPLE 134
2-(4-methoxyphenyl)-6-methyl-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 4-methoxyphenylboronic acid and the 2-iodo-6-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 29, 2-(4-methoxy-phenyl)-6-methyl-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of an ecru powder (yield=70%).
M.p.=86-90° C.
[α]D28=−25° (c=0.12; DMSO).
EXAMPLE 135
5-(4-chlorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 4-chlorophenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(4-chlorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of off-white crystals (yield=74%).
M.p.=202-203° C.
[α]D29=−47° (c=0.48; DMSO).
EXAMPLE 136
5-(4-methoxy-3-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 4-methoxy-3-methylphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(4-methoxy-3-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=21%).
M.p.=181° C.
[α]D23=+55° (c=0.13; DMSO).
EXAMPLE 137
5-(2,4-dimethoxyphenyl)-3-pyridinyl 5-thio-α-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 2,4-dimethoxyphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(2,4-dimethoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=71%).
M.p.=184° C.
[α]D29=66° (c=0.1×DMSO).
EXAMPLE 138
5-(2-fluoro-5-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 122 starting from 2-fluoro-5-methylphenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(2-fluoro-5-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=48%).
M.p.=198° C. (crystallized from an ethanol/water mixture).
[α]D30=−58° (c=0.18; DMSO).
EXAMPLE 139
5-(phenylsulfonyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
0.495 g (1 mM) of 5-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 4 ml of DMSO, 0.025 g (0.05 mM) of benzene/copper trifluoro-methanesulfonate complex, 0.196 g (1.2 mM) of phenyl sulfinate and 0.0088 g (0.1 mM) of N,N′-dimethylethylenediamine are mixed under an argon atmosphere in a reactor adapted for microwaves. The mixture is heated at 130° C. for 3 hours by microwaves. Water is added to the cooled reaction mixture and extraction is carried out with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a toluene/acetone mixture (9/1; v/v) as the eluent to give the expected product in the form of a white solid with a yield of 43%.
M.p.=97-99° C.
[α]D30=−48° (c=0.17; DMSO).
EXAMPLE 140
5-(phenylsulfonyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 139, 5-(phenylsulfonyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a cottony white solid (yield=76%).
M.p.=86° C.
[α]D29=−75° (c=0.20; DMSO).
EXAMPLE 141
5-[(4-fluorophenyl)sulfonyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 139 starting from 5-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluorophenyl sulfinate, 5-[(4-fluorophenyl)sulfonyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=24%).
M.p.=128° C.
[α]D29=55° (c=0.26; DMSO).
EXAMPLE 142
5-[(4-fluorophenyl)sulfonyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 141, 5-[(4-fluorophenyl)sulfonyl]-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a cottony white solid (yield=90%).
M.p.=93-96° C.
[α]d29=−95° (c=0.20; DMSO).
EXAMPLE 143
5-(2,4,6-trifluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
0.5 g (1.11 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 10 ml of DME, 0.027 g (0.033 mM) of [1,1-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane, 0.564 g (2.23 mM) of bispinacolborane and 0.379 g (3.86 mM) of potassium acetate are mixed under an argon atmosphere in a reactor adapted for microwaves. The mixture is heated for 30 minutes at 110° C. by microwaves, cooled and filtered. 0.47 g (2.23 mM) of 2,4,6-trifluoro-1-bromobenzene, 0.091 g (0.11 mM) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane and a solution of 0.177 g (1.67 mM) of sodium carbonate in 1 ml of water are added to the filtrate. The reaction mixture is heated for 30 minutes at 130° C. in a microwave oven. Water is added to the cooled medium and extraction is carried out with ethyl acetate. The organic phase is washed with aqueous sodium bicarbonate solution and then with water, dried over sodium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (8/2; v/v) as the eluent to give the desired product in the form of a white solid with a yield of 39%.
M.p.=143° C.
[α]d27=−21° (c=0.20; DMSO).
EXAMPLE 144
5-(2,4,6-trifluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 143, 5-(2,4,6-trifluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=56%).
M.p. 228° C.
[α]d28=−63° (c=0.22; DMSO).
EXAMPLE 145
5-(3,5-difluoro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
0.334 g (1.5 mM) of 4-bromo-2,6-difluoroanisole, 12 ml of DME, 0.569 g (2.25 mM) of bispinacolborane, 0.036 g (0.045 mM) of [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) dichloromethane and 0.441 g (4.5 mM) of potassium acetate are mixed in a reactor adapted for microwaves. The reactor is heated at 110° C. for 30 minutes by microwaves. After cooling, the reaction mixture is filtered and 0.672 g (1.8 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 1.122 g (0.12 mM) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane and a solution of 0.196 g (1.8 mM) of sodium carbonate in 1.5 ml of water are then added to the filtrate. The mixture is heated at 130° C. for 30 minutes by microwaves. Water is added to the cooled reaction mixture and extraction is carried out with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a dichloromethane/methanol mixture (99/1; v/v) as the eluent. The product obtained is recrystallized from ether and filtered off to give the desired product in the form of a white powder with a yield of 64%.
M.p.=203° C.
[α]d29=−18° (c=0.30; DMSO).
EXAMPLE 146
5-(3,5-difluoro-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 145, 5-(3,5-difluoro-4-methoxyphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=74%).
M.p.=203° C.
[α]D29=64° (c=0.35; DMSO).
EXAMPLE 147
5-(2-cyano-4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 145 starting from 2-bromo-5-fluorobenzonitrile, 5-(2-cyano-4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a cream-colored solid (yield=29%).
M.p.=170-172° C.
[α]D23=−23° (c=0.14; DMSO).
EXAMPLE 148
5-(2-cyano-4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 147, 5-(2-cyano-4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a beige solid (yield=70%).
M.p.=198-200° C. (crystallized from diethyl ether).
[α]D23=−70° (c=0.20; DMSO).
EXAMPLE 149
5-(4-cyano-3-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 145 starting from 4-bromo-2-methylbenzonitrile, 5-(4-cyano-3-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of an off-white solid (yield=61%).
M.p.=74-80° C.
[α]D23=−15° (c=0.16; DMSO).
EXAMPLE 150
5-(4-cyano-3-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 149, 5-(4-cyano-3-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=79%).
M.p.=198-200° C.
[α]D23=−72° (c=0.25; DMSO).
EXAMPLE 151
5-(3-chloro-4-cyanophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 145 starting from 4-bromo-2-chlorobenzonitrile, 5-(3-chloro-4-cyanophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=39%).
M.p.=148-150° C. (crystallized from ethyl acetate).
[α]D24=6° (c=0.16; DMSO).
EXAMPLE 152
5-(3-chloro-4-cyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 151, 5-(3-chloro-4-cyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=35%).
M.p.=202-204° C.
[α]D25=−73° (c=0.10; DMSO).
EXAMPLE 153
5-(4-cyano-2-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 145 starting from 4-bromo-3-methylbenzonitrile, 5-(4-cyano-2-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of off-white crystals (yield=54%).
M.p.=136-138° C. (crystallized from diethyl ether).
[α]D25=−7° (c=0.18; DMSO).
EXAMPLE 154
5-(4-cyano-2-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 2 starting from the compound obtained in Example 153, 5-(4-cyano-2-methylphenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=73%).
M.p.=202-206° C.
[α]D25=−62° (c=0.17; DMSO).
EXAMPLE 155
5-(3,4-dicyanophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 145 starting from 4-iodo-1,2-benzenedicarbonitrile, 5-(3,4-dicyanophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=45%).
M.p.=114° C.
[α]D28=−11° (c=0.39; DMSO).
EXAMPLE 156
5-(3,4-dicyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the compound obtained in Example 155, 5-(3,4-dicyanophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of white crystals (yield=19%).
M.p.=192° C. (crystallized from methanol).
[α]D28=−43° (c=0.20; DMSO).
EXAMPLE 157
6-[4-(1-piperidinyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 43 starting from [4-(1-piperidinyl)phenyl]boronic acid and 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, the expected compound is obtained in the form of a gray powder (yield=14%).
M.p.=212° C.
[α]D28=+14° (c=0.12; DMSO).
EXAMPLE 158
6-[4-(1-piperidinyl)phenyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the product obtained in Example 157, 6-[4-(1-piperidinyl)phenyl]-3-pyridinyl 5-thio-β-D-xylo-pyranoside is obtained in the form of a white solid with a yield of 72%.
M.p.=221° C.
[α]D26=−15° (c=0.13; DMSO).
EXAMPLE 159
5-[(N,N-diethylamino)carbonyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside
A procedure analogous to the first part of Example 143 is followed starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and bis-pinacolborane. After filtration and evaporation of the reaction mixture, the residue is extracted with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure to give a brown oil which, when triturated in an ethyl ether/diisopropyl ether mixture, gives 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside. The product obtained is used directly in the next step.
1 g (2.02 mM) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 0.5 ml (3.95 mM) of diethylcarbamoyl chloride, 50 mg (0.06 mM) of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane and 15 ml of THF are placed under an argon atmosphere in a reactor adapted for microwaves. The mixture is heated at 110° C. for 30 minutes by microwaves. The cooled reaction mixture is filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using pure dichloromethane and then a dichloromethane/methanol mixture (9/1; v/v) as the eluent. After washing with an ether/isopropyl ether mixture, the brown solid obtained is used directly in the deacetylation reaction described in Example 160.
EXAMPLE 160
5-[(N,N-diethylamino)carbonyl]-3-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the product obtained in Example 159, 5-[(N,N-diethylamino)carbonyl]-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a beige solid with a yield of 59%.
M.p.=143° C. (crystallized from water).
[α]D25=−53° (c=0.11; DMSO).
EXAMPLE 161
2-(4-fluoro-2-methylphenyl)-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside
By following a procedure analogous to Example 76 starting from 4-fluoro-2-methylphenylboronic acid, 2-(4-fluoro-2-methylphenyl)-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid with a yield of 72%.
M.p.=137° C.
[α]D29=−14° (c=0.28; DMSO).
EXAMPLE 162
2-(4-fluoro-2-methylphenyl)-4-pyridinyl 5-thio-β-D-xylopyranoside
By following a procedure analogous to Example 6 starting from the product obtained in Example 161, 2-(4-fluoro-2-methylphenyl)-4-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white solid with a yield of 70%.
M.p.=147° C. (crystallized from a water/DMSO mixture).
[α]D32=−52° (c=0.20; DMSO).
The structures of the compounds of formula I described above are summarized in the Table below:
(I)
R1
Ex.
Position of N
X
R2
R
1
3
6-acetyl
H
Ac
2
3
6-acetyl
H
H
3
3
2-acetyl
H
Ac
4
3
2-acetyl
H
H
5
3
2-CO
4-cyanophenyl
H
Ac
6
3
2-CO
4-cyanophenyl
H
H
7
3
6-CO
4-(trifluoromethyl)phenyl
H
Ac
8
3
6-CO
4-(trifluoromethyl)phenyl
H
H
9
3
6-sb
4-cyanophenyl
H
Ac
10
3
6-sb
4-cyanophenyl
H
H
11
3
2-sb
4-cyanophenyl
H
Ac
12
3
2-sb
4-cyanophenyl
H
H
13
3
5-sb
phenyl
H
Ac
14
3
5-sb
phenyl
H
H
15
3
5-sb
4-cyanophenyl
H
Ac
16
3
5-sb
4-cyanophenyl
H
H
17
3
6-SO2
4-cyanophenyl
H
Ac
18
3
6-SO2
4-cyanophenyl
H
H
19
3
2-methylsulfonyl
H
Ac
20
3
2-methylsulfonyl
H
H
21
3
6-methylsulfonyl
H
Ac
22
3
6-methylsulfonyl
H
H
23
3
2-sb
phenyl
H
Ac
24
3
2-sb
phenyl
H
H
25
3
5-O
phenyl
H
Ac
26
3
5-O
phenyl
H
H
27
3
4-sb
4-cyanophenyl
H
Ac
28
3
4-sb
4-cyanophenyl
H
H
29
3
5-CO
benzylamino
H
H
30
3
6-sb
phenyl
5-F
Ac
31
3
6-sb
phenyl
5-F
H
32
3
5-sb
4-cyanophenyl
2-F
Ac
33
3
5-sb
4-cyanophenyl
2-F
H
34
3
4-sb
trifluoromethylphenyl
H
Ac
35
3
4-sb
trifluoromethylphenyl
H
H
36
3
5-sb
4-(trifluoromethoxy)phenyl
H
H
37
3
5-sb
3-acetylphenyl
H
H
38
3
5-sb
4-fluorophenyl
H
H
39
3
2-(1-piperidinyl)carbonyl
H
Ac
40
3
2-(1-piperidinyl)carbonyl
H
H
41
3
2-(dimethylaminocarbonyl)
H
Ac
42
3
2-(dimethylaminocarbonyl)
H
H
43
3
5-sb
4-methoxyphenyl
H
Ac
44
3
5-sb
4-methoxyphenyl
H
H
45
3
5-sb
4-(hydroxymethyl)phenyl
H
Ac
46
3
5-sb
4-(hydroxymethyl)phenyl
H
H
47
3
5-sb
4-(1-piperidinyl)phenyl
H
Ac
48
3
5-sb
4-(1-piperidinyl)phenyl
H
H
49
3
5-sb
4-(dimethylamino)phenyl
H
Ac
50
3
5-sb
4-(dimethylamino)phenyl
H
H
51
3
5-sb
4-methylphenyl
H
Ac
52
3
5-sb
4-methylphenyl
H
H
53
3
5-sb
4-(trifluoromethyl)phenyl
H
Ac
53′
3
5-sb
4-(trifluoromethyl)phenyl
H
H
54
3
5-sb
3-cyanophenyl
H
Ac
55
3
5-sb
3-cyanophenyl
H
H
56
3
4-sb
4-fluorophenyl
H
Ac
57
3
4-sb
4-fluorophenyl
H
H
58
3
5-sb
4-fluoro-3-methylphenyl
H
Ac
59
3
5-sb
4-fluoro-3-methylphenyl
H
H
60
3
5-sb
4-fluoro-2-methylphenyl
H
Ac
61
3
5-sb
4-fluoro-2-methylphenyl
H
H
62
3
5-sb
3-cyano-4-fluorophenyl
H
Ac
63
3
5-sb
3-cyano-4-fluorophenyl
H
H
64
3
5-sb
3-chloro-4-methoxyphenyl
H
Ac
65
3
5-sb
3-chloro-4-methoxyphenyl
H
H
66
3
5-sb
3-methoxyphenyl
H
Ac
67
3
5-sb
3-methoxyphenyl
H
H
68
3
5-sb
4-(1-methylethoxy)phenyl
H
Ac
69
3
5-sb
4-(1-methylethoxy)phenyl
H
H
70
3
5-sb
3,4-dimethoxyphenyl
H
Ac
71
3
5-sb
3,4-dimethoxyphenyl
H
H
72
3
2-sb
4-fluorophenyl
H
Ac
73
3
2-sb
4-fluorophenyl
H
H
74
3
2-sb
4-methoxyphenyl
4-methyl
Ac
75
3
2-sb
4-methoxyphenyl
4-methyl
H
76
4
2-sb
4-methoxyphenyl
H
Ac
77
4
2-sb
4-methoxyphenyl
H
H
78
3
5-sb
3-fluoro-4-(1-methylethoxy)phenyl
H
Ac
79
3
5-sb
3-fluoro-4-(1-methylethoxy)phenyl
H
H
80
3
5-sb
2,6-difluoro-4-methoxyphenyl
H
Ac
81
3
5-sb
2,6-difluoro-4-methoxyphenyl
H
H
82
3
5-sb
3,5-dimethyl-4-methoxyphenyl
H
Ac
83
3
5-sb
3,5-dimethyl-4-methoxyphenyl
H
H
84
3
5-sb
2,4-difluorophenyl
H
Ac
85
3
5-sb
2,4-difluorophenyl
H
H
86
3
5-sb
4-fluoro-2-methoxyphenyl
H
Ac
87
3
5-sb
4-fluoro-2-methoxyphenyl
H
H
88
3
5-sb
2-chloro-4-fluorophenyl
H
Ac
89
3
5-sb
2-chloro-4-fluorophenyl
H
H
90
3
5-sb
4-cyano-3-fluorophenyl
H
Ac
91
3
5-sb
4-cyano-3-fluorophenyl
H
H
92
3
6-sb
4-methoxyphenyl
H
Ac
93
3
6-sb
4-methoxyphenyl
H
H
94
3
6-sb
4-hydroxymethylphenyl
H
Ac
95
3
6-sb
4-hydroxymethylphenyl
H
H
96
3
6-sb
4-trifluoromethylphenyl
H
Ac
97
3
6-sb
4-trifluoromethylphenyl
H
H
98
3
6-sb
4-methylphenyl
H
Ac
99
3
6-sb
4-methylphenyl
H
H
100
3
4-sb
4-methoxyphenyl
H
Ac
101
3
4-sb
4-methoxyphenyl
H
H
102
3
5-sb
3-fluoro-4-methoxyphenyl
H
Ac
103
3
5-sb
3-fluoro-4-methoxyphenyl
H
H
104
3
5-sb
4-methoxy-2-methylphenyl
H
Ac
105
3
5-sb
4-methoxy-2-methylphenyl
H
H
106
3
5-sb
3-fluoro-4-methylphenyl
H
Ac
107
3
5-sb
3-fluoro-4-methylphenyl
H
H
108
3
5-sb
3,4-dimethylphenyl
H
Ac
109
3
5-sb
3,4-dimethylphenyl
H
H
110
3
5-sb
2-chloro-4-methylphenyl
H
Ac
111
3
5-sb
2-chloro-4-methylphenyl
H
H
112
3
5-sb
2-chloro-4-methoxyphenyl
H
Ac
113
3
5-sb
2-chloro-4-methoxyphenyl
H
H
114
3
5-methylsulfonyl
H
Ac
115
3
5-methylsulfonyl
H
H
116
3
6-[(phenylmethyl)amino]carbonyl
H
Ac
117
3
6-[(phenylmethyl)amino]carbonyl
H
H
118
3
5-acetyl
H
Ac
119
3
5-acetyl
H
H
120
3
4-acetyl
H
Ac
121
3
4-acetyl
H
H
122
3
2-sb
4-methoxyphenyl
H
H
123
3
5-sb
3-fluorophenyl
H
H
124
3
6-sb
3-acetylphenyl
H
H
125
3
6-sb
4-(trifluoromethoxy)phenyl
H
H
126
3
5-sb
2-fluorophenyl
H
H
127
3
2-sb
4-(trifluoromethoxy)phenyl
H
H
128
3
2-sb
3-acetylphenyl
H
H
129
3
6-sb
4-fluorophenyl
H
H
130
3
5-sb
2-cyanophenyl
H
H
131
3
5-sb
3-chloro-4-fluorophenyl
H
H
132
3
5-sb
3,4-difluorophenyl
H
H
133
3
5-sb
2-methoxyphenyl
H
H
134
3
2-sb
4-methoxyphenyl
6-methyl
H
135
3
5-sb
4-chlorophenyl
H
H
136
3
5-sb
4-methoxy-3-methylphenyl
H
H
137
3
5-sb
2,4-dimethoxyphenyl
H
H
138
3
5-sb
2-fluoro-5-methylphenyl
H
H
139
3
5-SO2
phenyl
H
Ac
140
3
5-SO2
phenyl
H
H
141
3
5-SO2
4-fluorophenyl
H
Ac
142
3
5-SO2
4-fluorophenyl
H
H
143
3
5-sb
2,4,6-trifluorophenyl
H
Ac
144
3
5-sb
2,4,6-trifluorophenyl
H
H
145
3
5-sb
3,5-difluoro-4-methoxyphenyl
H
Ac
146
3
5-sb
3,5-difluoro-4-methoxyphenyl
H
H
147
3
5-sb
2-cyano-4-fluorophenyl
H
Ac
148
3
5-sb
2-cyano-4-fluorophenyl
H
H
149
3
5-sb
4-cyano-3-methylphenyl
H
Ac
150
3
5-sb
4-cyano-3-methylphenyl
H
H
151
3
5-sb
3-chloro-4-cyanophenyl
H
Ac
152
3
5-sb
3-chloro-4-cyanophenyl
H
H
153
3
5-sb
4-cyano-2-methylphenyl
H
Ac
154
3
5-sb
4-cyano-2-methylphenyl
H
H
155
3
5-sb
3,4-dicyanophenyl
H
Ac
156
3
5-sb
3,4-dicyanophenyl
H
H
157
3
6-sb
4-(1-piperidinyl)phenyl
H
Ac
158
3
6-sb
4-(1-piperidinyl)phenyl
H
H
159
3
5-[(N,N-diethylamino)carbonyl]
H
Ac
160
3
5-[(N,N-diethylamino)carbonyl]
H
H
161
4
2-sb
4-fluoro-2-methylphenyl
H
Ac
162
4
2-sb
4-fluoro-2-methylphenyl
H
H
Ac = COCH3
sb = carbon-carbon single bond
The antithrombotic activity of the compounds according to the invention was studied in vivo in the rat by means of a test that reproduces a venous thrombosis.
The venous thrombosis was induced according to the protocol described in Thromb. Haemost., 1992, 67(1), 176-179. The oral activity was studied according to the following operating protocol:
The experiments are performed on non-fasted Wistar male rats weighing 250 to 280 g, divided into groups of 10 animals each. The test products are administered orally (tubage) dissolved or suspended in a solution of methyl cellulose (0.5% in water). The concentration of the compounds is calculated so that the amount of solution absorbed is 10 ml/kg by oral administration. A thrombosis is induced at a time T (2 or 8 hours) after administration of the product, and the thrombus formed is removed and weighed. To induce this thrombosis, a venous stasis is created under hypercoagulation according to the technique described by WESSLER (J. Applied Physiol., 1959, 943-946), the hypercoagulating agent used being a solution of activated factor X (Xa) having a concentration of 7.5 nKat/kg, supplied by Biogenic (Montpellier). The venous stasis is effected exactly 10 seconds after injection of the hypercoagulating agent. The activity of the test compounds was checked at different doses after they had been administered. The thrombosis was induced 2 hours or 8 hours after administration of the compound. By way of example, the results of the above tests are shown in the Table below for a few compounds according to the invention (the activity is expressed as the percentage inhibition of thrombus formation observed in the presence of the compound according to the invention, relative to the weight of the thrombus formed in the absence of the compound).
TABLE I
Oral activity
Dose
Time
Activity
Example
(mg/kg)
(h)
(%)
2
6
2
63
3
8.6
2
92
4
6
2
96
6
6
2
61
6
6
8
26
8
6
2
46
12
6
2
14
14
6
2
50
15
8.2
2
84
59
6
2
82
61
6
2
98
89
6
2
100
99
6
2
72
101
6
2
97
103
6
2
100
123
6
2
97
126
6
2
91
131
6
2
80
These results show that the compounds according to the invention exhibit a venous antithrombotic activity.
The present invention therefore relates to a compound of formula (I) according to the invention, and its pharmaceutically acceptable salts with an acid, solvates and hydrates, for use as drugs. The compound of formula (I), or one of its pharmaceutically acceptable salts, solvates or hydrates, may be used for the preparation of an antithrombotic drug intended in particular for the treatment or prevention of disorders of the venous circulation and especially for correcting certain hematological parameters perceptible in the venous system or for compensating a cardiac insufficiency.
The present invention therefore further relates to pharmaceutical compositions containing a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates or hydrates. These pharmaceutical compositions generally contain suitable excipients. Said excipients are chosen according to the desired pharmaceutical form and the desired mode of administration, particularly oral administration or administration by injection.
These pharmaceutical compositions are prepared by the conventional methods well known to those skilled in the art. For example, the compounds according to the invention can be formulated with physiologically acceptable excipients to give an injectable form for direct use, an injectable form to be prepared immediately before use, or a solid form for oral administration, e.g. a capsule or a tablet.
By way of example, an injectable form can preferably be prepared by the lyophilization of a sterilized filtered solution containing the compound according to the invention and a soluble excipient in a necessary and sufficient amount to give an isotonic solution after the addition of injectable water immediately before use. The resulting solution may be administered either in a single subcutaneous or intramuscular injection or in the form of a slow perfusion. A form for oral administration will preferably be presented in the form of a capsule containing the finely ground or, preferably, micronized compound of the invention mixed with excipients known to those skilled in the art, e.g. lactose, pregelatinized starch and magnesium stearate.
To obtain the desired therapeutic or prophylactic effect, each unit dose can contain 10 to 500 mg of at least one compound according to the invention.
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11909489
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laboratories fournier s.a.
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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514/336
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Mar 31st, 2022 02:21PM
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Mar 31st, 2022 02:21PM
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AbbVie
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Health Care
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Pharmaceuticals & Biotechnology
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|
nyse:abbv
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AbbVie
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Jan 18th, 2011 12:00AM
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Nov 7th, 2006 12:00AM
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https://www.uspto.gov?id=US07872021-20110118
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LXR receptor modulators
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Benzenesulfonamide derivative compounds corresponding to the general formula (I):
and their pharmaceutically acceptable addition salts; a process for preparation of such compounds; pharmaceutical compositions containing such compounds, and the use of such compounds as a pharmacologically active substance, in particular in the treatment of neurodegenerative diseases, cardiovascular diseases, inflammatory diseases; hypercholesterolemia, and diabetes.
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7872021
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1. A benzenesulfonamide compound corresponding to formula I:
wherein
(H) represents a nitrogen-containing 5-membered saturated heterocyclic ring condensed with a phenyl or cyclohexyl ring, optionally substituted by a halogen, a C1-C4 alcoxy group or an N(R)2 group in which R represents the hydrogen atom or a C1-C4 alkyl group,
R1 represents:
a chlorine atom,
a C3-C6 alkyl group, branched or cyclized,
a C2-C6 linear or branched alkoxy group,
a phenoxy group, optionally substituted by a halogen,
a phenyl group, or
an aminomethyl group, optionally substituted by an acetyl or trifluoroacetyl group,
R2 represents a hydrogen atom, or,
R1 and R2 together form an oxygen-containing or nitrogen-containing heterocycle, optionally substituted by one or more C1-C3 alkyl groups, an acyl group or a C2-C3 perfluoroacyl group,
Y represents:
a single bond,
a C1-C4, linear or branched or C3-C4 cyclized alkylene group, optionally substituted by a C1-C3 alkoxy group, a phenyl group, an N(R)2 group, or a COOH group,
a —(CH2)n—O— group,
a —(CH2)n—S— group, or
a —(CH2)m—CO— group,
n is equal to 2 or 3,
m is equal to 1, 2 or 3,
R represents the hydrogen atom or a C1-C4 alkyl group
Ar represents an aromatic or heteroaromatic ring selected from the group consisting of phenyl, naphthalenyl, tetrahydronaphthalenyl, pyridinyl and indolyl groups, optionally substituted by one or two identical or different R3, R4 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, phenyl, phenoxy, trifluoromethyl, amino, hydroxy, and groups of formula —X—[C(R)2]p—COR5 in which:
X represents a single bond, an oxygen atom, a sulfur atom or an NH group,
R5 represents OR or N(R)2,
R represents the hydrogen atom or a C1-C4 alkyl group, and
p is equal to 0, 1 or 2;
or R3 and R4 together forming a methylenedioxy group;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein the asymmetric carbon which carries the carboxamide functional group has an S— configuration corresponding to Formula (Ia):
3. A pharmaceutical composition comprising an active compound according to claim 1 and at least one pharmaceutical carrier or adjuvant.
4. A method of treating or inhibiting a disease state selected from the group consisting of atherosclerosis, dyslipidemia, obesity, diabetes, and hypercholesterolemia in a patient in need thereof, said method comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1.
5. A method according to claim 4, wherein said disease state is hypercholesterolemia.
6. A method according to claim 4, wherein said disease state is diabetes.
7. A process for preparing a compound according to claim 1, said process comprising:
a) reacting an acid of formula:
in which
(H) represents a nitrogen-containing 5-membered saturated heterocyclic ring condensed with a phenyl or cyclohexyl ring, optionally substituted by a halogen, a C1-C4 alcoxy group or an N(R)2 group in which R represents the hydrogen atom or a C1-C4 alkyl group,
with an amine of formula
NH2—Y—Ar III
in which:
Y represents:
a single bond,
a linear, branched or cyclized C1-C4 alkylene group, optionally substituted by a C1-C3 alkoxy group, a phenyl group, an amino group protected by an amino-protecting group other than Boc, or an N(R)2 group in which R represents the hydrogen atom or a C1-C4 alkyl group,
a —(CH2)n—O— group,
a —(CH2)n—S— group, or
a —(CH2)m—CO— group,
n is equal to 2 or 3,
m is equal to 1, 2 or 3,
Ar represents an aromatic or heteroaromatic ring selected from the group consisting of phenyl, naphthalenyl, tetrahydronaphthalenyl, pyridinyl and indolyl groups, optionally substituted by one or two substituents R3, R4 that are identical or different and are selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, phenyl, phenoxy, trifluoromethyl, hydroxy, amino protected by an amino-protecting group other than Boc, and groups of formula —X—[C(R)2]p—COR5 in which:
X represents a single bond, an oxygen atom or a sulfur atom,
R5 represents OH, OR or N(R)2,
R represents a C1-C4 alkyl group, and
p is equal to 0, 1 or 2;
or R3 and R4 together form a methylenedioxy group,
in an anhydrous solvent and in the presence of a catalyst at a temperature of about ambient temperature and for between 2 and 20 hours in order to obtain an amide of formula IV
in which (H), Y and Ar retain the meanings given above;
b) reacting the amide of formula IV obtained in step a) with trifluoroacetic acid in a solvent at ambient temperature for between 2 and 20 hours in order to obtain a compound of formula V:
in which (H), Y and Ar retain the meanings given above;
c) reacting the compound of formula V with a benzenesulfonyl chloride of formula VI:
in which
R1 represents a chlorine atom, a C3-C6 alkyl group branched or cyclized, a C2-C6 linear or branched alkoxy group, a phenoxy group optionally substituted by a halogen, a phenyl group, or an aminomethyl group optionally substituted by an acetyl or trifluoroacetyl group, and
R2 represents a hydrogen atom, or,
R1 and R2 together form an oxygenated or nitrogenous heterocycle, optionally substituted by one or more C1-C3 alkyl groups, by an acyl group or by a C2-C3 perfluoroacyl group,
in a solvent at ambient temperature for between 2 and 20 hours in order to obtain a compound of formula I
in which R1, R2, (H), Y and Ar retain the meanings given above; and
d) if R3 or R4 represents an amino group protected by an amino-protecting group, eliminating the amino-protecting group to obtain a corresponding free amine.
8. A process according to claim 7, wherein said catalyst comprises dicyclohexylcarbodiimide (DCC) or 1-hydroxy-7-azabenzotriazole (HOAT).
9. A process for preparing a compound according to claim 1, said process comprising:
a) reacting a benzenesulfonyl chloride of formula VI
in which
R1 represents a chlorine atom, a C3-C6 alkyl group branched or cyclized, a C2-C6 linear or branched alkoxy group, a phenoxy group optionally substituted by a halogen, a phenyl group, or an aminomethyl group substituted by an acetyl or trifluoroacetyl group, and
R2 represents a hydrogen atom, or
R1 and R2 together form an oxygen-containing or nitrogen-containing heterocycle, optionally substituted by one or more C1-C3 alkyl groups, by an acyl group or by a C2-C3 perfluoroacyl group,
with an ester of formula VII:
in which (H) represents a nitrogen-containing 5- or 6-membered saturated heterocyclic ring condensed with a phenyl or cyclohexyl ring, optionally substituted by a halogen or a C1-C4 alcoxy group,
in an anhydrous solvent, at ambient temperature and for between 2 and 10 hours in order to obtain an ester of formula VIII:
in which (H), R1 and R2 retain the meanings given above,
b) converting the ester of formula VIII into acid by treatment with a base in hydroalcoholic medium to obtain an acid of formula IX:
in which (H), R1 and R2 remain unchanged,
c) reacting the acid of formula IX with a primary amine of formula III
NH2—Y—Ar III
in which
Y represents:
a single bond,
a C1-C4 alkylene, linear or branched or C3-C4 cyclized group, optionally substituted by a C1-C3 alkoxy group, a phenyl group, an N(R)2 group or a COOH group,
a —(CH2)n—O— group,
a —(CH2)n—S— group, or
a —(CH2)m—CO— group,
n is equal to 2 or 3,
m is equal to 1, 2 or 3,
R represents the hydrogen atom or a C1-C4 alkyl group,
Ar represents an aromatic or heteroaromatic ring selected from the group consisting of phenyl, naphthalenyl, tetrahydronaphthalenyl, pyridinyl and indolyl groups, optionally substituted by one or two identical or different R3, R4 substituents selected from the group consisting of halogen, a C1-C4 alkyl, C1-C4 alkoxy, nitro, phenyl, phenoxy, trifluoromethyl, hydroxy, amino protected by an amino-protecting group, and groups of formula —X—[C(R)2]p—COR5 in which:
X represents a single bond, am oxygen atom or a sulfur atom,
R5 represents OH, OR or N(R)2,
R represents a C1-C3 alkyl group, and
p is equal to 0, 1 or 2;
or R3 and R4 together form a methylenedioxy group,
in an anhydrous solvent and in the presence of a catalyst at a temperature of about ambient temperature and for between 2 and 20 hours in order to obtain a compound of formula (I)
in which (H), R1, R2, Y and Ar retain the meanings given above.
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9
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of international patent application no. PCT/FR2005/001139, filed May 9, 2005, designating the United States of America and published in French on Dec. 22, 2005 as WO 2005/121093, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on French patent application no. FR 04 04958, filed May 7, 2004.
BACKGROUND OF THE INVENTION
The object of this invention is new compounds capable of modulating the activity of nuclear LXR receptors, a method of producing these and pharmaceutical compounds containing them.
Liver X receptors (LXR) are transcription factors belonging to the super family of nuclear receptors to which retinoic acid receptors (RXR), farnesoid X receptors (FXR) and peroxisome proliferator-activated receptors (PPARs) also belong. LXR receptors form, by linking to the RXR receptor, a heterodimer which bonds in a specific manner to the ADN response elements (LXRE) leading to the transactivation of target genes (Genes dev. 1995; 9: 1033-45).
These receptors are involved in a number of metabolic routes and are in particular involved in the homeostasis of cholesterol, bile acids, triglycerides and glucose.
Modulation of the activity of these nuclear receptors affects the progression of metabolic disorders such as Type II diabetes, dyslipidemias and the development of atherosclerosis.
The LXR/RXR heterodimer can be activated by LXR and/or RXR ligands. The transactivation of the target genes calls for the recruitment of co-activators such as Grip-1. (Nature 1996; 383: 728-31).
The two types of LXR receptors identified today, namely LXRα and LXRβ, have a high degree of similarity in terms of their amino acid sequence but differ in terms of their tissular distribution. LXRα is strongly expressed in the liver and to a lesser extent in the kidneys, the intestine, the adipose tissue and the spleen. LXRβ is distributed in a ubiquitous manner (Gene 2000; 243: 93-103, N.Y. Acad. Sci. 1995; 761: 38-49).
Although cholesterol does not directly activate the LXR receptors, mono-oxygenated derivatives of cholesterol (oxysterols) do, and more specifically 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol and 24(S),25-epoxycholesterol. These oxysterols are considered to be the physiological ligands of the LXR receptors (Nature 1996; 383: 728-31, J. Biol. chem 1997; 272: 3137-40). Furthermore, it has been shown that oxysterol 5,6,24(S),25-diepoxycholesterol is a specific ligand of LXRα, suggesting that it is possible to develop specific ligands of LXRα and/or LXRβ (Proc. Natl. Acad. Sci USA 1999; 96: 26-71, Endocrinology 2000; 141: 4180-4).
Furthermore, it has been possible to show that human plasma contains natural LXRα and β antagonists (Steroïds 2001; 66: 473-479).
Using the hepatocytes of rats, it has been possible to show that unsaturated fatty acids significantly increase the expression of LXRα without affecting LXRβ (Mol Endocrinol 2000; 14:161-171). Moreover, the α and γ PPARs activators also induce the expression of LXRα in the human primary macrophages.
The strong concentrations of LXRα in the liver and the identification of the endogenous ligands of LXR have suggested that these receptors play an essential role in cholesterol metabolism. Under physiological conditions, the homeostasis of cholesterol is maintained through regulation of the novo synthesis and catabolism channels. The accumulation of sterols in the liver leads via a feedback mechanism involving transcription factors such as SREBP-1 and SREBP-2 to the inhibition of cholesterol biosynthesis. (Cell 1997; 89: 331-40). The excess cholesterol also activates another metabolic route which leads to the conversion of cholesterol into bile acids. The conversion of cholesterol into 7α-hydroxy-cholesterol is performed by a localised enzyme in the liver (CYP7A: 7α-hydroxylase) (J. Biol. Chem. 1997; 272: 3137-40).
The involvement of LXR in the synthesis of bile acids and therefore in the regulation of cholesterol homeostasis has been demonstrated using LXRα deficient mice which, when subjected to a fat-rich diet, accumulate large quantities of cholesterol esters at the hepatic level (Cell 1998; 93 693-704). The LXRβ deficient mice have the same physiological resistance as the normal mice to a fat-enriched diet. The unchanged expression of the LXRβ in the LXR deficient mice tends to demonstrate that LXRβ is incapable on its own of significantly increasing cholesterol metabolism (J. Clin. Invest. 2001; 107: 565-573).
The LXR receptors expressed at the macrophage level play an important role in the regulation of certain functions of this. More specifically, they are involved in control of the inverse transport of cholesterol which allows export of excess cholesterol from the peripheral tissues towards the liver. The cholesterol is taken up by the pre-bHDL via the apoA1 and ABCA1 in order to be transported to the liver where it is catabolised into bile acids and then eliminated.
ABCA1 is a member of the super family of transport proteins (ATP-binding cassette) the importance of which is illustrated by the fact that a mutation at gene level of the ABCA1 is responsible for Tangier disease (Nat. Genet. 1999; 22: 336-45).
The expression of ABCA1 and the efflux of cholesterol are induced by the loading of the human macrophages with cholesterol and the activation of the LXR receptors (Biochem. Biophys. Res. Comm. 1999; 257: 29-33). It was also subsequently shown that the expression at the intestinal level of ABCG1, ABCG5 and ABCG8, other members of the ABC type transporters family, is also regulated by the RXR/LXR heterodimer (J. Biol. Chem. 2000; 275: 14700-14707, Proc. Natl. Acad. Sci. USA 2000; 97: 817-22, J. Biol. Chem. 2002; 277: 18793-18800, Proc. Natl. Acad. Sci. USA 2002; 99: 16237-16242).
It was also shown that LXR agonist ligands reduced atheromatous lesions in two different murine models (ApoE−/− mouse and LDLR−/− mouse) (Proc. Natl. Acad. Sci. USA 2002; 99:7604-7609, FEBS Letters 2003; 536: 6-11). These results suggest that the LXR ligands can constitute therapeutic agents for treating atherosclerosis.
Finally, it is known that the macrophages play an important role in inflammation in particular in the pathogenesis of atherosclerosis. It has been shown that the activation of the LXRs inhibits the expression of the genes involved in inflammation at the macrophage level. (Nature Medecine, 2003; 9: 213-219). In vitro, the expression of mediators, such as nitric oxide synthase, cyclo oxygenase-2(COX-2) and interleukine-6 (IL-6) is inhibited. In vivo, the LXR agonists reduce the inflammation in a dermatite model and inhibit the expression of the genes involved in the inflammation of the aortas of atheromatous mice.
Because cholesterol homeostasis seems also to play an essential role in the operation of the central nervous system and neurodegenerative mechanisms, the ABCA1 expression has also been studied in primary neurone, astrocyte and microglia cultures isolated from the brains of rat embryos. The results of these studies show that LXR activation leads to a reduction in β amyloid secretion and as a consequence to a reduction in amyloid deposits in the brain. This work suggests that LXR activation could represent a new approach to the treatment of Alzheimer's disease (J. Biol. Chem. 2003, 275 (15): 13244-13256, J. Biol. Chem. 2003, 278 (30): 27688-27694).
LXR receptors are also involved in regulating the expression of apolipoprotein E (ApoE). This protein is heavily involved in the hepatic clearance of lipoproteins and favors the efflux of cholesterol from lipid-rich macrophages. It has been shown that the activation of LXR receptors leads to an increased expression of ApoE via an LXR response element (LXRE) located in the ApoE promoter sequence (Proc. Natl. Acad. Sci. USA 2001; 98: 507-512).
Activation of LXR receptors also favored the inverse transport of cholesterol through modulation of the expression of CETP (cholesterol ester transfer protein) which is involved in the transfer of esterified cholesterol from the HDL lipoproteins to the triglyceride-rich lipoproteins eliminated by the liver (J. Clin. Invest. 2000; 105: 513-520).
In summary, activation of LXR receptors leads to an increase in the expression of a number of genes favoring the elimination of excess cholesterol from the peripheral tissues. In the cholesterol-loaded macrophage, activation of LXR receptors increases the expression of ABCA1, ABCG1, ABCG5, ABCG8 and ApoE bringing about an increase in the efflux of cholesterol from the macrophages to the liver where it is excreted in the form of bile acids. Induction of CETP and CYP7A expression in the liver leads to an increase in hepatic clearance of cholesterol esters from the HDL lipoproteins and to catabolism of the cholesterol, respectively.
Furthermore, it has also been shown that LXR receptors play an important role in the metabolism of glucose. Treatment of diabetic rodents with an LXR agonist leads to a drastic reduction in plasma glucose levels. In particular, in the insulin resistant Zucker rat (fa/fa), LXR activation inhibits the expression of the genes involved in gluconeogenesis and most particularly of phosphoenolpyruvate carboxykinase (PEPCK) (J. Biol. Chem. 2003, 278 (2): 1131-1136). It has also been described how the treatment of mice with an LXR agonist leads to a reduction in plasma glucose levels and in production of hepatic glucose by inhibiting the enzymes that play a key role in gluconeogenesis (Diabetes, 53, suppl 1, S36-S42 February 2004)
Moreover, it has been shown that an LXR agonist increases glucose tolerance in a murine insulin resistance and obesity model (Proc. Natl. Acad. Sci. USA 2003; 100: 5419-5424). The gene expression analysis also highlights regulation of the genes involved in the metabolism of glucose in the liver:
reduction in peroxisome proliferator-activated receptor coactivator-1α (PGC-1), phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase expression;
induction of glucokinase expression which favors the use of hepatic glucose.
A transcriptional induction of the insulin-responsive glucose transporter (GLUT4) in the adipose tissue has also been demonstrated. These results underline the importance of LXRs in the coordination of glucose metabolism. It is also known that LXR receptors are involved in the inflammation regulation process (Nature Medecine 2003 9, 213-219).
LXR receptor activity modulator compounds are known in the prior art in particular from documents WO 03/090869, WO 03/90746, WO 03/082192 or WO 03/082802; or also from documents WO 03/043985 and WO 04/005253 which describe compounds which are PPAR receptor agonists of the benzenesulfonamide type.
In this context, there is significant interest in finding LXR receptor activity modulator compounds that could be useful in the treatment of certain pathologies such as cardiovascular disease, hypercholesterolemia, dyslipidemia, myocardial infarction, atherosclerosis, diabetes, obesity, inflammation and neurodegenerative diseases.
The present invention is specifically based on the discovery of new LXR receptor activity modulator compounds.
Thus, according to a first aspect, the present invention aims to protect, as a new industrial product, a benzenesulfonamide compound, characterized in that it is chosen from among:
i) the compounds having the formula:
in which
(H) represents a nitrogen-containing 5- or 6-membered saturated heterocyclic ring condensed with a phenyl or cyclohexyl ring, optionally substituted by a halogen, a C1-C4 alcoxy group or an N(R)2 group in which R represents the hydrogen atom or a C1-C4 alkyl group,
R1 represents:
a chlorine atom,
a C3-C6 alkyl group, branched or cyclized,
a C2-C6 linear, branched or C3-C6 cyclized alkoxy group,
a phenoxy group, optionally substituted by a halogen,
a phenyl group, or
an aminomethyl group, optionally substituted by an acetyl or trifluoroacetyl group,
R2 represents a hydrogen atom or a halogen, or,
R1 and R2 together form an oxygen-containing or nitrogen-containing heterocycle, optionally substituted by one or more C1-C3 alkyl groups, an acyl group or a C2-C3 perfluoroacyl group,
Y represents:
a single bond,
a C1-C4, linear or branched or C3-C4 cyclized alkylene group, optionally substituted by a C1-C3 alkoxy group, a phenyl group, an N(R)2 group or a COOH group,
a —(CH2)n—O— group,
a —(CH2)n—S— group, or
a —(CH2)m—CO— group,
n is equal to 2 or 3,
m is equal to 1, 2 or 3,
R represents the hydrogen atom or a C1-C4 alkyl group
Ar represents an aromatic or heteroaromatic ring chosen from among the phenyl, naphthalenyl, tetrahydronaphthalenyl, pyridinyl or indolyl groups, optionally substituted by one or two identical or different R3, R4 substituents chosen from among a halogen, a C1-C4 alkyl, C1-C4 alkoxy, nitro, phenyl, phenoxy, trifluoromethyl, amino, hydroxy group, or a group with the formula —X—[C(R)2]p—COR5 in which:
X represents a single bond, an oxygen atom, a sulfur atom or an NH group,
R5 represents OR or N(R)2,
R represents the hydrogen atom or a C1-C4 alkyl group,
p is equal to 0, 1 or 2;
said substituents R3 and R4 also being able to form together a methylenedioxy group;
ii) the pharmaceutically acceptable salts of the compounds of formula (I).
According to a second aspect, the invention concerns the abovementioned compounds as a pharmacologically active substance. In particular, the invention concerns the use of at least one compound of formula (I) or one of its pharmaceutically acceptable salts as an active substance for the preparation of a medicinal product intended for therapeutic use, in particular for the treatment of hypercholesterolemia, dyslipidemia, diabetes, obesity and cardiovascular disease which are the consequence of an imbalance in the serum lipoproteins. More generally, the compounds of formula I according to the invention are useful for correcting deviations in the parameters indicative of a metabolic syndrome. The compounds according to the invention are also useful as active substances in medicinal products intended for preventing or treating atherosclerosis, myocardial infarction, certain inflammatory diseases such as dermatitis, and neurodegenerative diseases such as Alzheimer's.
DETAILED DESCRIPTION
In the present description, nitrogen-containing 5- or 6-membered saturated heterocyclic ring condensed with a phenyl or cyclohexyl ring, means a heterocycle such as 2,3-dihydroindole, octahydroindole, 1,2,3,4-tetrahydroquinoline, decahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and decahydroisoquinoline. A branched or cyclized C3-C6 alkyl group, means a hydrocarbonated chain having between 3 and 6 carbon atoms, branched or cyclized, for example and without limitation, the groups 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 1,1-dimethylpropyl, 1-methylpentyl, 1,1-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopentylmethyl. A C1-C4 alkyl group means a hydrocarbonated chain having between 1 and 4 carbon atoms, linear or branched, or also cyclical having 3 or 4 carbon atoms. Examples of C1-C4 alkyl groups include the methyl, ethyl, propyl, butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, cyclopropyl, methylcyclopropyl or cyclopropylmethyl groups. A C2-C6 linear, branched or cyclical alkoxy group means in particular, the ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 1-methylethoxy, 1-ethylethoxy or cylohexyloxy groups. A linear or branched C1-C4 alkoxy group means in particular the methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy, 1-ethylethoxy, 1- or 2-methylpropoxy groups.
A linear or branched C1-C4 alkylene group means a disubstituted saturated chain comprising between 1 and 4 carbon atoms, for example the —CH2—, —(CH2)2—, —(CH2)3—, —CH(CH3)—CH2—, or —CH2—CH(CH3)—CH2— groups.
A halogen means a fluorine, chlorine, bromine or iodine atom, fluorine and chlorine atoms being preferred.
The compounds according to the invention comprise an asymmetrical carbon (carboxamide function carrier) which can be either racemic, or of configuration R or, preferably, of configuration S (Figure Ia)
The compounds according to the invention can be prepared using a process that employs the steps of:
a) reacting an acid of formula:
in which (H) represents a nitrogen-containing 5- or 6-membered saturated heterocyclic ring condensed with a phenyl or cyclohexyl ring, optionally substituted by a halogen or a C1-C4 alcoxy group, or an N(R)2 group in which R represents the hydrogen atom or a C1-C4 alkyl group,
with an amine of formula
NH2—Y—Ar III
in which:
Y represents:
a single bond,
a linear or branched C1-C4 alkylene, or C3-C4 cyclized group, optionally substituted by a C1-C3 alkoxy group, a phenyl group, an amino group protected by an amino-protecting group (other than Boc) or an N(R)2 group, in which R represents the hydrogen atom or a C1-C4 alkyl group,
a —(CH2)n—O— group,
a —(CH2)n—S— group, or
a —(CH2)m—CO— group,
n is equal to 2 or 3,
m is equal to 1, 2 or 3,
Ar represents an aromatic or heteroaromatic ring chosen from among the phenyl, naphthalenyl, tetrahydronaphthalenyl, pyridinyl or indolyl groups, optionally substituted by one or two substituents R3, R4 that are identical or different and chosen from among a halogen, a C1-C4 alkyl, C1-C4 alkoxy, nitro, phenyl, phenoxy, trifluoromethyl or hydroxy group, an amino group protected by an amino-protecting group (other than Boc), or a group of formula —X—[C(R)2]p—COR5 in which:
X represents a single bond, an oxygen atom or a sulfur atom
R5 represents OH, OR or N(R)2
R represents a C1-C4 alkyl group
p is equal to 0, 1 or 2;
said substituents R3 and R4 also being able to form together a methylenedioxy group,
in an anhydrous solvent such as dichloromethane and in the presence of a catalyst such as DCC (dicyclohexylcarbodiimide) free or grafted to a resin or HOAT (1-hydroxy-7-azabenzotriazole), at a temperature close to ambient temperature and for between 2 and 20 hours in order to obtain the amide of formula IV
in which (H), Y and Ar retain the same significance as in the starting compounds,
b) reacting the resulting compound of formula IV with trifluoroacetic acid, in a solvent such as dichloromethane, at ambient temperature for between 2 and 20 hours in order to obtain the compound of formula V
in which (H), Y and Ar retain the same significance as in compound (IV),
c) reacting the compound of formula V with a benzenesulfonyl chloride of formula VI
in which
R1 represents a chlorine atom, a C3-C6 alkyl group branched or cyclized, a C2-C6 alkoxy group, linear, branched or cyclized, a phenoxy group optionally substituted by a halogen, a phenyl group, an aminomethyl group optionally substituted by an acetyl or trifluoroacetyl group,
R2 represents a hydrogen atom or a halogen, or,
R1 and R2 together form an oxygen-containing or nitrogen-containing heterocycle, optionally substituted by one or more C1-C3 alkyl groups, by an acyl group or by a C2-C3 perfluoroacyl group
in a solvent such as dichloromethane, at ambient temperature for between 2 and 20 hours in order to obtain the compound of formula I
in which R1, R2, (H), Y and Ar retain the same significance as in the starting compounds,
d) if necessary, where one of the substituents R3 or R4 of the Ar group represents a protected amino group, eliminating the amino-protecting group to obtain R3 or R4 in the form of a free amine.
As a variant to the process described above, the compounds of formula I according to the invention can be obtained according to a process consisting of
a) reacting a benzenesulfonyl chloride of formula VI
in which
R1 represents a chlorine atom, a C3-C6 alkyl group branched or cyclized, a C2-C6 alkoxy group linear, branched or cyclized, a phenoxy group optionally substituted by a halogen, a phenyl group, or an aminomethyl group substituted by an acetyl or trifluoroacetyl group,
R2 represents a hydrogen atom or a halogen, or
R1 and R2 together form an oxygen-containing or nitrogen-containing heterocycle, optionally substituted by one or more C1-C3 alkyl groups, by an acyl group or by a C2-C3 perfluoroacyl group,
with an ester of formula VII
in which (H) represents a nitrogen-containing 5- or 6-membered saturated heterocyclic ring condensed with a phenyl or cyclohexyl ring, optionally substituted by a halogen or a C1-C4 alcoxy group,
in an anhydrous solvent such as dichloromethane, at ambient temperature and for between 2 and 10 hours in order to obtain the compound of formula VIII
in which (H), R1 and R2 retain the same significance as in the starting compounds,
b) converting the ester VIII into acid, through the effect of a base in hydroalcoholic medium according to the methods well known to a person skilled in the art to obtain the acid of formula IX
in which (H), R1 and R2 remain unchanged,
c) reacting the acid compound (IX) with a primary amine of formula III
NH2—Y—Ar III
in which
Y represents:
a single bond,
a C1-C4 alkylene, linear or branched or C3-C4 cyclized group, optionally substituted by a C1-C3 alkoxy group, a phenyl group, an N(R)2 group or a COOH group,
a —(CH2)n—O— group,
a —(CH2)n—S— group, or
a —(CH2)m—CO— group,
n is equal to 2 or 3;
m is equal to 1, 2 or 3;
R represents the hydrogen atom or a C1-C4 alkyl group,
Ar represents an aromatic or heteroaromatic ring chosen from among the phenyl, naphthalenyl, tetrahydronaphthalenyl, pyridinyl or indolyl groups, optionally substituted by one or two identical or different R3, R4 substituents chosen from among a halogen, a C1-C4 alkyl, C1-C4 alkoxy, nitro, phenyl, phenoxy, trifluoromethyl, hydroxy or N(R)2 group, an amino group protected by an amino-protecting group, or a group of formula —X—[C(R)2]p—COR5 in which:
X represents a single bond, an oxygen atom or a sulfur atom,
R5 represents OH, OR or N(R)2,
R represents a C1-C4 alkyl group,
p is equal to 0, 1 or 2;
said substituents R3 and R4 also being capable of forming together a methylenedioxy group,
according to a method analogous to that described under step (a) of the above process, in order to obtain the compound of formula (I)
in which (H), R1, R2, Y and Ar retain the same significance as in the starting compounds.
The following examples of the preparation of compounds according to formula (I) will allow a better understanding of the invention. In these examples the term “preparation” is used for examples describing the synthesis of intermediate compounds and the term “examples” for those describing the synthesis of compounds of the formula (I) according to the invention. The melting points are measured on the Kofler test bed and the Nuclear Magnetic Resonance spectral values are characterized by the chemical displacement calculated in relation to the TMS, by the number of protons associated with the signal and by the shape of the signal (s for singlet, d for doublet, dd for double doublet, t for triplet, q for quadruplet, and m for multiplet). The operating frequency and the solvent used are indicated for each compound. The ambient temperature is 20° C.±2° C.
In these examples the following abbreviations have been used:
mmol=millimole
Boc=t-butoxycarbonyl (or: 1,1-dimethylethoxycarbonyl)
HOAT=1-hydroxy-7-azabenzotriazole
Preparation I
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-2-quinolinylcarboxylic acid, methyl ester
A solution is prepared of 300 mg (1.32 mmol) of 1,2,3,4-tetrahydro-2-quinolinylcarboxylic acid methyl ester in 20 ml of acetonitrile and, at ambient temperature, 309 mg (1.32 mmol) of 4-(1,1-dimethylethyl)-benzenesulfonyl chloride are added, then 0.29 ml (2.64 mmol) of N-methylmorpholine. The reaction mixture is agitated for 18 hours with solvent reflux and then concentrated under reduced pressure. The evaporation residue is collected in 50 ml of ethyl acetate and washed with a solution of hydrochloric acid 1 N then by a solution of saturated sodium bicarbonate. The organic phase is dried on magnesium sulfate and concentrated under reduced pressure. The raw product is purified by silica gel chromatography eluting with the help of a methylcyclohexane/ethyl acetate mixture (99/1 then 95/5; v/v). In this way the expected product is obtained in the form of a white solid (yield=22%).
NMR 1H (DMSO, 300 MHz) δ: 7.52-7.61 (m, 5H); 7.19-7.24 (m, 1H); 7.05-7.10 (m, 2H); 5.03 (t, 1H); 3.65 (s, 3H); 2.41-2.49 (m, 1H); 2.12-2.17 (m, 1H); 1.89-1.95 (m, 1H); 1.73-1.80 (m, 1H); 1.26 (s, 9H).
Preparation II
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-1,2,3,4-tetrahydro-2-quinolinylcarboxylic acid
112 mg (0.289 mmol) of the compound obtained according to preparation I are mixed with 6 ml of tetrahydrofurane and 4 ml of water and, under agitation and at ambient temperature, 18 mg (0.429 mmol) of lithine are added. This reaction mixture is agitated at ambient temperature for 2 hours, then the acidity is increased to pH 1 by a solution of hydrochloric acid, diluted with water and then extracted by 3 times 25 ml of ethyl acetate. The organic phases collected are dried on magnesium sulfate and concentrated under reduced pressure. In this way the expected product is obtained in the form of an orange solid (yield=86%).
NMR 1H (DMSO, 300 MHz), δ: 7.49-7.74 (m, 6H); 7.16-7.23 (m, 1H); 7.05 (dd, 1H); 4.9 (t, 1H); 2.42-2.51 (m, 1H); 1.80-2.07 (m, 3H); 1.27 (s, 9H).
Example 1
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-N-(2-phenylethyl)-1,2,3,4-tetrahydro-2-quinolinylcarboxamide
150 mg (0.20 mmol) of PS-carbodiimide resin (polystyrene resin functionalised with a carbodiimide group supplied by Argonaut Technologies) are conditioned in 5 ml of dichloromethane for 30 minutes then the solvent is eliminated by filtration. The resin is rinsed by 4 ml of dichloromethane, then 50 mg (0.134 mmol) of the acid obtained according to preparation II in solution in 5 ml of dichloromethane, 25 μl (0.2 mmol) of 2-phenylethanamine and 5 mg of HOAT are added. This reaction mixture is agitated at ambient temperature for 18 hours, and then 200 mg of IR120 resin are added and the reaction mixture is again agitated for 3 hours at ambient temperature. The liquid phase of the mixture is separated by filtration and concentrated under reduced pressure. The raw product is purified by silica gel chromatography eluting using a methylcyclohexane/ethyl acetate mixture (70/30; v/v). In this way the expected product is obtained in the form of a white solid (yield=55%).
Melting point=142-143° C.
NMR 1H (DMSO, 300 MHz) δ: 7.94 (t, 1H); 7.65 (dd, 1H); 7.54 (d, 2H); 7.44 (d, 2H); 7.04-7.24 (m, 8H); 4.66 (t, 1H); 3.29 (m, 2H); 2.66 (t, 2H); 2.27-2.34 (m, 1H); 1.87-1.92 (m, 1H); 1.48-1.66 (m, 2H); 1.26 (s, 9H).
Preparation III
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-(2S)-1H-indole-2-carboxylic acid, methyl ester
A solution of 4.25 g (19.9 mmol) of 2,3-dihydro-(2S)-1H-indole-2-carboxylic acid methyl ester hydrochloride in 100 ml of THF (tetrahydrofurane) is prepared and 5.55 ml (39.8 mmol) of triethylamine are added. The mixture is agitated and cooled to 0° C. and a solution of 6.02 g (25.86 mmol) of 4-(1,1-dimethylethyl)benzenesulfonyl chloride in 40 ml of THF is slowly added. The reaction mixture is maintained under agitation for 20 hours at ambient temperature and then hydrolysed with 140 ml of water, and extracted 3 times with 200 ml ethyl acetate. The organic phases collected are washed 3 times with 50 ml of water, then dried on magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by silica gel chromatography eluting with the help of a methylcyclohexane/ethyl acetate mixture (90/10 then 80/20; v/v). In this way the expected product is obtained in the form of white crystals (yield=53%).
Melting point=122° C.
NMR 1H (DMSO, 300 MHz) δ: 7.78 (d, 2H, Harom.), 7.58 (d, 2H, Harom.), 7.38 (d, 1H, Harom.), 7.23-7.14 (m, 2H, Harom.), 6.99 (t, 1H, Harom.), 5.02 (dd, 1H, NCHCO), 3.71 (s, 3H, OCH3), 3.40 (dd, 1H, CH2CHCO), 3.06 (dd, 1H, CH2CHCO), 1.25 (s, 9H, tBu).
Preparation IV
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-(2S)-1H-indole-2-carboxylic acid
2 g (5.36 mmol) of the ester obtained according to preparation III are dissolved in 20 ml of dioxane and 5 ml of water are added, then 0.43 g (10.7 mmol) of sodium hydroxide. The reaction mixture is concentrated under reduced pressure. The white residue is dissolved in 30 ml of water and the solution obtained is acidified by a solution of hydrochloric acid 1M, to pH1. The white precipitate is separated by filtration and then dried in a desiccator. In this way the acid expected is obtained in the form of a white powder (yield=85%).
NMR 1H (DMSO, 300 MHz) δ: 13.10 (s, 1H, COOH), 7.77 (d, 2H, Harom.), 7.57 (d, 2H, Harom.), 7.36 (d, 1H, Harom.), 7.20-7.13 (m, 2H, Harom.), 6.98 (t, 1H, Harom.), 4.88 (dd, 1H, NCHCO), 3.35 (dd, 1H, CH2CHCO), 3.02 (dd, 1H, CH2CHCO), 1.25 (s, 9H, tBu).
Example 2
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-(2-phenoxy-ethyl)-(2S)-1H-indole-2-carboxamide
400 mg (equivalent to 0.556 mmol) of PS-EDC resin (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide combined with polystyrene resin) are conditioned in 4 ml of dichloromethane under agitation for 15 minutes, and then the solvent is eliminated by filtration. The resin is rinsed several times with 4 ml of dichloromethane, and then a solution of 100 mg (0.278 mmol) of acid obtained according to preparation IV and 25.4 mg (0.185 mmol) of 2-phenoxyethanamine in solution in 6 ml of dichloromethane are added. The mixture is agitated for 20 hours at ambient temperature and 0.278 mmol of isocyanate resin are added. The mixture is agitated for 2 hours at ambient temperature and 0.278 mmol of Amberlite IRA 400 resin are added. The mixture is again agitated for 2 hours and then the resins are eliminated by filtration. The filtrate is then concentrated under reduced pressure. In this way the expected compound is obtained in the form of a white powder (yield=58%).
NMR 1H (DMSO, 250 MHz) δ: 8.37 (t, 1H, NHCO), 7.70 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.32-7.20 (m, 3H, Harom.), 7.10 (d, 1H, Harom.), 7.03-6.93 (m, 4H, Harom.), 4.80 (dd, 1H, NCHCO), 4.02 (t, 2H, CH2OPh), 3.50 (m, 2H, CH2NCO), 3.11 (dd, 1H, CH2CHCO), 2.91 (dd, 1H, CH2CHCO), 1.25 (s, 9H, tBu).
Working in a similar way to example 2, the following compounds are obtained:
Example 3
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(4-nitro-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=17%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.22 (t, 1H, NHCO), 8.07 (d, 2H, Harom.), 7.66 (d, 2H, Harom.), 7.54 (d, 2H, Harom.), 7.45 (m, 3H, Harom.), 7.22 (t, 1H, Harom.), 7.08 (d, 1H, Harom.), 7.02 (t, 1H, Harom.), 4.68 (dd, 1H, NCHCO), 3.41 (m, 2H, CH2NCO), 2.99 (dd, 1H, CH2CHCO), 2.89 (t, 2H, CH2Ph), 2.79 (dd, 1H, CH2CHCO), 1.24 (s, 9H, tBu).
MS (ESI+) m/z 508 (MH+).
Example 4
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(3-fluoro-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=26%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.22 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.32-7.20 (m, 2H, Harom.), 7.10-6.99 (m, 5H, Harom.), 4.69 (dd, 1H, NCHCO), 3.37 (m, 2H, CH2NCO), 3.04 (dd, 1H, CH2CHCO), 2.81 (dd, 1H, CH2CHCO), 2.75 (t, 2H, CH2Ph), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 481 (MH+).
Example 5
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(2,6-dichlorophenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=23%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.38 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.47-7.40 (m, 3H, Harom.), 7.29-7.22 (m, 2H, Harom.), 7.10 (d, 1H, Harom.), 7.03 (t, 1H, Harom.), 4.69 (dd, 1H, NCHCO), 3.33 (m, 2H, CH2NCO), 3.09-3.00 (m, 3H, CH2CHCO, CH2Ph), 2.87 (dd, 1H, CH2CHCO), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 531 (MH+).
Example 6
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-(2-phenyl-propyl)-2S-1H-indole-2-carboxamide
Yield=15%; colorless oil;
NMR 1H (DMSO, 300 MHz), δ: 8.08 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.44 (t, 1H, Harom.), 7.30-7.18 (m, 6H, Harom.), 7.09 (t, 1H, Harom.), 7.01 (td, 1H, Harom.), 4.72 (dd, 1H, NCHCO), 3.27 (m, 2H, CH2NCO), 3.05-2.90 (m, 2H, CH2CHCO, CHPh), 2.75 (dd, 1H, CH2CHCO), 1.25 (s, 9H, tBu); 1.18 (d, 3H, CH3).
MS (ESI+) m/z 477 (MH+).
Example 7
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(2-methyl-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=19%; colorless oil;
NMR 1H (DMSO, 300 MHz), δ:8.17 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.22-7.10 (m, 3H, Harom.), 7.04-6.96 (m, 4H, Harom.), 4.71 (dd, 1H, NCHCO), 3.32 (m, 2H, CH2NCO), 3.05 (dd, 1H, CH2CHCO), 2.84 (dd, 1H, CH2CHCO), 2.69 (t, 2H, CH2Ph), 2.27 (s, 3H, CH3), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 477 (MH+).
Example 8
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(3,4-dichlorophenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=18%; colorless oil;
NMR 1H (DMSO, 300 MHz), δ: 8.21 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.47 (m, 3H, Harom.), 7.22-7.09 (m, 3H, Harom.), 7.01 (t, 1H, Harom.), 4.68 (dd, 1H, NCHCO), 3.35 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.83-2.78 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 531 (MH+).
Example 9
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(2-fluoro-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=92%; colorless oil;
NMR 1H (DMSO, 300 MHz), δ: 8.25 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.27-7.20 (m, 3H, Harom.), 7.15-7.01 (m, 4H, Harom.), 4.68 (dd, 1H, NCHCO), 3.35 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.85-2.74 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 481 (MH+).
Example 10
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(methoxy)-1-(phenylmethyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=11%; colorless oil;
NMR 1H (DMSO, 300 MHz), δ: 8.01 (d, 1H, NHCO), 7.68 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.47 (d, 1H, Harom.), 7.18-7.03 (m, 8H, Harom.), 4.74 (dd, 1H, NCHCO), 4.05 (m, 1H, CHNCO), 3.31 (d, 2H, OCH2CHN), 3.28 (s, 3H, OCH3), 3.02 (dd, 1H, CH2CHCO), 2.78-2.71 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 507 (MH+).
Example 11
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[E-phenyl-cyclopropyl]-2S-1H-indole-2-carboxamide
Yield=24%; white powder;
NMR 1H (DMSO, 300 MHz), δ: 8.48 (t, 1H, NHCO), 7.73 (d, 2H, Harom.), 7.57 (dd, 2H, Harom.), 7.42 (dd, 1H, Harom.), 7.26-7.11 (m, 7H, Harom.), 7.00 (t, 1H, Harom.), 4.67 (dd, 1H, NCHCO), 3.16 (m, 1H, CHNCO), 2.96-2.83 (m, 2H, CH2CHCO), 2.00 (m, 1H, CHPh), 1.25 (s, 9H, tBu), 1.18 (m, 2H, PhCHCH2);
MS (ESI+) m/z 475 (MH+).
Example 12
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-(3,3-diphenylpropyl)-2S-1H-indole-2-carboxamide
Yield=34%; colorless oil;
NMR 1H (DMSO, 250 MHz), δ: 8.22 (t, 1H, NHCO), 7.72 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.29-7.11 (m, 12H, Harom.), 7.01 (t, 1H, Harom.), 4.71 (dd, 1H, NCHCO), 4.01 (t, 1H; CH(Ph)2), 3.45 (m, 2H, CH2NCO), 3.17-2.86 (m, 2H, CH2CHCO), 2.22 (m, 2H, CH2—CH), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 553 (MH+).
Example 13
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(2-chloro-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=31%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.26 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.40 (d, 1H, Harom.), 7.25-7.20 (m, 4H, Harom.), 7.10 (d, 1H, Harom.), 7.03 (t, 1H, Harom.), 4.69 (dd, 1H, NCHCO), 3.35 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.89-2.80 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 497 (MH+).
Example 14
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(3-chloro-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=26%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.20 (t, 1H, NHCO), 7.70 (d, 2H, Harom.), 7.56 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.29-7.10 (m, 6H, Harom.), 7.03 (t, 1H, Harom.), 4.69 (dd, 1H, NCHCO), 3.35 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.84-2.72 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 497 (MH+).
Example 15
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(4-chloro-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=24%; white powder;
NMR 1H (DMSO, 300 MHz), δ: 8.17 (t, 1H, NHCO), 7.68 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.30-7.18 (m, 5H, Harom.), 7.10 (d, 1H, Harom.), 7.05 (t, 1H, Harom.), 4.69 (dd, 1H, NCHCO), 3.35 (m, 2H, CH2NCO), 3.02 (dd, 1H, CH2CHCO), 2.80 (dd, 1H, CH2CHCO), 2.72 (t, 2H, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 497 (MH+).
Example 16
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(2,4-dichlorophenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=24%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.24 (t, 1H, NHCO), 7.68 (d, 2H, Harom.), 7.57-7.54 (m, 3H, Harom.), 7.46 (d, 1H, Harom.), 7.24 (m, 3H, Harom.), 7.11 (d, 1H, Harom.), 7.02 (t, 1H, Harom.), 4.69 (dd, 1H, NCHCO), 3.34 (m, 2H, CH2NCO), 3.01 (dd, 1H, CH2CHCO), 2.87-2.78 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 531 (MH+).
Example 17
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-(3-phenyl-propyl)-2S-1H-indole-2-carboxamide
Yield=19%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.20 (t, 1H, NHCO), 7.73 (d, 2H, Harom.), 7.57 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.30-7.11 (m, 7H, Harom.), 7.01 (t, 1H, Harom.), 4.72 (dd, 1H, NCHCO), 3.16-3.08 (m, 3H, CH2NCO, CH2CHCO), 2.91 (dd, 1H, CH2CHCO), 2.58 (t, 2H, CH2Ph), 1.73 (m, 2H, CH2CH2Ph) 1.25 (s, 9H, tBu).
MS (ESI+) m/z 477 (MH+).
Example 18
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-(4-phenyl-butyl)-2S-1H-indole-2-carboxamide
Yield=25%; colorless oil;
NMR 1H (DMSO, 300 MHz) δ: 8.12 (t, 1H, NHCO), 7.71 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.44 (d, 1H, Harom.), 7.29-7.10 (m, 7H, Harom.), 7.00 (t, 1H, Harom.), 4.71 (dd, 1H, NCHCO), 3.15-3.04 (m, 3H, CH2NCO, CH2CHCO), 2.88 (dd, 1H, CH2CHCO), 2.58 (t, 2H, CH2Ph), 1.60-1.42 (m, 4H, CH2CH2CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 491 (MH+).
Example 19
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-(phenyl-methyl)-2S-1H-indole-2-carboxamide
Yield=42%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.72 (t, 1H, NHCO), 7.72 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.46 (d, 1H, Harom.), 7.32-7.22 (m, 6H, Harom.), 7.12 (d, 1H, Harom.), 7.01 (t, 1H, Harom.), 4.82 (dd, 1H, NCHCO), 3.34 (t, 2H, CH2NCO), 3.16 (dd, 1H, CH2CHCO), 2.94 (dd, 1H, CH2CHCO), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 449 (MH+).
Example 20
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(1H-indol-3-yl)ethyl]-2S-1H-indole-2-carboxamide
Yield=17%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.23 (t, 1H, NHCO), 7.71 (d, 2H, Harom.), 7.55 (m, 3H, Harom., NH), 7.46 (d, 1H, Harom.), 7.33 (d, 1H, Harom.), 7.20 (t, 1H, Harom.), 7.14-6.95 (m, 6H, Harom.), 4.74 (dd, 1H, NCHCO), 3.38 (m, 2H, CH2NCO), 3.04 (dd, 1H, CH2CHCO), 2.92-2.82 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 502 (MH+).
Example 21
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(3-pyridinyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=25%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.42 (m, 2H, Harom.), 8.24 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.59-7.54 (m, 3H, Harom.), 7.45 (d, 1H, Harom.), 7.28-7.22 (m, 2H, Harom.), 7.10 (d, 1H, Harom.), 7.02 (t, 1H, Harom.), 4.69 (dd, 1H, NCHCO), 3.38 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.83-2.73 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 464 (MH+).
Example 22
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-(2-oxo-2-phenylethyl)-2S-1H-indole-2-carboxamide
Yield=33%; colorless oil;
NMR 1H (DMSO, 300 MHz) δ: 8.46 (t, 1H, NHCO), 7.99 (d, 2H, Harom.), 7.72 (d, 2H, Harom.), 7.66 (d, 1H, Harom.), 7.58-7.46 (m, 5H, Harom.), 7.23 (t, 1H, Harom.), 7.14 (d, 1H, Harom.), 7.03 (t, 1H, Harom.), 4.95 (dd, 1H, NCHCO), 4.74 (dd, 1H, CH2NCO), 4.62 (dd, 1H, CH2NCO), 3.15 (dd, 1H, CH2CHCO), 3.01 (dd, 1H, CH2CHCO), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 477 (MH+).
Example 23
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(4-fluoro-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=11%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.17 (t, 1H, NHCO), 7.68 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.22-7.02 (m, 7H, Harom.), 4.69 (dd, 1H, NCHCO), 3.35 (m, 2H, CH2NCO), 3.02 (dd, 1H, CH2CHCO), 2.81 (dd, 1H, CH2CHCO), 2.71 (t, 2H, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 481 (MH+).
Example 24
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(2-pyridinyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=20%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.49 (dd, 1H, Harom.), 8.30 (t, 1H, NHCO), 7.70-7.66 (m, 3H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.23-7.19 (m, 3H, Harom.), 7.10 (d, 1H, Harom.), 7.02 (t, 1H, Harom.), 4.71 (dd, 1H, NCHCO), 3.47 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.91-2.82 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 464 (MH+).
Example 25
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(3,5-dimethoxyphenylethyl]-2S-1H-indole-2-carboxamide
Yield=21%; colorless oil;
NMR 1H (DMSO, 300 MHz) δ: 8.17 (t, 1H, NHCO), 7.70 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.44 (d, 1H, Harom.), 7.21 (t, 1H, Harom.), 7.10 (d, 1H, Harom.), 7.01 (t, 1H, Harom.), 6.39 (d, 2H, Harom.), 6.33 (t, 1H, Harom.), 4.72 (dd, 1H, NCHCO), 3.70 (s, 6H, OCH3), 3.32 (m, 2H, CH2NCO), 3.02 (dd, 1H, CH2CHCO), 2.85 (dd, 1H, CH2CHCO), 2.69 (t, 2H, CH2Ph), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 523 (MH+).
Example 26
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(4-ethylphenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=19%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.16 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.22 (t, 1H, Harom.), 7.10 (d, 1H, Harom.), 7.09 (s, 4H, Harom.), 7.01 (t, 1H, Harom.), 4.71 (dd, 1H, NCHCO), 3.31 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.82 (dd, 1H, CH2CHCO), 2.68 (t, 2H, CH2Ph), 2.56 (q, 2H, CH2CH3), 1.25 (s, 9H, tBu), 1.15 (t, 3H, CH3).
MS (ESI+) m/z 491 (MH+).
Example 27
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(2-phenoxyphenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=11%; colorless oil;
NMR 1H (DMSO, 250 MHz) δ: 8.21 (t, 1H, NHCO), 7.68 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.40-6.84 (m, 11H, Harom.), 6.84 (t, 1H, Harom.), 4.67 (dd, 1H, NCHCO), 3.36 (m, 2H, CH2NCO), 3.02 (dd, 1H, CH2CHCO), 2.86-2.73 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 555 (MH+).
Example 28
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[(1-naphthalenyl)methyl]-2S-1H-indole-2-carboxamide
Yield=13%; white powder;
NMR 1H (DMSO, 250 MHz) δ: 8.73 (t, 1H, NHCO), 8.05 (m, 1H, Harom.), 7.94 (m, 1H, Harom.), 7.85 (m, 1H, Harom.), 7.73 (dd, 2H, Harom.), 7.57-7.44 (m, 7H, Harom.), 7.22 (t, 1H, Harom.), 7.12 (d, 1H, Harom.), 7.01 (t, 1H, Harom.), 4.92-4.83 (m, 2H, NCHCO, CH2NCO), 4.72 (dd, 1H, CH2NCO), 3.15 (dd, 1H, CH2CHCO), 2.94 (dd, 1H, CH2CHCO), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 499 (MH+).
Example 29
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(4-methyl-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=12%; colorless oil;
NMR 1H (DMSO, 250 MHz) δ: 8.14 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.22 (t, 1H, Harom.), 7.12-7.01 (m, 6H, Harom.), 4.70 (dd, 1H, NCHCO), 3.29 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.83 (dd, 1H, CH2CHCO), 2.67 (t, 2H, CH2Ph), 2.26 (s, 3H, CH3), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 477 (MH+).
Example 30
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-2S-1H-indole-2-carboxamide
Yield=7%; colorless oil;
NMR 1H (DMSO, 250 MHz) δ: 8.52 (t, 1H, NHCO), 7.76 (dd, 2H, Harom.), 7.56 (dd, 2H, Harom.), 7.41 (dd, 1H, Harom.), 7.24-7.12 (m, 6H, Harom.), 6.99 (t, 1H, Harom.), 4.96 (m, 1H, CHNCO), 4.79 (m, 1H, NCHCO), 3.17 (m, 1H, CH2CHCO), 2.97 (m, 1H, CH2CHCO), 2.76 (m, 2H, CH2CH2CH2CHNCO), 1.92-1.69 (m, 4H, CH2CH2CHNCO), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 489 (MH+).
Example 31
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(2-methoxyphenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=7%; colorless oil;
NMR 1H (DMSO, 300 MHz) δ: 8.14 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.25-6.93 (m, 6H, Harom.), 6.84 (t, 1H, Harom.), 4.69 (dd, 1H, NCHCO), 3.78 (s, 3H, OCH3), 3.29 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.84 (dd, 1H, CH2CHCO), 2.72 (m, 2H, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 493 (MH+).
Example 32
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(4-pyridinyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=14%; colorless oil;
NMR 1H (DMSO, 300 MHz) δ: 8.64 (m, 2H, Harom.), 8.29 (t, 1H, NHCO), 7.68-7.63 (m, 4H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.23 (t, 1H, Harom.), 7.10 (d, 1H, Harom.), 7.02 (t, 1H, Harom.), 4.66 (dd, 1H, NCHCO), 3.35 (m, 2H, CH2NCO), 3.06-2.94 (m, 3H, CH2CHCO, CH2Ph), 2.80 (dd, 1H, CH2CHCO), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 464 (MH+).
Example 33
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(1,3-benzodioxol-5-yl)ethyl]-2S-1H-indole-2-carboxamide
Yield=10%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.14 (t, 1H, NHCO), 7.70 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.22 (t, 1H, Harom.), 7.10 (d, 1H, Harom.), 7.01 (t, 1H, Harom.), 6.78 (m, 2H, Harom.), 6.62 (d, 1H, Harom.), 5.95 (s, 2H, OCH2O), 4.71 (dd, 1H, NCHCO), 3.26 (m, 2H, CH2NCO), 3.04 (dd, 1H, CH2CHCO), 2.84 (dd, 1H, CH2CHCO), 2.64 (t, 2H, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 507 (MH+).
Example 34
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(4-phenyl-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=11%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.22 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.63 (d, 2H, Harom.), 7.55 (d, 4H, Harom.), 7.45 (t, 3H, Harom.), 7.37-7.22 (m, 4H, Harom.), 7.09 (d, 1H, Harom.), 7.01 (t, 1H, Harom.), 4.74 (dd, 1H, NCHCO), 3.36 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.88-2.75 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 539 (MH+).
Example 35
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-[4-(1,1-dimethylethyl)phenyl]ethyl]-2S-1H-indole-2-carboxamide
Yield=10%; white powder;
NMR 1H (DMSO, 300 MHz) δ: 8.17 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.28-7.22 (m, 3H, Harom.), 7.10 (d, 3H, Harom.), 7.01 (t, 1H, Harom.), 4.71 (dd, 1H, NCHCO), 3.31 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.82 (dd, 1H, CH2CHCO), 2.68 (t, 2H, CH2Ph), 1.25 (s, 18H, tBu).
MS (ESI+) m/z 519 (MH+).
Example 36
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(3,4-dimethylphenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=10%; colorless oil;
NMR 1H (DMSO, 300 MHz), δ: 8.14 (t, 1H, NHCO), 7.70 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.22 (t, 1H, Harom.), 7.10 (d, 1H, Harom.), 7.03-6.97 (m, 3H, Harom.), 6.89 (d, 1H, Harom.), 4.71 (dd, 1H, NCHCO), 3.31 (m, 2H, CH2NCO), 3.05 (dd, 1H, CH2CHCO), 2.84 (dd, 1H, CH2CHCO), 2.65 (t, 2H, CH2Ph), 2.18 (s, 6H, CH3), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 491 (MH+).
Example 37
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(2,3-dimethoxyphenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=6%; colorless oil;
NMR 1H (DMSO, 300 MHz), δ: 8.22 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.46 (d, 1H, Harom.), 7.22 (t, 1H, Harom.), 7.10 (d, 1H, Harom.), 7.04-6.90 (m, 3H, Harom.), 6.70 (d, 1H, Harom.), 4.70 (dd, 1H, NCHCO), 3.78 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.29 (m, 2H, CH2NCO), 3.04 (dd, 1H, CH2CHCO), 2.86 (dd, 1H, CH2CHCO), 2.72 (t, 2H, CH2Ph), 1.25 (s, 9H, tBu);
MS (ESI+) m/z 523 (MH+).
Example 38
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(3-methyl-phenyl)ethyl]-2S-1H-indole-2-carboxamide
Yield=14%; colorless oil;
NMR 1H (DMSO, 300 MHz), δ: 8.17 (t, 1H, NHCO), 7.70 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.22-7.10 (m, 3H, Harom.), 7.03-6.98 (m, 4H, Harom.), 4.71 (dd, 1H, NCHCO), 3.31 (m, 2H, CH2NCO), 3.05 (dd, 1H, CH2CHCO), 2.84 (dd, 1H, CH2CHCO), 2.69 (t, 2H, CH2Ph), 2.27 (s, 3H, CH3), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 477 (MH+).
Example 39
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-[3-(trifluoromethyl)phenyl]ethyl]-2S-1H-indole-2-carboxamide
Yield=9%; colorless oil;
NMR 1H (DMSO, 300 MHz), δ: 8.22 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.57-7.46 (m, 7H, Harom.), 7.22 (t, 1H, Harom.), 7.08 (d, 1H, Harom.), 7.01 (t, 1H, Harom.), 4.69 (dd, 1H, NCHCO), 3.39 (m, 2H, CH2NCO), 3.03 (dd, 1H, CH2CHCO), 2.87-2.75 (m, 3H, CH2CHCO, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 531 (MH+).
Example 40
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(2,5-dimethoxyphenyl)ethyl]-2S-1H-indole-2-carboxamide
420 mg (0.556 mmol) of PS-carbodiimide resin are conditioned in 4 ml of dichloromethane. After 10 minutes of agitation, the resin is filtered and then rinsed 3 times with 4 ml of dichloromethane. 4 ml of dichloromethane and 4 ml of tetrahydrofurane (THF) are added, and then 100 mg (0.278 mmol) of acid obtained according to preparation IV, 33.5 mg (0.185 mmol) of 2,5-dimethoxybenzeneethanamine and 3.8 mg (0.019 mmol) of HOAT are introduced in succession. The reaction medium is then agitated at ambient temperature. After 16 hours of agitation, 0.278 mmol of IRA400 resin are introduced into the reaction medium and then, after 2 hours of agitation, 0.278 mmol of isocyanate resin. After 1 hour of agitation, the reaction medium is filtered and then the resins are washed 3 times with 3 ml of dichloromethane. The filtrates collected are concentrated and then dried under reduced pressure. In this way the expected compound is obtained in the form of a colorless oil (yield=60%).
NMR 1H (DMSO, 300 MHz) δ: 8.14 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.44 (d, 1H, Harom.), 7.21 (t, 1H, Harom.), 7.10 (d, 1H, Harom.), 7.00 (t, 1H, Harom.), 6.87 (d, 1H, Harom.), 6.74 (m, 2H, Harom.), 4.69 (dd, 1H, NCHCO), 3.73 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 3.29 (m, 2H, CH2NCO), 3.05 (dd, 1H, CH2CHCO), 2.84 (dd, 1H, CH2CHCO), 2.69 (m, 2H, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 523 (MH+).
Example 41
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(4-amino-phenyl)ethyl]-2S-1H-indole-2-carboxamide
A solution of 100 mg (0,278 mmol) of the acid obtained according to preparation IV is prepared in 4 ml of dichloromethane and 4 ml of THF and then 64 mg (0.334 mmol) of EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and 7.8 mg (0.028 mmol) of HOAT are added. After 10 minutes under agitation at ambient temperature, 45.5 mg (0.334 mmol) of 4-aminobenzeneethanamine are added, as well as 4 ml of dichloromethane/THF mixture (50/50) and 58 μl (0.682 mmol) of triethylamine. The reaction medium is then agitated at ambient temperature for 2 hours. The medium is then treated by the addition of 20 ml of water followed by extraction 3 times with 50 ml of ethyl acetate. The organic phases are then regrouped and washed 3 times with 50 ml of water. The organic phase is then dried on magnesium sulfate, followed by concentration at reduced pressure. The raw product obtained is then purified by silica gel chromatography eluting with the help of a dichloromethane/ethyl acetate mixture (95/5 then 90/10; v/v). In this way the expected product is obtained in the form of a white foam (yield=30%).
NMR 1H (DMSO, 300 MHz) δ: 8.09 (t, 1H, NHCO), 7.68 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.22 (t, 1H, Harom.), 7.11 (d, 1H, Harom.), 7.01 (t, 1H, Harom.), 6.82 (d, 2H, Harom.), 6.47 (d, 2H, Harom.), 4.84 (s, 2H, PhNH2), 4.71 (dd, 1H, NCHCO), 3.23 (m, 2H, CH2NCO), 3.04 (dd, 1H, CH2CHCO), 2.85 (dd, 1H, CH2CHCO), 2.53 (t, 2H, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 478 (MH+).
Example 42
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[2-(4-hydroxyphenyl)ethyl]-2S-1H-indole-2-carboxamide
A solution is prepared of 100 mg (0.278 mmol) of the acid obtained according to preparation IV in 4 ml of dichloromethane and 4 ml of THF and then 64 mg (0.334 mmol) of EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and 7.8 mg (0.028 mmol) of HOAT are added. After 10 minutes under agitation at ambient temperature, 45.8 mg (0.334 mmol) of 4-(2-aminoethyl)phenol are added, along with 4 ml of dichloromethane/THF mixture (50/50) and 58 μl (0.682 mmol) of triethylamine. The reaction medium is then agitated at ambient temperature for 2 hours. The medium is then treated by the addition of 20 ml of water followed by extraction 3 times with 50 ml of ethyl acetate. The organic phases are then regrouped and washed 3 times with 50 ml of water. The organic phase is then dried on magnesium sulfate, then concentrated under reduced pressure. The raw product obtained is then purified by silica gel chromatography eluting with the help of a dichloromethane/ethyl acetate mixture (95/5 then 90/10; v/v). In this way the expected product is obtained in the form of a white solid (yield=40%).
NMR 1H (DMSO, 300 MHz) δ: 9.15 (s, 1H, PhOH), 8.12 (t, 1H, NHCO), 7.69 (d, 2H, Harom.), 7.55 (d, 2H, Harom.), 7.45 (d, 1H, Harom.), 7.22 (t, 1H, Harom.), 7.10 (d, 1H, Harom.), 7.04-6.95 (m, 3H, Harom.), 6.65 (d, 2H, Harom.), 4.71 (dd, 1H, NCHCO), 3.25 (m, 2H, CH2NCO), 3.04 (dd, 1H, CH2CHCO), 2.84 (dd, 1H, CH2CHCO), 2.60 (t, 2H, CH2Ph), 1.25 (s, 9H, tBu).
MS (ESI+) m/z 479 (MH+).
Preparation V
2,3-dihydro-2-[[(2-phenylethyl)amino]carbonyl]-(2S)-1H-indole-1-carboxylic acid, 1,1-dimethyl ethyl ester
564 mg (0.75 mmol) of DCC resin (cyclohexylcarbodiimide) are conditioned for 30 minutes at ambient temperature in 8 ml of dichloromethane. The solvent is eliminated by filtration, and then 8 ml of dichloromethane, 132 mg (0.5 mmol) of 2,3-dihydro-(2S)1H-indole-1,2-dicarboxylic acid 1-(1,1-dimethylethyl) ester, 10 mg of HOAT, and then 94 μl (0.75 mmol) of 2-phenylethanamine are added. The reaction mixture is agitated for 16 hours at ambient temperature, and then 1 g of IR 120 resin is added. The mixture is again agitated for 3 hours, and then the resins are eliminated by filtration. The filtrate is then agitated for 2 hours in the presence of 1 g of IRA 400 resin. The resin is eliminated by filtration and the filtrate is concentrated under reduced pressure. In this way the expected amide is obtained in the form of a colorless oil (yield=88%).
NMR 1H (DMSO, 300 MHz) δ: 8.14 (s, 1H, NHCO), 7.72 (s, 1H, Harom.), 7.31-7.12 (m, 7H, Harom.), 7.89 (t, 1H, Harom.), 4.68 (dd, 1H, NCHCO), 3.44-3.33 (m, 2H, CH2CHCO, CH2NCO), 3.23 (m, 1H, CH2NCO), 2.82-2.71 (m, 3H, CH2Ph, CH2CHCO), 1.42 (s, 9H, tBu).
MS (ESI+) m/z 367 (MH+).
Preparation VI
2,3-dihydro-N-(2-phenylethyl)-(2S)-1H-indole-2-carboxamide
A solution of 4.3 g (11.7 mmol) of ester obtained according to preparation V in 5 ml of dichloromethane is prepared. Then 4 ml of concentrated trifluoroacetic acid are added and the reaction medium is then agitated at ambient temperature for 24 h. The reaction mixture is then concentrated under reduced pressure and is then neutralised to pH 8 by addition of an aqueous solution of sodium bicarbonate at 10%. The solution obtained is then extracted 3 times with 50 ml of ethyl acetate, and then the organic phase is washed 3 times with 50 ml of water and dried on magnesium sulfate, before being concentrated under reduced pressure. The residue obtained is then purified by silica gel chromatography eluting with a toluene/isopropanol mixture (100/5; v/v). In this way the expected compound is obtained in the form of a beige solid (yield=82%).
Melting point=112-116° C.
Example 43
1-[[4-(1-methylethyl)phenyl]sulfonyl]-2,3-dihydro-N-(2-phenylethyl)-2S-1H-indole-2-carboxamide
96 mg (0.38 mmol) of morpholine resin (morpholinomethyl PS-HL 2% resin DVB Novabiochem) are conditioned in 3 ml of dichloromethane. Following elimination of the solvent, 1 ml of acetonitrile, 52.4 mg (0.24 mmol) of 4(1-methylethyl)benzenesulfonyl chloride, 50 mg (0.187 mmol) of the compound obtained according to preparation VI, and then 3 mg (0.19 mmol) of cesium fluoride are added in succession. The reaction medium is then agitated at ambient temperature. After 20 hours of agitation, the resin is filtered and the filtrate is recovered in 3 ml of dichloromethane and treated with 92 mg (0.24 mmol) of polyamine resin (polyamine resin HL Novabiochem). After 20 hours of agitation, the resin is filtered and the filtrate is recovered in 3 ml of dichloromethane and treated with 0.37 mmol of IR120 Amberlite resin. After 20 hours of agitation, the resin is filtered and the filtrate is concentrated and then dried under reduced pressure. In this way the expected product is obtained in the form of a white solid (yield=45%).
NMR 1H (DMSO, 300 MHz) δ: 8.17 (t, 1H, NHCO), 7.68 (d, 2H, Harom.), 7.47-7.40 (m, 3H, Harom.), 7.27-7.17 (m, 6H, Harom.), 7.10 (d, 1H, Harom.), 7.01 (t, 1H, Harom.), 4.71 (dd, 1H, NCHCO), 3.34 (m, 2H, CH2NCO), 3.02-2.91 (m, 2H, CH2CHCO, CH(CH3)2), 2.82 (dd, 1H, CH2CHCO), 2.73 (t, 2H, CH2Ph), 1.16 (d, 6H, CH(CH3)2).
MS (ESI+) m/z 449 (MH+).
Working in a manner similar to example 43, the following compounds are obtained:
Example 44
1-[(3,4-dichlorophenyl)sulfonyl]-2,3-dihydro-N-(2-phenylethyl)-2S-1H-indole-2-carboxamide
Yield=46%; white solid;
NMR 1H (DMSO, 300 MHz) δ: 8.25 (t, 1H, NHCO), 8.02 (d, 1H, Harom.), 7.83 (d, 1H, Harom.), 7.72 (dd, 1H, Harom.), 7.43 (d, 1H, Harom.), 7.27-7.14 (m, 7H, Harom.), 7.04 (t, 1H, Harom.), 4.84 (dd, 1H, NCHCO), 3.36 (m, 2H, CH2NCO), 3.13 (dd, 1H, CH2CHCO), 2.85 (dd, 1H, CH2CHCO), 2.73 (t, 2H, CH2Ph).
Rf=0.8 (CH2Cl2/AcOEt: 9/1);
MS (ESI+) m/z 475 (MH+).
Example 45
1-[(4-phenylphenyl)sulfonyl]-2,3-dihydro-N-(2-phenylethyl)-2S-1H-indole-2-carboxamide
Yield=28%; white solid;
NMR 1H (DMSO, 250 MHz) δ: 8.22 (t, 1H, NHCO), 7.84 (s, 4H, Harom.), 7.70 (d, 2H, Harom.), 7.51-7.45 (m, 4H, Harom.), 7.27-7.03 (m, 8H, Harom.), 4.79 (dd, 1H, NCHCO), 3.36 (m, 2H, CH2NCO), 3.08 (dd, 1H, CH2CHCO), 2.85 (dd, 1H, CH2CHCO), 2.74 (t, 2H, CH2Ph).
Rf=0.6 (CH2Cl2/AcOEt: 9/1);
MS (ESI+) m/z 483 (MH+).
Example 46
2,3-dihydro-1-[(4-phenoxyphenyl)sulfonyl]-N-(2-phenylethyl)-(2S)-1H-indole-2-carboxamide
NMR 1H (DMSO, 250 MHz) δ: 8.16 (t, 1H); 7.75 (d, 2H); 7.42-7.46 (m, 3H); 7.01-7.30 (1m, 3H); 4.71 (dd, 1H); 3.33 (m, 2H); 3.06 (dd, 1H); 2.84 (dd, 1H); 2.72 (t, 2H).
Example 47
1-[(3,4-dihydro-2,2-dimethyl-2H-benzopyran-6-yl)sulfonyl]-2,3-dihydro-N-(2-phenylethyl)-(2S)-1H-indole-2-carboxamide
NMR 1H (DMSO, 250 MHz) δ: 8.13 (t, 1H); 7.54 (d, 1H); 7.44 (d, 1H); 7.25 (dd, 1H); 7.15-7.25 (m, 6H); 7.12 (d, 1H); 7.02 (td, 1H); 6.76 (d, 1H); 4.68 (dd, 1H); 3.33 (m, 2H); 3.00 (dd, 1H); 2.62-2.83 (dd, 1H); 2.78 (m, 4H); 1.75 (t, 2H); 1.26 (d, 6H).
Example 48
2,3-dihydro-N-(2-phenylethyl)-1-[[1,2,3,4-tetrahydro-2-(trifluoro-acetyl)-7-isoquinolinyl]sulfonyl]-(2S)-1H-indole-2-carboxamide
NMR 1H (DMSO, 250 MHz) δ: 8.15 (m, 1H); 7.80 (dd, 1H); 7.55 (m, 1H); 7.46 (d, 1H); 7.34 (d, 1H); 7.09-7.32 (m, 7H); 7.01 (td, 1H); 4.65-4.91 (m, 3H); 3.78 (t, 2H); 3.35 (q, 2H); 2.81-3.06 (m, 4H); 2.73 (t, 2H).
Example 49
2,3-dihydro-1-[[4-(1-methylethoxy)phenyl]sulfonyl]-N-(2-phenyl-ethyl)-(2S)-1H-indole-2-carboxamide
NMR 1H (DMSO, 250 MHz) δ: 8.15 (t, 1H); 7.64 (d, 1H); 7.44 (d, 2H); 7.10-7.26 (m, 7H); 6.98-7.05 (m, 3H); 4.68 (m, 2H); 3.33 (m, 2H); 3.00 (dd, 1H); 2.83 (dd, 1H); 2.72 (t, 2H); 1.24 (d, 6H).
Working in a manner similar to preparation V, the following compounds are obtained:
Preparation VII
Octahydro-2-[[(2-phenylethyl)amino]carbonyl]-(2S)-1H-indole-1-carboxylic, acid 1,1-dimethyl ethyl ester
Yield=48%; white solid;
NMR 1H (DMSO, 250 MHz) δ: 7.82 (s, 1H, NHCO), 7.32-7.19 (m, 5H, Harom.), 3.99 (dd, 1H, NCHCO), 3.64 (m, 1H, CHNCOOtBu), 3.37-3.20 (m, 2H, CH2NCO), 2.72 (t, 2H, CH2Ph), 2.21 (m, 1H, CHCH2CHCO), 1.90-1.11 (m, 19H, CH2CH2CH2CH2CHCH2CHCO, tBu).
MS (ESI+) m/z 373 (MH+).
Preparation VIII
2,3-dihydro-N-(2-phenylethyl)-(2S)-1H-indole-2-carboxamide, trifluoroacetate
A solution is prepared of 182 mg (0.36 mmol) of the compound obtained according to preparation V in 1.5 ml of dichloromethane and 1.5 ml of trifluoroacetic acid are added. The reaction mixture is agitated at ambient temperature for 16 hours and then the dichloromethane is expelled under reduced pressure. The evaporation residue is then recovered in 5 ml of a water-acetonitrile mixture (90/10; v/v) and the solution obtained is lyophilised. In this way the expected compound is obtained in the form of a white solid (yield=93%).
NMR 1H (DMSO, 250 MHz) δ: 7.99 (t, 1H, NHCO), 7.30-7.15 (m, 5H, Harom.), 7.06-6.97 (m, 2H, Harom.), 6.68 (t, 2H, Harom.), 4.40 (s, 1H, NHCHCO), 4.24 (dd, 1H, NCHCO), 3.37-3.25 (m, 3H, CH2CHCO, CH2NCO), 2.88 (dd, 1H, CH2CHCO), 2.73 (t, 2H, CH2Ph).
MS (ESI+) m/z 267 (MH+).
Working in a manner similar to preparation VIII, the following compound is obtained:
Preparation IX
Octahydro-N-(2-phenylethyl)-1H-(2S)-indole-2-carboxamide, trifluoro-acetate
Yield=91%; white solid;
NMR 1H (DMSO, 250 MHz), δ: 9.57 (s, 1H, NH2+), 8.55 (t, 1H, NHCO), 7.91 (m, 1H, NH2+), 7.33-7.18 (m, 5H, Harom.), 4.13 (m, 1H, NCHCO), 3.61-3.48 (m, 2H, CHNH2+, CH2NCO), 3.34 (m, 1H, CH2NCO), 2.79 (td, 2H, CH2Ph), 2.23 (m, 2H, CHCH2CHCO), 1.76-1.23 (m, 9H, CH2CH2CH2CH2CHCH2CHCO).
MS (ESI+) m/z 273 (MH+).
Example 50
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-(2-phenyl-ethyl)-(2S)-1H-indole-2-carboxamide
A mixture is prepared of 144 mg (0.39 mmol) of the compound obtained according to preparation VIII and 0.5 g of IRA400 resin in 2 ml of dichloromethane and this mixture is maintained under agitation at ambient temperature for 3 hours. The resin is then eliminated by filtration and the filtrate is added to a suspension of 202 mg (0.787 mmol) of morpholine resin previously conditioned in 3 ml of dichloromethane. 101 mg (0.432 mmol) of 4-(1,1-dimethylethyl)benzenesulfonyl chloride are added and the reaction mixture is agitated at ambient temperature for 16 hours. The resin is eliminated and the filtrate is agitated for 2 hours, at ambient temperature, with 0.5 g (1.3 mmol) of polyamine resin. This resin is then eliminated by filtration and the filtrate is agitated in the presence of 0.5 g of IR120 resin, for 2 hours at ambient temperature. Following separation of the resin, the filtrate is concentrated under reduced pressure and in this way the expected product is obtained in the form of a brown solid (yield=49%).
NMR 1H (DMSO, 300 MHz) δ: 7.93 (m, 1H, NHCO), 7.66 (d, 2H, Harom.), 7.54 (d, 2H, Harom.), 7.43 (d, 1H, Harom.), 7.25-6.99 (m, 8H, Harom.), 4.70 (dd, 1H, NCHCO), 3.35 (m, 2H, CH2NCO), 3.01 (dd, 1H, CH2CHCO), 2.89 (dd, 1H, CH2CHCO), 2.73 (t, 2H, CH2Ph), 1.24 (s, 9H, tBu).
MS (ESI+) m/z 463 (MH+).
Working in a manner similar to example 50, starting with the compound obtained according to preparation IX, the following compound is obtained:
Example 51
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-octahydro-N-(2-phenyl-ethyl)-2S-1H-indole-2-carboxamide
Yield=76%; colorless oil;
NMR 1H (DMSO, 300 MHz) δ: 7.82-7.78 (m, 3H, NHCO, Harom.), 7.62 (d, 2H, Harom.), 7.32-7.20 (m, 5H, Harom.), 3.93 (t, 1H, NCHCO), 3.60 (m, 1H, CHNSO2), 3.37 (m, 2H, CH2NCO), 2.75 (t, 2H, CH2Ph), 1.76-1.10 (m, 20H, CH2CH2CH2CH2CHCH2CHCO, tBu).
MS (ESI+) m/z 469 (MH+).
Example 52
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzoic acid, methyl ester
Working in a manner similar to example 2, starting with the compound obtained according to preparation IV and 4-(2-aminoethoxy)benzoic acid methyl ester, the expected compound is obtained in the form of a colorless oil. (yield=85%).
NMR 1H (DMSO, 300 MHz): δ: 8.40 (t, 1H); 7.90 (d, 2H); 7.70 (d, 2H); 7.55 (d, 2H); 7.44 (d, 1H); 7.21 (t, 1H); 7.15-6.95 (m, 4H); 4.79 (dd, 1H); 4.12 (t, 2H); 3.81 (s, 3H); 3.65-3.35 (m, 2H); 3.11 (dd, 1H); 2.90 (dd.1H); 1.25 (s, 9H).
Example 53
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzoic acid
Working in a manner similar to preparation II, starting with the compound obtained according to example 52 and following purification by silica gel chromatography eluting with a dichloromethane/ethanol mixture (98/2; v/v), the expected compound is obtained in the form of a white solid (yield=33.5%)
NMR 1H (DMSO, 300 MHz) δ: 12.57 (s wide, 1H); 8.40 (t, 1H); 7.88 (d, 2H); 7.71 (d, 2H); 7.55 (d, 2H); 7.44 (d, 1H); 7.21 (t, 1H); 7.10 (d, 1H); 7.05-6.9 (m, 3H); 4.79 (dd, 1H); 4.11 (t, 2H); 3.65-3.35 (m, 2H); 3.11 (dd, 1H); 2.9 (dd, 1H); 1.25 (s, 9H).
Example 54
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzeneacetic acid, methyl ester
Working in a manner similar to example 2, starting with the compound obtained according to preparation IV and 4-(2-aminoethoxy)benzeneacetic acid methyl ester, the expected compound is obtained in the form of an oil (yield=35%)
NMR 1H (DMSO, 300 MHz): δ: 8.37 (t, 1H); 7.71 (d, 2H); 7.55 (d, 2H); 7.44 (d, 1H); 7.25-7.05 (m, 4H); 7.01 (t, 1H); 6.88 (d, 2H); 4.79 (dd, 1H); 4.00 (t, 2H); 3.60 (s, 3H); 3.59 (s, 2H); 3.6-3.3 (m, 2H); 3.10 (dd, 1H); 2.90 (dd, 1H); 1.25 (s, 9H).
Example 55
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzeneacetic acid
Working in a manner similar to preparation II, starting with the compound obtained according to example 54, the expected compound is obtained in the form of an oil (yield=81%)
NMR 1H (DMSO, 300 MHz) δ: 12.20 (s wide, 1H); 8.37 (t, 1H); 7.71 (d, 2H); 7.55 (d, 2H); 7.44 (d, 1H); 7.25-7.05 (m, 4H); 7.01 (t, 1H); 6.88 (d, 2H); 4.80 (dd, 1H); 4.00 (t, 2H); 3.6-3.3 (m, 4H); 3.10 (dd, 1H); 2.90 (dd, 1H); 1.25 (s, 9H).
Preparation X
1-[(3-cyanophenyl)sulfonyl]-2,3-dihydro-N-(2-phenylethyl)-(2S)-1H-indole-2-carboxamide
Working in a manner similar to example 43, starting with 3-cyanobenzenesulfonyl chloride, the expected compound is obtained in the form of a beige solid. (yield=88%).
Melting point=50° C.
Preparation XI
1-[[3-(aminomethyl)phenyl]sulfonyl]-2,3-dihydro-N-(2-phenylethyl)-(2S)-1H-indole-2-carboxamide
A solution is prepared of 1 g (2.31 mmol) of the compound obtained according to preparation X in 55 ml anhydrous ethanol and 100 mg Raney nickel are added. The mixture is agitated under a hydrogen atmosphere, at ambient temperature and at atmospheric pressure for 8 hours. The catalyst is then eliminated by filtration and the filtrate is concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography eluting with a dichloromethane/methanol/ammonium mixture (95/5/0.5; v/v/v). In this way the expected compound is obtained in the form of beige solid (yield=48%).
NMR 1H (DMSO, 300 MHz) δ: 8.16 (t, 1H); 7.76 (s, 1H); 7.42-7.60 (m, 4H); 7.15-7.30 (m, 6H); 7.09 (dd, 1H); 7.02 (td, 1H); 4.76 (dd, 1H); 3.71 (s, 2H); 3.34 (m, 2H); 2.97 (dd, 1H); 2.83 (dd, 1H); 2.73 (t, 2H).
Example 56
2,3-dihydro-N-(2-phenylethyl)-1-[[3-[[(trifluoroacetyl)amino]methyl]phenyl]sulfonyl]-(2S)-1H-indole-2-carboxamide
474 mg (1.1 mmol) of the compound obtained according to preparation XI are dissolved in 7.5 ml of dichloromethane and 300 μl of triethylamine and 185 μl of trifluoroacetic anhydride are added. The reaction mixture is agitated for 15 hours at ambient temperature, and then hydrolysed on 5 ml of water. The organic phase is separated, dried on magnesium sulfate and concentrated under reduced pressure. The raw product is purified by silica gel chromatography eluting with a dichloromethane/ethyl acetate mixture (85/15; v/v). In this way the expected compound is obtained in the form of a white solid (yield=80%).
Melting point=70° C.
NMR 1H (DMSO, 300 MHz): δ: 10.00 (s, 1H); 8.18 (t, 1H); 7.75 (s, 1H); 7.63 (dt, 1H); 7.47-7.57 (m, 2H); 7.43 (d, 1H); 7.15-7.28 (m, 6H); 7.09 (dd, 1H); 7.01 (td, 1H), 4.76 (dd, 1H); 4.41 (s, 2H); 3.33 (m, 2H); 2.98 (dd, 1H); 2.84 (dd, 1H); 2.72 (t, 2H).
Example 57
N-[2-(dimethylamino)-2-phenylethyl]-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-(2S)-1H-indole-2-carboxamide
A solution of 100 mg (0.278 mmol) of the acid obtained according to preparation IV is prepared in 4 ml of dichloromethane and 59 mg (0.306 mmol) of EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-chloride) and 2.8 mg (0.028 mmol) of HOAT are added. After 10 minutes under agitation at ambient temperature, 51 mg (0.31 mmol) of 2-(dimethylamino)-2-phenylethanamine dissolved in 1 ml of dichloromethane are added. The reaction medium is then agitated at ambient temperature for 20 hours. The medium is then treated by addition of 20 ml of water and then extracted 3 times with 50 ml of dichloromethane. The organic phases are then regrouped and washed 3 times with 50 ml of water, then dried on magnesium sulfate and concentrated under reduced pressure. The raw product obtained is then purified by silica gel chromatography eluting with the help of a dichloromethane/ethanol mixture (95/5; v/v). In this way the expected product is obtained in the form of a white foam (yield=55%).
NMR 1H (DMSO, 250 MHz) δ: 7.9-7.75 (m, NH); 7.68 (d, 2H); 7.54 (d, 2H); 7.42 (dd, 1H); 7.40-7.15 (m, 6H); 7.15-6.95 (m, 2H); 4.76 (dd, 1H); 3.75-3.25 (m, 3H); 3.05-2.85 (m, 1H); 2.85-2.55 (m, 1H); 2.10 (s, 3H); 2.09 (s, 3H); 1.25 (s, 9H).
Preparation XII
N,N-dimethyl-4-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]benzeneacetamide
A solution is prepared of 1.2 g (4.06 mmol) of 4-[2-(Boc-amino)ethoxy]benzeneacetic acid in 4 ml of dichloromethane and then 932 mg (4.87 mmol) of EDCI and 55 mg (0.406 mmol) of HOAT are added. After 10 minutes under agitation at ambient temperature, 400 mg (4.87 mmol) of dimethylamine hydrochloride are added. The reaction medium is then agitated at ambient temperature for 24 hours. The medium is then treated by the addition of 20 ml of water and then extracted 3 times with 50 ml of dichloromethane. The organic phases are then regrouped and washed 3 times with 50 ml of water, then dried on magnesium sulfate, and concentrated under reduced pressure. The raw product obtained is then purified by silica gel chromatography eluting with the help of a dichloromethane/ethanol mixture (95/5; v/v). In this way the expected product is obtained in the form of a colorless oil (yield=46%).
NMR 1H (DMSO, 300 MHz) δ: 7.11 (d, 2H); 7.05-6.9 (m, NH); 6.85 (d, 2H); 3.92 (t, 2H); 3.59 (s, 2H); 3.35-3.20 (m, 2H); 2.97 (s, 3H); 2.81 (s, 3H); 1.38 (s, 9H).
Preparation XIII
4-(2-aminoethoxy)-N,N-dimethyl-benzeneacetamide
200 mg (0.62 mmol) of the product obtained according to preparation XII are dissolved in 5 ml of dichloromethane, 940 μl of trifluoroacetic acid are added. Agitation takes place for 1 hour at ambient temperature. The dichloromethane and the trifluoroacetic acid are evaporated, the product is recovered in water, and the aqueous phase obtained is washed with the help of dichloromethane. The aqueous phase is given an alkaline pH through the addition of a saturated solution of sodium bicarbonate. Extraction is performed with dichloromethane, the organic phase is washed with a minimum of water, and then dried on sodium sulfate and concentrated under reduced pressure. The expected product is obtained in the form of a pale yellow solid with a yield of 20%.
NMR 1H (DMSO, 250 MHz) δ: 7.11 (d, 2H); 6.85 (d, 2H); 3.88 (t, 2H); 3.59 (s, 2H); 2.97 (s, 3H); 2.85 (t, 2H); 2.81 (s, 3H).
Example 58
N-[2-[4-[2-(dimethylamino)-2-oxoethyl]phenoxy]ethyl]-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-(2S)-1H-indole-2-carboxamide
Working in a manner similar to example 57, starting with the acid obtained according to preparation IV and the product obtained according to preparation XIII, the expected compound is obtained in the form of a colorless oil (yield=48%).
NMR 1H (DMSO, 250 MHz) δ: 8.37 (t, NH); 7.72 (d, 2H); 7.54 (d, 2H); 7.45 (d, 1H); 7.21 (t, 1H); 7.2-7.1 (m, 3H); 7.00 (t, 1H); 6.88 (d, 2H); 4.80 (dd, 1H); 4.00 (t, 2H); 3.60 (s, 2H); 3.6-3.35 (m, 2H); 3.11 (dd, 1H); 2.98 (s, 3H); 2.91 (dd, 1H); 2.81 (s, 3H); 1.25 (s, 9H).
Preparation XIV
4-methoxy-2,3-dihydro-1H-indole-2-carboxylic acid, methyl ester
119 mg (4.90 mmol) of magnesium chips are added to a solution of 500 mg (2.44 mmol) of 4-methoxy-1H-indole-2-carboxylic acid in 10 ml of methanol. The mixture is agitated for 3 hours in a bath at 10° C. and then for 1 hour at ambient temperature. 20 ml of hydrochloric acid are added at 0° C. and agitation takes place for one hour. Then a solution of ammonia 3N is added until a pH of 10 is reached and extraction takes place 3 times by 50 ml of ethyl acetate. The organic phases are dried on magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/ethyl acetate mixture (98/2 then 95-5; v/v). The expected product is obtained in the form of a brown oil with a yield of 64%.
NMR 1H (DMSO, 250 MHz) δ: 6.91 (t, 1H); 6.24-6.20 (m, 2H); 5.97 (d, 1H); 4.41-4.34 (m; 1H); 3.70 (s, 3H); 3.65 (s, 3H); 3.17 (dd, 1H); 3.01 (dd, 1H).
Preparation XV
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-4-methoxy-2,3-dihydro-1H-indole-2-carboxylic acid, methyl ester
Working in a manner similar to example 43, starting with the product obtained according to preparation XIV and with 4-(1,1-dimethylethyl)benzenesulfonyl chloride, the expected compound is obtained in the form of a brown solid (yield=79%).
NMR 1H (DMSO, 300 MHz) δ: 7.77 (d, 2H); 7.58 (d, 2H); 7.20 (t, 1H); 7.01 (d, 1H); 6.67 (d, 1H); 5.02 (dd, 1H); 3.72 (s; 6H); 3.26 (dd, 1H); 2.92 (dd, 1H); 1.27 (s, 9H).
Preparation XVI
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-4-methoxy-2,3-dihydro-1H-indole-2-carboxylic acid
Working in a manner similar to preparation II, starting with the product obtained according to preparation XV, the expected compound is obtained in the form of a black solid (yield=89%).
NMR 1H (DMSO, 250 MHz) δ: 13.10 (s wide, 1H); 7.76 (d, 2H); 7.57 (d, 2H); 7.19 (t, 1H); 6.99 (d, 1H); 6.66 (d, 1H); 4.99 (dd, 1H); 3.72 (s; 3H); 3.24 (dd, 1H); 2.87 (dd, 1H); 1.25 (s, 9H).
Example 59
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-4-methoxy-N-(2-phenyl ethyl)-2,3-dihydro-1H-)indole-2-carboxamide
Working in a manner similar to preparation V, starting with the product obtained according to preparation XVI and benzeneethanamine, the expected compound is obtained in the form of a white solid (yield=72%).
Melting point=188-192° C.
NMR 1H (DMSO, 250 MHz) δ: 8.15 (t, 1H); 7.70 (d, 2H); 7.56 (d, 2H); 7.28-7.16 (m, 6H); 7.08 (d, 1H); 6.68 (d, 1H); 4.72 (dd, 1H); 3.72 (s; 3H); 3.35-3.29 (m, 2H); 2.92 (dd, 1H); 2.76-2.65 (m, 3H); 1.25 (s, 9H).
Preparation XVII
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-5-fluoro-2,3-dihydro-1H-indole-2-carboxylic acid, methyl ester
Working in a manner similar to preparation XV, starting with 2,3-dihydro-5-fluoro-1H-indole-2-carboxylic acid methyl ester, the expected compound is obtained in the form of a pink solid (yield=72%).
NMR 1H (DMSO, 300 MHz) δ: 7.74 (d, 2H); 7.58 (d, 2H); 7.40-7.35 (m, 1H); 7.07-7.02 (m, 2H); 5.05 (dd, 1H); 3.72 (s; 3H); 3.26 (dd, 1H); 3.06 (dd, 1H); 1.26 (s, 9H).
Preparation XVIII
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-5-fluoro-2,3-dihydro-1H-indole-2-carboxylic acid
Working in a manner similar to preparation II, starting with the product obtained according to preparation XVII, the expected compound is obtained in the form of a red solid (yield=84%).
NMR 1H (DMSO, 250 MHz) δ: 13.10 (s wide, 1H); 7.74 (d, 2H); 7.56 (d, 2H); 7.38-7.33 (m, 1H); 7.07-7.00 (m, 2H); 4.91 (dd, 1H); 3.28 (dd, 1H); 3.02 (dd, 1H); 1.25 (s, 9H).
Example 60
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-5-fluoro-N-(2-phenylethyl)-2,3-dihydro-1H-indole-2-carboxamide
Working in a manner similar to preparation V, starting with the product obtained according to preparation XVIII and benzeneethanamine, the expected compound is obtained in the form of a yellow solid (yield=75
Melting point=168-172° C.
NMR 1H (DMSO, 300 MHz) δ: 8.19 (t, 1H); 7.66 (d, 2H); 7.56 (d, 2H); 7.47-7.43 (m, 1H); 7.26-6.98 (m, 7H); 4.72 (dd, 1H); 3.37-3.27 (m, 2H); 2.93 (dd, 1H); 2.82 (dd, 1H); 2.72 (t, 2H); 1.25 (s, 9H).
Preparation XIX
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-(2S)-1H-indole-2-carbonyl chloride
14.11 g (111 mmol) of oxalyl chloride are added drop by drop to a solution of 20 g (55.6 mmol) of the acid obtained according to preparation IV in 150 ml of toluene, followed by agitation at ambient temperature. The solvent is evaporated and the product is then recovered in 100 ml of toluene and the solvent is once again eliminated under reduced pressure. The expected product is obtained in the form of a beige solid with a yield of 95%.
Melting point=148° C.
Example 61
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]-N,N-dimethyl-benzenethaneaminium, trifluoroacetate
A solution of 132 mg (1.27 mmol) N,N-dimethyl-4-(2-aminoethoxy) benzeneethanamine, bis trifluoroacetate is prepared in 10 ml of dichloromethane, 200 mg (0.529 mmol) of the product obtained according to preparation XIX are added and 402 mg (3.96 mmol) of triethylamine. Agitation takes place for 16 hours at ambient temperature. Water is added to the reaction medium, then extraction takes place with dichloromethane. The organic phase is dried on magnesium sulfate and the solvents are evaporated. The raw product is purified firstly by silica gel chromatography eluting with the help of a toluene/ethanol/ammonia mixture (8/2/0.1; v/v/v), and then secondly by inverse phase chromatography eluting with the help of an acetonitrile/water/trifluoroacetic acid mixture. The expected product is obtained in the form of a colorless oil with a yield of 26%.
NMR 1H (DMSO, 250 MHz) δ: 9.32 (sl, NH); 8.35 (t, NH); 7.71 (dd, 2H); 7.55 (dd, 2H); 7.45 (d, 1H); 7.30-7.15 (m, 3H); 7.11 (d, 1H); 7.01 (t, 1H); 6.92 (d, 2H); 4.79 (dd, 1H); 3.99 (dd, 2H); 3.6-3.4 (m, 2H); 3.3-3.2 (m, 2H); 3.2-3.0 (m, 1H); 3.0-2.75 (m, 3H); 2.83 (s, 3H); 2.81 (s, 3H); 1.25 (s, 9H).
Preparation XX
4-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-3-fluoro benzoic acid, methyl ester
227 mg (1.32 mmol) of 3-fluoro-4-hydroxybenzoic acid methyl ester, 278 mg (1.72 mmol) of (2-hydroxyethyl)carbamic acid 1,1-dimethyl ester, and 452 mg (2.12 mmol) of triphenylphosphine are mixed in 10 ml of anhydrous toluene. Cooling takes place to −10° C. and then 349 mg (1.72 mmol) of diisopropyl-azodicarboxylate (DIAD) are slowly added. Agitation takes place at −10° C. for 15 minutes and then for 16 hours at ambient temperature. The solvents are evaporated and then the evaporation residue is purified by silica column chromatography eluting with the help of a toluene/ethyl acetate mixture (100/0 for 30 minutes then 80/20; v/v). The expected product is obtained in the form of a white solid with a yield of 93%.
NMR 1H (DMSO, 250 MHz) δ: 7.78-7.66 (m, 2H); 7.30 (t, 1H); 7.02 (t, 1H); 4.14 (t, 2H); 3.82 (s, 3H); 3.32 (q, 2H); 1.37 (s, 9H).
Preparation XXI
4-(2-aminoethoxy)-3-fluorobenzoic acid, methyl ester
387 mg (1.235 mmol) of the product obtained according to preparation XX are dissolved in 2 ml of dichloromethane and then 1 ml of trifluoroacetic acid are added and agitation takes place for 16 hours at ambient temperature. The solvents are evaporated, ethyl acetate is added and the organic phase is washed with a solution of sodium carbonate at 10%. The organic phase is then dried on magnesium sulfate, filtered and concentrated under reduced pressure. The expected product is obtained in the form of a white solid with a yield of 89%.
NMR 1H (DMSO, 300 MHz) δ: 7.78 (d, 1H); 7.70 (d, 1H); 7.29 (t, 1H); 4.09 (t, 2H); 3.82 (s, 3H); 2.91 (t, 2H); NH2 not visible
Example 62
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]-3-fluorobenzoic acid, methyl ester
230 mg (1.079 mmol) of the product obtained according to preparation XXI are dissolved in 10 ml of anhydrous dichloromethane and then, under argon, 408 mg (1.079 mmol) of 1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-(2S)-1H-indole-2-carbonyl chloride and 180.5 μl (1.29 mmol) of triethylamine are added. Agitation takes place for 16 hours at ambient temperature. The dichloromethane is evaporated under reduced pressure, the evaporation residue is recovered in solution in ethyl acetate and the organic phase is washed in water. The organic phase is dried on magnesium sulfate, filtered and evaporated. The evaporation residue is purified by silica column chromatography eluting with the help of a toluene/isopropanol mixture (95/5; v/v). The expected product is obtained in the form of a white solid, with a yield of 46%.
NMR 1H (DMSO, 250 MHz) δ: 8.42 (t, 1H); 7.80-7.67 (m, 4H); 7.54 (d, 2H); 7.44 (d, 1H); 7.32 (t, 1H); 7.20 (t, 1H); 7.10 (d, 1H); 6.99 (t, 1H); 4.78 (dd, 1H); 4.21 (t, 2H); 3.82 (s, 3H); 3.60-3.48 (m, 2H); 3.11 (dd, 1H); 2.90 (dd, 1H); 1.24 (s, 9H).
Example 63
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]-3-fluorobenzoic acid
Working in a manner similar to preparation II, starting with the product obtained according to example 62, the expected compound is obtained in the form of a white solid (yield=79%).
NMR 1H (DMSO, 300 MHz) δ: 12.95 (s wide, 1H); 8.43 (t, 1H); 7.76-7.64 (m, 4H); 7.56 (d, 2H); 7.44 (d, 1H); 7.29 (t, 1H); 7.21 (t, 1H); 7.10 (d, 1H); 6.99 (t, 1H); 4.78 (dd, 1H); 4.20 (t, 2H); 3.60-3.47 (m, 2H); 3.11 (dd, 1H); 2.90 (dd, 1H); 1.26 (s, 9H).
Preparation XXII
4-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-3-fluoro benzeneacetic acid, methyl ester
Working in a manner similar to preparation XX, starting with 3-fluoro-4-hydroxybenzeneacetic acid methyl ester, the expected compound is obtained in the form of a white solid (yield=92%).
NMR 1H (DMSO, 300 MHz) δ: 7.18-6.98 (m, 4H); 4.01 (t, 2H); 3.62 (s, 2H); 3.60 (s, 3H); 3.29 (q, 2H); 1.37 (s, 9H).
Preparation XXIII
4-(2-aminoethoxy)-3-fluorobenzeneacetic acid, methyl ester
Working in a manner similar to preparation XXI, starting with the product obtained according to preparation XXII, the expected compound is obtained in the form of a colorless oil (yield=91%).
NMR 1H (DMSO, 300 MHz) δ: 7.16-6.99 (m, 3H); 4.35 (s wide, 2H); 4.03 (t, 2H); 3.63 (s, 2H); 3.61 (s, 3H); 2.99 (t, 2H).
Example 64
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]-3-fluoro-benzeneacetic acid, methyl ester
Working in a manner similar to example 62, starting with the product obtained according to preparation XXIII, the expected compound is obtained in the form of a beige paste (yield=61%).
NMR 1H (DMSO, 300 MHz) δ: 8.40 (t, 1H); 7.71 (d, 2H); 7.55 (d, 2H); 7.44 (d, 1H); 7.21 (t, 1H); 7.16-6.98 (m, 5H); 4.81 (dd; 1H); 4.08 (t, 2H); 3.63 (s, 2H); 3.61 (s, 3H); 3.58-3.44 (m, 2H); 3.11 (dd, 1H); 2.90 (dd, 1H); 1.25 (s, 9H).
Example 65
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]-3-fluoro-benzeneacetic acid
Working in a manner similar to preparation II, starting with the product obtained according to example 64, the expected compound is obtained in the form of a white solid (yield=34%).
NMR 1H (DMSO, 300 MHz) δ: 12.40 (s wide, 1H); 8.40 (t, 1H); 7.71 (d, 2H); 7.55 (d, 2H); 7.44 (d, 1H); 7.21 (t, 1H); 7.16-6.98 (m, 5H); 4.79 (dd; 1H); 4.08 (t, 2H); 3.63-3.40 (m, 4H); 3.11 (dd, 1H); 2.90 (dd, 1H); 1.25 (s, 9H).
Example 66
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-N-[(3-hydroxyphenyl)methyl]-2,3-dihydro-(2S)-1H-indole-2-carboxamide
54 mg (0.53 mmol) of triethylamine are added to a suspension of 42.26 mg (0.265 mmol) of 3-(aminomethyl)phenol hydrochloride in 8 ml of dichloromethane at ambient temperature, then a solution of 100 mg (0.265 mmol) of 1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-(2S)-1H-indole-2-carbonyl chloride in 2 ml of dichloromethane is added over 10 minutes. This is left to agitate at ambient temperature for 1 hour. The reaction medium is washed with water, dried on magnesium sulfate, the solvents are evaporated and the evaporation residue is purified by silica column chromatography eluting with the help of a toluene/ethyl acetate mixture (8/2; v/v). The expected product is obtained in the form of a white solid with a yield of 51%.
Melting point=94° C.
Example 67
1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-N-[(4-chlorophenyl)methyl]-2,3-dihydro-(2S)-1H-indole-2-carboxamide
Working in a manner similar to example 66, starting with 4-chloro-benzenemethanamine hydrochloride, the expected compound is obtained in the form of a white solid (yield=98%).
Melting point=69° C.
Example 68
4-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]benzoic acid, methyl ester
Working in a manner similar to example 66, starting with the 4-(aminomethyl)benzoic acid methyl ester hydrochloride, the expected compound is obtained in the form of a white solid (yield=80%).
Melting point=190° C.
Example 69
4-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]benzoic acid
Working in a manner similar to preparation II, starting with the product obtained according to example 68, the expected compound is obtained in the form of a white solid (quantitative yield).
Melting point=105-120° C.
Example 70
4-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]benzenepropanoic acid, methyl ester
Working in a manner similar to example 66, starting with the (4-aminomethyl)benzenepropanoic acid methyl ester hydrochloride, the expected compound is obtained in the form of a white solid (yield=89%).
Melting point=56° C.
Example 71
4-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]benzenepropanoic acid
Working in a manner similar to preparation II, starting with the product obtained according to example 70, the expected compound is obtained in the form of a white solid (yield=97%).
Melting point=80-85° C.
Example 72
4-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]benzeneacetic acid, methyl ester
Working in a manner similar to example 67, starting with the (4-aminomethyl)benzeneacetic acid methyl ester hydrochloride, the expected compound is obtained in the form of a colorless oil (yield=89%).
NMR 1H (DMSO, 300 MHz) δ: 8.69 (t, NH); 7.72 (d, 2H); 7.56 (d, 2H); 7.46 (d, 1H); 7.3-7.15 (m, 5H); 7.13 (d, 1H); 7.01 (t, 1H); 4.81 (dd, 1H); 4.4-4.2 (m, 2H); 3.65 (s, 2H); 3.60 (s, 3H); 3.13 (dd, 1H); 2.94 (dd, 1H); 1.25 (s, 9H).
Example 73
4-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]benzeneacetic acid
Working in a manner similar to preparation II, starting with the product obtained according to example 72, the expected compound is obtained in the form of a white solid (yield=94%).
Melting point=80-85° C.
Preparation XXXIV
(2S)-1-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid, methyl ester
Working in a manner similar to preparation I, starting with the (2S)-2,3-dihydro-1H-indole-2-carboxylic acid methyl ester hydrochloride and the 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl-sulfonyl chloride, the expected compound is obtained in the form of a yellow oil (yield=93%).
NMR 1H (DMSO, 300 MHz) δ: 7.62 (d, 1H); 7.46 (dd, 1H); 7.36 (d, 1H); 7.25-7.13 (m, 2H); 6.99 (t, 1H); 6.78 (d, 1H); 4.99 (dd, 1H); 3.71 (s, 3H); 3.33 (dd, 1H); 3.04 (dd, 1H); 2.83-2.66 (m, 2H); 1.75 (t, 2H); 1.25 (d, 6H).
Preparation XXXV
(2S)-1-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid
Working in a manner similar to preparation II, starting with the product obtained according to preparation XXXIV, the expected compound is obtained in the form of a white solid (yield=91%).
NMR 1H (DMSO, 300 MHz) δ: 13.05 (s wide, 1H); 7.62 (s, 1H); 7.46 (dd, 1H); 7.34 (d, 1H); 7.23-7.13 (m, 2H); 7.00 (t, 1H); 6.78 (d, 1H); 4.85 (dd, 1H); 3.31 (dd, 1H); 3.00 (dd, 1H); 2.83-2.66 (m, 2H); 1.75 (t, 2H); 1.25 (d, 6H).
Example 74
4-[2-[[[(2S)-1-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzoic acid, methyl ester
Working in a manner similar to preparation V, starting with the acid obtained according to preparation XXXV and the 4-(2-aminoethoxy)benzoic acid methyl ester, the expected compound is obtained in the form of a white solid (yield=82%).
NMR 1H (DMSO, 300 MHz) δ: 8.34 (t, 1H); 7.89 (d, 2H); 7.55 (d, 1H); 7.45-7.36 (m, 2H); 7.20 (t, 1H); 7.11-6.95 (m, 4H); 6.76 (d, 1H); 4.75 (dd, 1H); 4.11 (t, 2H); 3.81 (s, 3H); 3.60-3.34 (m, 2H); 3.06 (dd, 1H); 2.88 (dd, 1H); 2.90-2.63 (m, 2H); 1.74 (t, 2H); 1.25 (d, 6H).
Example 75
4-[2-[[[(2S)-1-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzoic acid
Working in a manner similar to preparation II, starting with the product obtained according to example 74, the expected compound is obtained in the form of a white solid (yield=32%).
NMR 1H (DMSO, 300 MHz) δ: 12.57 (s wide, 1H); 8.34 (t, 1H); 7.87 (d, 2H); 7.55 (d, 1H); 7.45-7.36 (m, 2H); 7.21 (t, 1H); 7.22 (d, 1H); 7.03-6.98 (m, 3H); 6.75 (d, 1H); 4.75 (dd, 1H); 4.10 (t, 2H); 3.60-3.34 (m, 2H); 3.03 (dd, 1H); 2.89 (dd, 1H); 2.84-2.58 (m, 2H); 1.74 (t, 2H); 1.25 (d, 6H).
Preparation XXXVI
3-[3-(aminomethyl)phenoxy]propanoic acid, methyl ester hydrochloride
0.8 g (3.9 mmol) of the 3-(3-cyanophenoxy)propanoic acid methyl ester hydrochloride are dissolved in 20 ml of methanol. 0.4 ml of hydrochloric acid 10 N are added then, under an inert atmosphere, 100 mg of palladium on carbon. The mixture is agitated under a hydrogen atmosphere at ambient temperature and atmospheric pressure. The catalyst is eliminated by filtration, then the filtrate is concentrated under reduced pressure. The residue is recovered using toluene and evaporation is performed again. The product is recrystallised in a methanol/ethyl ether mixture (10/50; v/v), and dried under a vacuum. The expected product is obtained in the form of a white solid with a yield of 84%.
Melting point=134° C.
Example 76
3-[3-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]phenoxy]propanoic acid, methyl ester
Working in a manner similar to example 66, starting with the product obtained according to preparation XXXVI, the expected compound is obtained in the form of a white solid (yield=97%).
Melting point=103° C.
Example 77
3-[3-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]phenoxy]propanoic acid
Working in a manner similar to preparation II, starting with the product obtained according to example 76, the expected compound is obtained in the form of a white foam (yield=33%).
Melting point=122° C.
NMR 1H (DMSO, 250 MHz) δ: 8.69 (t, NH); 7.72 (d, 2H); 7.55 (d, 2H); 7.46 (d, 1H); 7.3-7.1 (m, 3H); 7.02 (t, 1H); 6.9-6.7 (m, 3H); 4.82 (dd, 1H); 4.4-4.2 (m, 2H); 4.12 (t, 2H); 3.13 (dd, 1H); 2.93 (dd, 1H); 2.56 (t, 2H); 1.25 (s, 9H).
Preparation XXXVII
(2S)-2,3-dihydro-1-[[4-(1-methylethoxy)phenyl]sulfonyl]-1H-indol-2-carboxylic acid, methyl ester
Working in a manner similar to preparation I, starting with the (2S)-2,3-dihydro-1H-indole-2-carboxylic acid methyl ester and the [4-(1-methylethoxy)phenyl]sulfonyl chloride, the expected compound is obtained in the form of a white solid (yield=76%).
NMR 1H (DMSO, 300 MHz) δ: 7.73 (d, 2H); 7.36 (d, 1H); 7.22-7.13 (m, 2H); 7.05-6.97 (m, 3H); 4.99 (dd, 1H); 4.69 (hep, 1H); 3.72 (s, 3H); 3.32 (dd, 1H); 3.04 (dd, 1H); 1.24 (d, 6H).
Preparation XXXVIII
(2S)-2,3-dihydro-1-[[4-(1-methylethoxy)phenyl]sulfonyl]-1H-indol-2-carboxylic acid
Working in a manner similar to preparation II, starting with the product obtained according to preparation XXXVII, the expected compound is obtained in the form of a white solid (yield=98%).
NMR 1H (DMSO, 300 MHz) δ: 13.11 (s wide, 1H); 7.72 (d, 2H); 7.35 (d, 1H); 7.22-7.12 (m, 2H); 7.02-6.95 (m, 3H); 4.84 (dd, 1H); 4.68 (hep, 1H); 3.31 (dd, 1H); 3.01 (dd, 1H); 1.24 (d, 6H).
Example 78
4-[2-[[[(2S)-2,3-dihydro-1-[[4-[(1-methylethoxy)phenyl]sulfonyl]-1H-indol-2-yl]carbonyl]amino]ethoxy]benzeneacetic acid
50 mg (0.139 mmol) of acid obtained according to preparation XXXVIII are mixed with 1 ml of dichloromethane. Agitation is performed at 0° C. and 42 μl of triethylamine and 22 μl (0.3 mmol) of thionyl chloride are added. Agitation is performed for 30 minutes at 0° C. The temperature of the reaction medium is allowed to rise to ambient temperature and the solvents are evaporated. A suspension of 30 mg 4-(2-aminoethoxy)benzeneacetic acid in 43 μl of triethylamine and 2 ml of dichloromethane is added to the evaporation residue, and then agitation is performed overnight at ambient temperature. The reaction medium is recovered in 10 ml of dichloromethane, and washing is performed with water. The organic phase is dried on sodium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/methanol mixture (95/5; v/v). The expected product is obtained in the form of a white solid with a yield of 21%.
NMR 1H (DMSO, 250 MHz) δ: 12.25 (s wide, 1H); 8.33 (t, 1H); 7.66 (d, 2H); 7.44 (d, 1H); 7.23-6.86 (m, 9H); 4.79-4.63 (m, 2H); 3.99 (t, 2H); 3.55-3.35 (m, 4H); 3.07 (dd, 1H); 2.90 (dd, 1H); 1.24 (d, 6H)
Preparation XXXIX
7-[[(phenylmethoxy)carbonyl]amino]-1H-indole-2-carboxylic acid, ethyl ester
0.8 g (3.925 mmol) of 7-amino-1H-indole-2-carboxylic acid ethyl ester are mixed with 16 ml of tetrahydrofurane and 1.08 g (7.83 mmol) of potassium carbonate. The reaction medium is cooled to 0° C. and 0.615 ml (4.30 mmol) of benzyl chloroformate are added. Agitation is performed for 1 hour 30 minutes at 0° C., and then the temperature of the mixture is allowed to rise again to ambient temperature over one hour. Then 30 ml of water are added and the product is extracted using ethyl acetate. The combined organic phases are dried on magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a methylcyclohexane/ethyl acetate mixture (90/1; v/v). The expected product is obtained in the form of white crystals with a yield of 61%.
NMR 1H (DMSO, 250 MHz) δ: 11.67 (s wide, 1H); 9.68 (s wide, 1H); 7.82 (d, 1H); 7.49-7.34 (m, 6H); 7.16 (s, 1H); 7.05 (t, 1H); 5.21 (s, 2H); 4.35 (q, 2H); 1.34 (t, 3H).
Preparation XL
7-[[(phenylmethoxy)carbonyl]amino]-2,3-dihydro-1H-indole-2-carboxylic acid, methyl ester
Working in a manner similar to preparation XIV, starting with the product obtained according to preparation XXXIX, the expected compound is obtained in the form of a brown solid (yield=59%).
NMR 1H (DMSO, 250 MHz) δ: 9.07 (s wide, 1H); 7.47-7.31 (m, 5H); 7.28 (d, 1H); 6.81 (d, 1H); 6.59 (t, 1H); 5.78 (d, 1H); 5.14 (s, 2H); 4.48-4.41 (m, 1H); 3.67 (s, 3H); 3.32 (dd, 1H); 3.14 (dd, 1H).
Preparation XLI
1-[[4-(dimethylethyl)phenyl]sulfonyl]-7-[[(phenylmethoxy) carbonyl]amino]-2,3-dihydro-1H-indole-2-carboxylic acid, methyl ester
Working in a manner similar to preparation I, starting with the product obtained according to preparation XL, the expected compound is obtained in the form of a yellow paste (yield=71%).
NMR 1H (DMSO, 250 MHz) δ: 8.86 (s, 1H); 7.76 (d, 1H); 7.79-7.32 (m, 9H); 7.16 (t, 1H); 6.86 (d, 1H); 5.20-5.15 (m, 3H); 3.64 (s, 3H); 2.86 (d, 1H); 2.36 (dd, 1H); 1.24 (s, 9H).
Preparation XLII
1-[[4-(dimethylethyl)phenyl]sulfonyl]-7-[[(phenylmethoxy)carbonyl]amino]-2,3-dihydro-1H-indole-2-carboxylic acid
Working in a manner similar to preparation II, starting with the product obtained according to preparation XLI, the expected compound is obtained in the form of a white solid (yield=84%).
NMR 1H (DMSO, 250 MHz) δ: 13.13 (s wide, 1H); 8.92 (s, 1H); 7.77 (d, 1H); 7.72-7.35 (m, 9H); 7.15 (t, 1H); 6.85 (d, 1H); 5.20 (s, 2H); 5.03 (dd, 1H); 2.83 (d, 1H); 2.28 (dd, 1H); 1.24 (s, 9H).
Preparation XLIII
1-[[4-(dimethylethyl)phenyl]sulfonyl]-N-(2-phenylethyl)-7-[[(phenyl methoxy)carbonyl]amino]-2,3-dihydro-1H-indole-2-carboxamide
Working in a manner similar to example 57, starting with the product obtained according to preparation XLII, the expected compound is obtained in the form of a white solid (yield=67%).
NMR 1H (DMSO, 250 MHz) δ: 9.57 (s, 1H); 8.87 (t, 1H); 7.63 (d, 1H); 7.50-7.31 (m, 9H); 7.16 (t, 1H); 7.09-7.06 (m, 3H); 6.97-6.94 (m, 2H); 6.79 (d, 1H); 5.22 (s, 2H); 4.68 (d, 1H); 3.32-3.20 (m, 2H); 2.77 (d, 1H); 2.62 (t, 2H); 2.06 (dd, 1H); 1.25 (s, 9H)
Example 79
7-amino-1-[[4-(dimethylethyl)phenyl]sulfonyl]-N-(2-phenylethyl)-2,3-dihydro-1H-indole-2-carboxamide
30 mg (0.049 mmol) of the product obtained according to preparation XLIII are mixed with 3 ml of methanol. Under a protective atmosphere, 3 mg of palladium on carbon are added and the reaction mixture is agitated under a hydrogen atmosphere at ambient temperature and atmospheric pressure for 5 hours. The reaction medium is filtered, the catalyst is washed with methanol and filtrates are concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a methylcyclohexane/ethyl acetate mixture (75/25; v/v). The expected product is obtained in the form of a white solid with a yield of 83%.
NMR 1H (DMSO, 300 MHz) δ: 8.12 (t, 1H); 7.55-7.49 (m, 4H); 7.22-7.03 (m, 5H); 6.84 (t, 1H); 6.59 (d, 1H); 6.22 (d, 1H); 5.49 (s, 2H); 4.67 (d, 1H); 3.31-3.24 (m, 2H); 2.73-2.63 (m, 3H); 2.07 (dd, 1H); 1.25 (s, 9H).
Example 80
4-[2-[[[(2S)-1-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzeneacetic acid
Working in a manner similar to example 78, starting with the acid obtained according to preparation XXXV and 4-(2-aminoethoxy)benzeneacetic acid, the expected compound is obtained in the form of a yellow solid (yield=74%).
NMR 1H (DMSO, 250 MHz) δ: 12.23 (s wide, 1H); 8.30 (t, 1H); 7.55 (s, 1H); 7.45-7.36 (m, 2H); 7.22-7.09 (m, 4H); 7.00 (t, 1H); 6.87 (m, 2H); 6.76 (d, 1H); 4.76 (dd, 1H); 3.99 (t, 2H); 3.52-3.41 (m, 4H); 3.07-2.62 (m, 4H); 1.75 (t, 2H); 1.25 (d, 6H).
Preparation XLIV
4-[(2-aminoethyl)thio]-3-chloro-benzene acetic acid methyl ester hydrochloride
50 mg (0.144 mmol) of 3-chloro-4-[2-[[(1,1-dimethylethoxy)carbonyl]-amino]-ethylthio]benzeneacetic acid methyl ester are dissolved in 322 μl of trifluoroacetic acid. Agitation is performed for 2 hours at ambient temperature. The trifluoroacetic acid is eliminated by coevaporation with methylcyclohexane. The evaporation residue is dissolved in ethyl acetate and neutralisation takes place by addition of a solution of sodium carbonate at 10%. The organic phase is dried on magnesium sulfate, filtration takes place and concentration under reduced pressure. The expected product is obtained in the form of an orange oil with a quantitative yield.
NMR 1H (DMSO, 250 MHz) δ: 8.24 (s wide, 3H); 7.49-7.43 (m, 2H); 7.27 (d, 1H); 3.71 (s, 2H); 3.62 (s, 3H); 3.32-3.21 (m, 2H); 3.00 (t, 2H).
Example 81
3-chloro-4-[[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethyl]thio]benzeneacetic acid, methyl ester
53.6 mg (0,142 mmol) of the product obtained according to preparation XLIV are dissolved in 4 ml of anhydrous dichloromethane, and then 109 mg (3.42 mmol) of resin-based morpholine and 40 mg (0.142 mmol) of [4-(1,1-dimethylethyl)phenyl]sulfonyl chloride are added, agitation takes place for 4 days at ambient temperature. The resin is filtered, the filtrate is concentrated under reduced pressure and the expected product is obtained in the form of a grey solid with a yield of 95%.
NMR 1H (DMSO, 250 MHz) δ: 8.46 (t, 1H); 7.71 (d, 2H); 7.55 (d, 2H); 7.49-7.46 (m, 2H); 7.38 (s, 1H); 7.26-7.20 (m, 2H); 7.12 (d, 1H); 7.01 (t, 1H); 4.73 (dd, 1H); 3.68 (s, 2H); 3.61 (s, 3H); 3.42-3.02 (m, 5H); 2.94 (dd, 1H); 1.25 (s, 9H).
Example 82
3-chloro-4-[[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl) sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethyl]thio]benzeneacetic acid
Working in a manner similar to preparation II, starting with the product obtained according to example 81, the expected compound is obtained in the form of a white solid (yield=60%).
NMR 1H (DMSO, 300 MHz) δ: 12.40 (s wide, 1H); 8.46 (t, 1H); 7.71 (d, 2H); 7.55 (d, 2H); 7.48-7.45 (m, 2H); 7.37 (s, 1H); 7.26-7.20 (m, 2H); 7.12 (d, 1H); 7.01 (t, 1H); 4.73 (dd, 1H); 3.56 (s, 2H); 3.42-3.02 (m, 5H); 2.94 (dd, 1H); 1.25 (s, 9H).
Preparation XLV
3-(4-cyanophenoxy)propanoic acid, methyl ester
A solution of 3.80 g (19.9 mmol) of 3-(4-cyanophenoxy)propanoic acid in 10 ml of methanol is cooled by an ice bath. 3 ml (40 mmol) of thionyl chloride are added drop by drop and then the reaction medium is agitated with solvent reflux for 2 hours. The reaction mixture is then concentrated under reduced pressure and the evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/methanol mixture (99/1; v/v). The expected product is obtained in the form of a white solid with a yield of 79%.
Melting point=51° C.
Preparation XLVI
3-[4-(aminomethyl)phenoxy]propanoic acid, methyl ester (hydrochloride)
Working in a manner similar to preparation XXXVI, starting with the product obtained according to preparation XLV, the expected compound is obtained in the form of a white solid (yield=60%).
Melting point=217° C.
Example 83
3-[4-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]phenoxy]propanoic acid, methyl ester
Working in a manner similar to example 66, starting with the product obtained according to preparation XLVI, the expected compound is obtained in the form of a white solid (yield=83%).
Melting point=50-52° C.
Example 84
3-[4-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]phenoxy]propanoic acid
Working in a manner similar to preparation II, starting with the product obtained according to example 83, the expected compound is obtained in the form of a white solid (yield=41%).
Melting point=75° C.
Example 85
(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[(4-nitrophenyl)methyl]-1H-indole-2-carboxamide
Working in a manner similar to example 66, starting with 4-(aminomethyl)-nitrobenzene, the expected compound is obtained in the form of a white solid (yield=68%).
Melting point=75-80° C.
Example 86
(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-N-[(4-aminophenyl)methyl]-1H-indole-2-carboxamide
Working in a manner similar to preparation XXXVI, starting with the product obtained according to example 85, the expected compound is obtained in the form of a white solid (yield=82%).
Melting point=83-87° C.
Example 87
N-[4-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]phenyl]glycine, methyl ester
400 mg (0.864 mmol) of the product obtained according to example 86, 264 mg (1.728 mmol) of methyl bromoacetate and 120 mg (0.864 mmol) of potassium carbonate in 8 ml of acetone are mixed in a test tube under microwaves. The mixture is heated to 130° C. for one hour with the help of microwaves. The reaction medium is filtered, then the filtrate is concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a toluene/ethyl acetate mixture (95/5 then 90/10; v/v). The expected product is obtained in the form of a white solid with a yield of 31%.
Melting point=70° C.
Example 88
N-[4-[[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]methyl]phenyl]glycine
Working in a manner similar to preparation II, starting with the product obtained according to example 87, the expected compound is obtained in the form of a yellowish solid (yield=24%).
Melting point=110° C.
Preparation XLVII
2,3-dihydro-2-[[[2-[4-(2-methoxy-2-oxoethyl)phenoxy]ethyl]amino]carbonyl]-(2S)-1H-indole-1-carboxylic acid, 1,1-dimethyl ethyl ester
Working in a manner similar to preparation XII, starting with 1-[(1,1-dimethylethoxy)carbonyl]-2,3-dihydro-(2S)-1H-indole-2-carboxylic acid, the expected compound is obtained in the form of a white foam (yield=48
Preparation XLVIII
4-[2-[[[(2S)-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzeneacetic acid, methyl ester
Working in a manner similar to preparation XXI, starting with the product obtained according to preparation XLVII, the expected compound is obtained in the form of a beige solid (yield=89%).
NMR 1H (DMSO, 250 MHz) δ: 8.03 (t, NH); 7.16 (dd, 2H); 7.05-6.80 (m, 4H); 6.65-6.5 (m, 2H); 5.93 (d, NH); 4.22 (ddd, 1H); 3.99 (t, 2H); 3.59 and 3.58 (2s, 5H); 3.55-3.4 (m, 2H); 3.31 (dd, 1H); 2.90 (dd, 1H).
Example 89
4-[2-[[[(2S)-1-[[4-(4-fluorophenoxy)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzeneacetic acid, methyl ester
0.2 g (0.564 mmol) of the product obtained according to preparation XLVIII are dissolved in 4 ml of dichloromethane. 0.086 g (0.846 mmol) of triethylamine and 0.178 g (0.621 mmol) of (4-fluorophenoxy)benzene-sulfonyl chloride are added, and agitation takes place for 20 hours at ambient temperature. The dichloromethane is evaporated, and the evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/ethyl acetate mixture (9/1; v/v). The expected product is obtained in the form of a colorless oil with a yield of 76%.
NMR 1H (DMSO, 300 MHz) δ: 8.36 (t, NH); 7.77 (d, 2H); 7.43 (d, 1H); 7.35-7.1 (m, 8H); 7.1-6.95 (m, 3H); 6.88 (d, 2H); 4.79 (dd, 1H); 4.00 (t, 2H); 3.60 (s, 5H); 3.65-3.35 (m, 2H); 3.12 (dd, 1H); 2.92 (dd, 1H).
Example 90
4-[2-[[[(2S)-1-[[4-(4-fluorophenoxy)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzeneacetic acid
Working in a manner similar to preparation II, starting with the product obtained according to example 89, the expected product is obtained in the form of a white solid with a yield of 65%.
Melting point=65° C.
Preparation IL
(2S)-2,3-dihydro-1-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]indole-2-carboxylic acid
1 g (6.13 mmol) of 2,3-dihydro-(2S)-1H-indole-2-carboxylic acid, and 0.97 g (7.05 mmol) of potassium carbonate are solubilised in 2 ml of water. 1.6 g (6.13 mmol) of 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-sulfonyl chloride solubilised in 12 ml of acetonitrile and 2 ml of water are added. Agitation is allowed to take place for 5 hours at ambient temperature. Water is added to the reaction medium, washing is performed with ethyl acetate, the acidity of the aqueous phase is raised to pH 3 by a solution of hydrochloric acid 1 N, and then extraction is performed using ethyl acetate. The organic phases are collected, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/methanol (9/1; v/v) mixture. The expected product is obtained in the form of a beige foam with a yield of 73%.
NMR 1H (DMSO, 300 MHz) δ: 7.59 (s, 1H); 7.44 (m, 1H); 7.31 (m, 1H); 7.20-7.05 (m, 2H); 6.96 (t, 1H); 6.75 (d, 1H); 7.74 (s wide, 1H); 3.1-2.85 (m, 2H); 2.85-2.60 (m, 2H); 1.73 (t, 2H); 1.25 (m, 6H).
Example 91
(βS)-β-[[[(2S)-1-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]benzene butanoic acid 1,1-dimethyl ethyl ester
Working in a manner similar to example 87, starting with the product obtained according to preparation IL and (βS)-β-amino-benzenebutanoic acid t-butyl ester, the expected product is obtained in the form of a white foam with a yield of 15%.
NMR 1H (DMSO, 300 MHz) δ: 8.02 (d, 1H); 7.51-7.46 (m, 2H); 7.34 (dd, 1H); 7.25 (t, 1H); 7.16-7.01 (m, 7H); 6.76, (d, 1H); 4.63 (dd, 1H); 4.25 (hex, 1H); 2.94 (dd, 1H); 2.75-2.65 (m, 5H); 2.46-2.30 (m, 2H); 1.75 (t, 2H); 1.39 (s, 9H); 1.26 (m, 6H).
Example 92
(βS)-β-[[[(2S)-1-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]benzene butanoic acid
Working in a manner similar to preparation XIII, starting with the product obtained according to example 91, the expected product is obtained in the form of a white foam with a yield of 34%.
NMR 1H (DMSO, 300 MHz) δ: 12.30 (s wide, 1H); 8.04 (d, 1H); 7.52 (d, 1H); 7.46 (d, 1H); 7.34 (dd, 1H); 7.24 (t, 1H); 7.18-7.01 (m, 7H); 6.76 (d, 1H); 4.65 (dd, 1H); 4.25 (hex, 1H); 2.96 (dd, 1H); 2.81-2.63 (m, 5H); 2.54-2.30 (m, 2H); 1.75 (t, 2H); 1.26 (m, 6H).
Preparation L
(2S)-2,3-dihydro-1-[[4-(phenylmethoxy)phenyl]sulfonyl]indole-2-carboxylic acid, methyl ester
Working in a manner similar to preparation IL, starting with the 4-(phenylmethoxy)benzenesulfonyl chloride and 2,3-dihydro-(2S)-1H-indole-2-carboxylic acid methyl ester, the expected product is obtained in the form of a white powder with a yield of 81%.
NMR 1H (DMSO, 300 MHz) δ: 7.73 (d, 2H); 7.55 (d, 1H); 7.37-7.33 (m, 5H); 7.20 (t, 1H); 7.07-6.95 (m, 4H); 5.06 (s, 2H); 4.78 (dd, 1H); 3.79 (s, 3H); 3.25-3.05 (m, 2H).
Preparation LI
(2S)-2,3-dihydro-1-[(4-hydroxyphenyl)sulfonyl]indole-2-carboxylic acid, methyl ester
Working in a manner similar to preparation XLIII, starting with the compound obtained according to preparation L, the expected product is obtained in the form of a beige solid with a yield of 98%.
NMR 1H (DMSO, 300 MHz) δ: 10.67 (s wide, 1H); 7.66-7.61 (m, 2H); 7.36-7.33 (m, 1H); 7.22-7.12 (m, 2H); 7.02-6.96 (m, 1H); 6.85-6.81 (m, 2H); 4.97-4.90 (m, 1H); 3.72 (s, 3H); 3.5-3.20 (m, 1H); 3.05-2.95 (m, 1H).
Preparation LII
(2S)-2,3-dihydro-1-[[4-(1,1-dimethylethoxy)phenyl]sulfonyl]indole-2-carboxylic acid methyl ester
A solution is prepared of 2.4 g (7.2 mmol) of ester obtained according to preparation LI in 140 ml of toluene with heating and 9.6 ml (40 mmol) of N,N-dimethylformamide di-t-butylacetal are slowly added. The reaction mixture is maintained under agitation at 100° C. for 2 hours, then concentrated under reduced pressure. The oily residue is purified by silica gel chromatography eluting with the help of a cyclohexane/ethyl acetate mixture (85/15; v/v). In this way the expected product is obtained in the form of a grey powder with a yield of 38%.
NMR 1H (CDCL3, 300 MHz) δ: 7.72 (d, 2H); 7.55 (d, 1H); 7.22 (t, 1H); 7.12-6.95 (m, 4H); 4.81 (dd, 1H); 3.80 (s, 3H) 3.25-3.07 (m, 2H); 1.27 (s, 9H).
Preparation LIII
(2S)-2,3-dihydro-1-[[4-(1,1-dimethylethoxy)phenyl]sulfonyl]indole-2-carboxylic acid
Working in a manner similar to preparation II, starting with the compound obtained according to preparation LII, the expected product is obtained in the form of a white solid with a yield of 91%.
NMR 1H (CDCL3, 300 MHz) δ: 7.65-7.58 (m, 3H); 7.26-7.20 (m, 1H); 7.06-6.95 (m, 4H); 4.77 (dd, 1H); 3.27-3.06 (m, 2H); 1.39 (s, 9H).
Preparation LIV
(2S)-2,3-dihydro-1-[[4-(1,1-dimethylethoxy)phenyl]sulfonyl]indole-2-carbonyl chloride
Working in a manner similar to preparation XIX, starting with the compound obtained according to preparation LIII, the expected product is obtained with a yield of 98% in the form of a yellow solid that is quickly reacted for the synthesis of example 93.
Example 93
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethoxy)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzeneacetic acid, methyl ester
Working in a manner similar to example 61, starting with the compound obtained according to preparation LIV and 4-(2-aminoethoxy)benzeneacetic acid methyl ester, the expected product is obtained in the form of a light yellow solid with a yield of 50%.
NMR 1H (DMSO, 300 MHz) δ: 7.71 (d, 1H); 7.46 (d, 2H); 7.40 (t, 1H); 7.26-7.01 (m, 5H); 7.87 (d, 2H); 7.80 (d, 2H); 4.61 (dd, 1H); 4.01 (m, 2H); 3.80-3.60 (m, 5H); 3.56 (s, 2H); 3.24 (dd, 1H); 2.73 (dd, 1H); 1.36 (s, 9H).
Melting point=45-48° C.
Example 94
4-[2-[[[(2S)-1-[[4-(1,1-dimethylethoxy)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzeneacetic acid
Working in a manner similar to preparation II, starting with the compound obtained according to example 93, the expected product is obtained in the form of a white solid with a yield of 68%.
Melting point=68-71° C.
NMR 1H (DMSO, 300 MHz) δ: 12.5 (s wide, 1H); 8.37 (t, 1H); 7.66 (d, 2H); 7.44 (d, 1H); 7.24-6.99 (m, 7H); 6.88 (d, 2H); 4.78 (dd, 1H); 3.99 (dd, 2H); 3.60-3.40 (m, 4H); 3.09-2.85 (m, 2H); 1.34 (s, 9H).
Example 95
Sodium 4-[2-[[[(2S)-1-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2,3-dihydro-1H-indol-2-yl]carbonyl]amino]ethoxy]benzeneacetate
960.65 mg (1.791 mmol) of the product obtained in example 55 are dissolved in 1 ml of acetonitrile, and then 3.58 ml (1.791 mmol) of a solution of soda at 0.5 N are added and agitation takes place for 30 minutes at ambient temperature. The reaction medium is lyophilised, the lyophilisate is recrystallised in isopropanol and the desired product is obtained in the form of a white solid with a quantitative yield.
NMR 1H (DMSO, 250 MHz) δ: 8.42 (t, 1H); 7.72 (d, 2H); 7.55 (d, 2H); 7.44 (d, 2H); 7.21 (t, 1H); 7.14-7.10 (m, 3H); 6.99 (t, 1H); 6.80 (d, 1H); 4.81 (dd, 1H); 3.97 (t, 2H); 3.63-3.35 (m, 2H); 3.20 (s, 2H); 3.11 (dd, 1H); 2.90 (dd, 1H); 1.25 (s, 9H).
Biological Activity
Test for Transactivation of GAL4-LXR Chimeras Following Transitory Transfection in COS7 Cells
The transactivation tests are based on the capability of the nuclear receptors:
(1) to bond with a specific DNA sequence (RE=Response Element) situated in front of a promoter, via their DNA binding domain (or DBD), and
(2) to increase the transcription of a gene under the control of this promoter in the presence of an agonist ligand, via their ligand binding domain (or LBD).
The test for transactivation in COS7 cells developed here aims to evaluate the effect of compounds on the activity of the human LXRs: it allows a validation of the interaction of the compounds with the LXRs and determination of the EC50 of the interaction. This test is based on the use of Gal4-LXR chimera proteins containing the LBD of the LXR (human LXRα or human LXRβ) merged with the DBD of Gal4. The COS7 cells are thus co-transfected in a transitory manner with:
an expression vector coding for the Gal4(DBD)-LXRα(LBD) chimera protein or an expression vector coding for the Gal4(DBD)-LXRβ(LBD) chimera
a reporter vector comprising the Gal4-response element recognising the DBD of the Gal4, and situated in front of the minimal promoter PTK that controls the luciferase gene.
The activity of the luciferase produced in this way generates luminescence in the presence of an excess of substrate, a data item that reflects the interaction of the compound with the LBD of the LXR. The compounds of the invention are evaluated in relation to a reference compound (T-0901317, CAS RN: 293754-55-9). According to this test the compounds according to the invention have an EC 50 of less than 1 μM.
The biological properties of the compounds according to the invention demonstrate their potential interest and their utility for their application as active substances in medicinal products intended for the treatment or the prevention of diseases resulting from irregularities in the LXR α and LXR β receptor functions, in particular hypercholesterolemia, dyslipidemia, as well as obesity, diabetes, cardiovascular diseases, certain neurodegenerative diseases and inflammatory diseases. The compounds according to the invention are also of therapeutic interest when it is necessary to correct the parameters indicative of a metabolic syndrome.
Depending on the pathologies to be treated, the compounds of the invention can be used alone or in combination with known treatments for diabetes such as metformine, sulfonylurates, acarbose, PPARγ activators insulin or also in combination with similar compounds of GLP-1 (glucagon-like peptides), DPP-IV, PPARα/γ, PPARδ/γ, PPARδ and panPPAR inhibitors, 11β-HSD1 (11 beta hydroxysteroid dehydrogenase) inhibitors, PTP-1B (protein tyrosin phosphatase) inhibitors, CB1 (cannabinoide) receptor antagonists, glucagon receptor antagonists, PDK (pyruvate dehydrogenase kinase) inhibitors, hepatic glucokinase activators and GSK-3 (glycogen synthase kinase) inhibitors.
The invention also relates to pharmaceutical compositions intended for the treatment or inhibition of the abovementioned diseases when these contain as the active substance at least one of the compounds of formula I according to the invention. These pharmaceutical compositions use conventional formulations comprising pharmaceutically acceptable excipients in order to obtain forms that can preferably be administered orally, such as tablets or gelatine capsules.
In practice, where the compound is administered orally, the daily dosage in humans will preferably be between 5 and 500 mg.
Ex
(H)
R1
R2
A
B
Ar
1
Q
C(CH3)3
H
(CH2)2
—
2
I
C(CH3)3
H
(CH2)2
—O—
3
I
C(CH3)3
H
(CH2)2
—
4
I
C(CH3)3
H
(CH2)2
—
5
I
C(CH3)3
H
(CH2)2
—
6
I
C(CH3)3
H
—CH2—CH(CH3)—
—
7
I
C(CH3)3
H
(CH2)2
—
8
I
C(CH3)3
H
(CH2)2
—
9
I
C(CH3)3
H
(CH2)2
—
10
I
C(CH3)3
H
—
11
I
C(CH3)3
H
—
12
I
C(CH3)3
H
—
13
I
C(CH3)3
H
(CH2)2
—
14
I
C(CH3)3
H
(CH2)2
—
15
I
C(CH3)3
H
(CH2)2
—
16
I
C(CH3)3
H
(CH2)2
—
17
I
C(CH3)3
H
(CH2)3
—
18
I
C(CH3)3
H
(CH2)4
—
19
I
C(CH3)3
H
—CH2—
—
20
I
C(CH3)3
H
(CH2)2
—
21
I
C(CH3)3
H
(CH2)2
—
22
I
C(CH3)3
H
—CH2—
—CO—
23
I
C(CH3)3
H
(CH2)2
—
24
I
C(CH3)3
H
(CH2)2
—
25
I
C(CH3)3
H
(CH2)2
—
26
I
C(CH3)3
H
(CH2)2
—
27
I
C(CH3)3
H
(CH2)2
—
28
I
C(CH3)3
H
—CH2—
—
29
I
C(CH3)3
H
(CH2)2
—
30
I
C(CH3)3
H
—
—
31
I
C(CH3)3
H
(CH2)2
—
32
I
C(CH3)3
H
(CH2)2
—
33
I
C(CH3)3
H
(CH2)2
—
34
I
C(CH3)3
H
(CH2)2
—
35
I
C(CH3)3
H
(CH2)2
—
36
I
C(CH3)3
H
(CH2)2
—
37
I
C(CH3)3
H
(CH2)2
—
38
I
C(CH3)3
H
(CH2)2
—
39
I
C(CH3)3
H
(CH2)2
—
40
I
C(CH3)3
H
(CH2)2
—
41
I
C(CH3)3
H
(CH2)2
—
42
I
C(CH3)3
H
(CH2)2
—
43
I
CH(CH3)2
H
(CH2)2
—
44
I
4-Cl
3-Cl
(CH2)2
—
45
I
H
(CH2)2
—
46
I
H
(CH2)2
—
47#
I
(CH2)2
—
48#
I
(CH2)2
—
49
I
—O—CH(CH3)2
H
(CH2)2
—
50
I
—C(CH3)3
H
(CH2)2
—
51
HI
—C(CH3)3
H
(CH2)2
—
52
I
—C(CH3)3
H
(CH2)2
—O—
53
I
—C(CH3)3
H
(CH2)2
—O—
54
I
—C(CH3)3
H
(CH2)2
—O—
55
I
—C(CH3)3
H
(CH2)2
—O—
56
I
H
3-FAM*
(CH2)2
—
57
I
—C(CH3)3
H
—
58
I
—C(CH3)3
H
(CH2)2
—O—
59**
4-OMe—I
—C(CH3)3
H
(CH2)2
—
60**
5-F—I
—C(CH3)3
H
(CH2)2
—
61
I
—C(CH3)3
H
(CH2)2
—O—
62
I
—C(CH3)3
H
(CH2)2
—O—
63
I
—C(CH3)3
H
(CH2)2
—O—
64
I
—C(CH3)3
H
(CH2)2
—O—
65
I
—C(CH3)3
H
(CH2)2
—O—
66
I
—C(CH3)3
H
CH2
—
67
I
—C(CH3)3
H
CH2
—
68
I
—C(CH3)3
H
CH2
—
69
I
—C(CH3)3
H
CH2
—
70
I
—C(CH3)3
H
CH2
—
71
I
—C(CH3)3
H
CH2
—
72
I
—C(CH3)3
H
CH2
—
73
I
—C(CH3)3
H
CH2
—
74#
I
(CH2)2
—O—
75#
I
(CH2)2
—O—
76
I
—C(CH3)3
H
CH2
—
77
I
—C(CH3)3
H
CH2
—
78
I
—O—CH(CH3)2
H
(CH2)2
—O—
79**
7-NH2—I
—C(CH3)3
H
(CH2)2
—
80#
I
(CH2)2
—O—
81
I
—C(CH3)3
(CH2)2
—S—
82
I
—C(CH3)3
H
(CH2)2
—S—
83
I
—C(CH3)3
H
CH2
—
84
I
—C(CH3)3
H
CH2
—
85
I
—C(CH3)3
H
CH2
—
86
I
—C(CH3)3
H
CH2
—
87
I
—C(CH3)3
H
CH2
—
88
I
—C(CH3)3
H
CH2
—
89
I
H
(CH2)2
—O—
90
I
H
(CH2)2
—O—
91#
I
—
92#
I
—
93
I
—O—C(CH3)3
H
(CH2)2
—O—
94
I
—O—C(CH3)3
H
(CH2)2
—O—
95
I
—C(CH3)3
H
(CH2)2
—O—
Me=CH3
Q=1,2,3,4-tetrahydroquinoline
I=indoline (4-OMe-I=4-methoxy-indolin)
HI=octahydroindole
*3-FAM=3-(trifluoroacetylaminomethyl)
**: racemic compound
#: in this example the formula R1 and R2 represents the unit
The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.
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11593474
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laboratories fournier s.a.
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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514/317
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Mar 31st, 2022 02:21PM
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Mar 31st, 2022 02:21PM
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AbbVie
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:abbv
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AbbVie
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Jan 1st, 2013 12:00AM
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Mar 21st, 2007 12:00AM
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https://www.uspto.gov?id=US08343540-20130101
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Process for producing fenofibrate tablets
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The invention provides processes using suspensions to produce fenofibrate compositions. The resulting fenofibrate compositions can be made in the form of a capsule.
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8343540
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1. A process for producing a capsule comprising fenofibrate, wherein the process comprises:
(i) preparing an aqueous suspension comprising at least one hydrophilic polymer and fenofibrate particles in micronized form having a particle size of less than 20 μm, wherein one hydrophilic polymer is a polyvinylpyrrolidone with a molecular weight between 20,000 and 100,000;
(ii) spraying the suspension onto inert carriers to form granulates; and
(iii) enclosing the granulates inside the capsule.
2. The process of claim 1, wherein step (i) of preparing the suspension comprises (a) preparing a solution comprising at least one hydrophilic polymer and (b) adding the fenofibrate to the solution to produce the suspension.
3. The process of claim 1, wherein step (i) of preparing the suspension comprises (a) preparing a solution comprising at least one hydrophilic polymer by dissolving the hydrophilic polymer and (b) adding the fenofibrate to the solution to produce the suspension.
4. The process of claim 1, wherein step (i) of preparing the suspension comprises (a) adding the fenofibrate to a solution to form the suspension, and (b) dissolving at least one hydrophilic polymer in the suspension.
5. The process of claim 1, wherein the suspension further comprises at least one surfactant.
6. The process of claim 1, wherein the suspension comprises fenofibrate and hydrophilic polymer in a weight ratio of fenofibrate/hydrophilic polymer between 1/10 and 4/1.
7. The process of claim 1, wherein the suspension comprises fenofibrate and hydrophilic polymer in a weight ratio of fenofibrate/hydrophilic polymer between 1/2 and 2/1.
8. The process of claim 1, wherein the fenofibrate has a particle size less than 10 μm.
9. The process of claim 1, wherein the suspension comprises fenofibrate in an amount from 1 to 40% by weight.
10. The process of claim 9, wherein the suspension comprises fenofibrate in an amount from 10 to 25% by weight.
11. The process of claim 1, wherein the suspension comprises the hydrophilic polymer in an amount from 5 to 40% by weight.
12. The process of claim 11, wherein the suspension comprises the hydrophilic polymer in an amount from 10 to 25% by weight.
13. The process of claim 1, wherein the at least one hydrophilic polymer further comprises; a poly(vinyl alcohol), a hydroxypropylcellulose, a hydroxy-methylcellulose, a hydroxypropylmethylcellulose, a gelatin, or a mixture of two or more thereof.
14. The process of claim 5, wherein the suspension comprises the surfactant in an amount of up to 10% by weight.
15. The process of claim 14, wherein the suspension comprises the surfactant in an amount of up to 5% by weight.
16. The process of claim 5, wherein the suspension comprises surfactant and hydrophilic polymer in a weight ratio of surfactant/hydrophilic polymer between 1/500 and 1/10.
17. The process of claim 5, wherein the suspension comprises surfactant and hydrophilic polymer in a weight ratio of surfactant/hydrophilic polymer between 1/100 and 5/100.
18. The process of claim 5, wherein the surfactant is sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, or a mixture of two or more thereof.
19. The process of claim 18, wherein the surfactant is sodium lauryl sulfate.
20. The process of claim 1, wherein the inert carriers are inert hydrosoluble carriers.
21. The process of claim 1, which further comprises, between steps (ii) an (iii), mixing the granulates with at least one pharmaceutical excipient.
22. The process of claim 21, wherein the pharmaceutical excipient is selected from the group consisting of at least one binder, at least one filler, at least one pigment, at least one disintegrating agent, at least one lubricant, at least one wetting agent, at least one buffer, and a mixture of two or more thereof.
23. The process of claim 21, wherein the pharmaceutical excipient is selected from the group consisting of microcrystalline cellulose, lactose, starch, colloidal silica, talc, glycerol esters, sodium stearyl fumarate, titanium dioxide, magnesium stearate, stearic acid, cross-linked polyvinyl pyrrolidone, carboxymethyl starch, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, and a mixture of two or more thereof.
24. The process of claim 1, wherein the capsule comprises from 5 to 50% by weight fenofibrate, from 10 to 75% by weight carrier, and from 20 to 60% by weight hydrophilic polymer.
25. The process of claim 1, wherein the capsule comprises from 20 to 45% by weight fenofibrate, from 20 to 50% by weight carrier, and from 25 to 45% by weight hydrophilic polymer.
26. The process of claim 24, wherein the capsule further comprises up to 10% by weight surfactant.
27. The process of claim 26, wherein the capsule comprises from 0.1 to 3% by weight surfactant.
28. A process for producing a capsule comprising fenofibrate, wherein the process comprises:
(i) preparing an aqueous suspension comprising at least one surfactant, at least one hydrophilic polymer, and fenofibrate particles in micronized form having a particle size of less than 20 μm, wherein one hydrophilic polymer is a poly vinylpyrrolidone with a molecular weight between 20,000 and 100,000;
(ii) spraying the aqueous suspension onto inert carriers to form granulates; and
(iii) enclosing the granulates inside a capsule.
29. The process of claim 28, wherein step (i) of preparing the aqueous suspension comprises (a) preparing an aqueous solution comprising at least one surfactant and at least one hydrophilic polymer and (b) adding the fenofibrate to the aqueous solution to produce the aqueous suspension.
30. The process of claim 28, wherein step (i) of preparing the aqueous suspension comprises (a) preparing an aqueous solution comprising at least one surfactant and at least one hydrophilic polymer by dissolving said surfactant and hydrophilic polymer and (b) adding the fenofibrate to the aqueous solution to produce the aqueous suspension.
31. The process of claim 28, wherein step (i) of preparing the aqueous suspension comprises (a) dissolving at least one surfactant in an aqueous solution, (b) dissolving at least one hydrophilic polymer in an aqueous solution, and (c) adding the fenofibrate to the aqueous solution to produce the aqueous suspension.
32. The process of claim 28, wherein step (i) of preparing an aqueous suspension comprises (a) dissolving at least one hydrophilic polymer in an aqueous solution, (b) dissolving at least one surfactant in an aqueous solution, and (c) adding the micronized fenofibrate to the aqueous solution to form the aqueous suspension.
33. The process of claim 28, wherein step (i) of preparing the aqueous suspension comprises (a) dissolving at least one surfactant in an aqueous solution, (b) adding the fenofibrate to the aqueous solution to form the aqueous suspension, and (c) dissolving at least one hydrophilic polymer in the aqueous suspension.
34. The process of claim 28, wherein step (i) of preparing the aqueous suspension comprises (a) dissolving at least one hydrophilic polymer in an aqueous solution, (b) adding the fenofibrate to the aqueous solution to form the aqueous suspension, and (c) dissolving at least one surfactant in the aqueous suspension.
35. The process of claim 28, wherein the suspension comprises fenofibrate and hydrophilic polymer in a weight ratio of fenofibrate/hydrophilic polymer between 1/10 and 4/1.
36. The process of claim 28, wherein the suspension comprises fenofibrate and hydrophilic polymer in a weight ratio of fenofibrate/hydrophilic polymer between 1/2 and 2/1.
37. The process of claim 28, wherein the fenofibrate has a particle size less than 10 μm.
38. The process of claim 28, wherein the suspension comprises fenofibrate in an amount from 1 to 40% by weight.
39. The process of claim 38, wherein the suspension comprises fenofibrate in an amount from 10 to 25% by weight.
40. The process of claim 28, wherein the suspension comprises the hydrophilic polymer in an amount from 5 to 40% by weight.
41. The process of claim 40, wherein the suspension comprises the hydrophilic polymer in an amount from 10 to 25% by weight.
42. The process of claim 28, wherein the at least one hydrophilic polymer further comprises; a poly(vinyl alcohol), a hydroxypropylcellulose, a hydroxy-methylcellulose, a hydroxypropylmethylcellulose, a gelatin, or a mixture of two or more thereof.
43. The process of claim 28, wherein the suspension comprises the surfactant in an amount of up to 10% by weight.
44. The process of claim 43, wherein the suspension comprises the surfactant in an amount of up to 5% by weight.
45. The process of claim 28, wherein the suspension comprises surfactant and hydrophilic polymer in a weight ratio of surfactant/hydrophilic polymer between 1/500 and 1/10.
46. The process of claim 28, wherein the suspension comprises surfactant and hydrophilic polymer in a weight ratio of surfactant/hydrophilic polymer between 1/100 and 5/100.
47. The process of claim 28, wherein the surfactant is sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, or a mixture of two or more thereof.
48. The process of claim 47, wherein the surfactant is sodium lauryl sulfate.
49. The process of claim 28, wherein the inert carriers are inert hydrosoluble carriers.
50. The process of claim 28, which further comprises, between steps (ii) and (iii), mixing the granulates with at least one pharmaceutical excipient.
51. The process of claim 50, wherein the pharmaceutical excipient is selected from the group consisting of at least one binder, at least one filler, at least one pigment, at least one disintegrating agent, at least one lubricant, at least one wetting agent, at least one buffer, and a mixture of two or more thereof.
52. The process of claim 50, wherein the pharmaceutical excipient is selected from the group consisting of microcrystalline cellulose, lactose, starch, colloidal silica, talc, glycerol esters, sodium stearyl fumarate, titanium dioxide, magnesium stearate, stearic acid, cross-linked polyvinyl pyrrolidone, carboxymethyl starch, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, and a mixture of two or more thereof.
53. The process of claim 28, wherein the capsule comprises from 5 to 50% by weight of fenofibrate, from 10 to 75% by weight of carrier, from 20 to 60% by weight of hydrophilic polymer, and up to 10% by weight of surfactant.
54. The process of claim 53, wherein the capsule comprises from 20 to 45% by weight of fenofibrate, from 20 to 50% by weight of carrier, from 25 to 45% by weight of hydrophilic polymer, and from 0.1 to 3% by weight of surfactant.
55. A process for producing a capsule comprising fenofibrate, wherein the process comprises:
(i) preparing an aqueous suspension comprising at least one surfactant, at least one hydrophilic polymer, and fenofibrate particles in micronized form having a particle size of less than 20 μm, wherein one hydrophilic polymer is a polyvinylpyrrolidone with a molecular weight between 20,000 and 100,000; by (a) preparing an aqueous solution comprising at least one surfactant and at least one hydrophilic polymer by dissolving the surfactant and the hydrophilic polymer and (b) adding the fenofibrate particles to the solution to produce the aqueous suspension;
(ii) spraying the aqueous suspension onto inert carriers to form granulates and
(iii) enclosing the granulates inside a capsule.
56. The process of claim 55, wherein the suspension comprises fenofibrate and hydrophilic polymer in a weight ratio of fenofibrate/hydrophilic polymer between 1/10 and 4/1.
57. The process of claim 55, wherein the suspension comprises fenofibrate and hydrophilic polymer in a weight ratio of fenofibrate/hydrophilic polymer between 1/2 and 2/1.
58. The process of claim 55, wherein the fenofibrate has a particle size less than 10 μm.
59. The process of claim 55, wherein the suspension comprises fenofibrate in an amount from 1 to 40% by weight.
60. The process of claim 59, wherein the suspension comprises fenofibrate in an amount from 10 to 25% by weight.
61. The process of claim 55, wherein the suspension comprises the hydrophilic polymer in an amount from 5 to 40% by weight.
62. The process of claim 61, wherein the suspension comprises the hydrophilic polymer in an amount from 10 to 25% by weight.
63. The process of claim 55, wherein the at least one hydrophilic polymer further comprises; and a poly(vinyl alcohol), a hydroxypropylcellulose, a hydroxy-methylcellulose, a hydroxypropylmethylcellulose, a gelatin, or a mixture of two or more thereof.
64. The process of claim 55, wherein the suspension comprises the surfactant in an amount of up to 10% by weight.
65. The process of claim 64, wherein the suspension comprises the surfactant in an amount of up to 5% by weight.
66. The process of claim 55, wherein the suspension comprises surfactant and hydrophilic polymer in a weight ratio of surfactant/hydrophilic polymer between 1/500 and 1/10.
67. The process of claim 55, wherein the suspension comprises surfactant and hydrophilic polymer in a weight ratio of surfactant/hydrophilic polymer between 1/100 and 5/100.
68. The process of claim 55, wherein the surfactant is sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate, lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, or a mixture of two or more thereof.
69. The process of claim 68, wherein the surfactant is sodium lauryl sulfate.
70. The process of claim 55, wherein the inert carriers are inert hydrosoluble carriers.
71. The process of claim 55, which further comprises, between steps (ii) and (iii), mixing the granulates with at least one pharmaceutical excipient.
72. The process of claim 71, wherein said pharmaceutical excipient is selected from the group consisting of at least one binder, at least one filler, at least one pigment, at least one disintegrating agent, at least one lubricant, at least one wetting agent, at least one buffer, and a mixture of two or more thereof.
73. The process of claim 71, wherein said pharmaceutical excipient is selected from the group consisting of microcrystalline cellulose, lactose, starch, colloidal silica, talc, glycerol esters, sodium stearyl fumarate, titanium dioxide, magnesium stearate, stearic acid, cross-linked polyvinyl pyrrolidone, carboxymethyl starch, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, and a mixture of two or more thereof.
74. The process of claim 55, wherein the capsule comprises from 5 to 50% by weight of fenofibrate, from 10 to 75% by weight of carrier, from 20 to 60% by weight of hydrophilic polymer, and up to 10% by weight of surfactant.
75. The process of claim 55, wherein the capsule comprises from 20 to 45% by weight of fenofibrate, from 20 to 50% by weight of carrier, from 25 to 45% by weight of hydrophilic polymer, and from 0.1 to 3% by weight of surfactant.
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75
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RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 10/665,520 filed Sep. 22, 2003, which is a continuation of U.S. application Ser. No. 10/288,425 filed Nov. 6, 2002, issued as U.S. Pat. No. 6,652,881; which is a continuation of U.S. application Ser. No. 10/126,875 filed Apr. 22, 2002, issued as U.S. Pat. No. 6,589,552; which is a continuation of U.S. application Ser. No. 10/078,500 filed Feb. 21, 2002, issued as U.S. Pat. No. 6,596,317; which is a continuation of U.S. application Ser. No. 09/899,026 filed Jul. 6, 2001, issued as U.S. Pat. No. 7,037,529; which is a continuation of U.S. application Ser. No. 09/572,330 filed May 18, 2000, issued as U.S. Pat. No. 6,277,405; which is a continuation of U.S. application Ser. No. 09/005,128 filed Jan. 9, 1998, issued as U.S. Pat. No. 6,074,670; which claims priority to French Application No. 97 00 479 filed Jan. 17, 1997. This application is also a continuation of U.S. application Ser. No. 10/290,333 filed Nov. 8, 2002, issued as U.S. Pat. No. 7,041,319.
BACKGROUND OF THE INVENTION
The present invention relates to a novel pharmaceutical composition having high bioavailability through improved dissolution, and a method for preparing it. The invention more particularly relates to a pharmaceutical composition for administration by oral route, containing an active ingredient of poor aqueous solubility.
Numerous active ingredients suffer from the disadvantage of being poorly soluble in an aqueous medium, thus having an insufficient dissolution profile and, consequently, poor bioavailability within the organism, following oral administration. The therapeutic dose required to be administered must thus be increased in order to obviate this disadvantage. This particularly applies to numerous hypolipemiant active ingredients, such as those belonging to the fibrate family.
Fenofibrate is a well-known hypolipemiant from the family of fibrates, which is commercially available in various doses (100 and 300 mg for example Secalip®) but in a form leading to poor bioavailability of the active ingredient. Indeed, due to it poor hydrosolubility, fenofibrate is poorly absorbed in the digestive tract and consequently its bioavailability is incomplete, irregular and often varies from one person to another.
To improve the dissolution profile of fenofibrate and its bioavailability, thereby reducing the dose requiring to be administered, it would be useful to increase its dissolution so that it could attain a level close to 100%.
Moreover, for patient comfort, it is advantageous to seek a dosage form that only requires the medicament to be taken once daily while giving the same effect as one administered several times daily.
EP-A-0330532 discloses a method for improving bioavailability of fenofibrate. This patent describes the effect of co-micronizing fenofibrate with a surfactant, for example sodium laurylsulfate in order to improve fenofibrate solubility and thereby increase its bioavailability. This patent teaches that co-micronizing fenofibrate with a solid surfactant improves fenofibrate bioavailability to a much greater extent than the improvement that would be obtained either by adding a surfactant, or through solely micronizing the fenofibrate, or, yet again, through intimately mixing the fenofibrate and surfactant, micronized separately. The dissolution method employed is the conventional rotating blade technique (European Pharmacopoeia): product dissolution kinetics are measured in a fixed volume of the dissolution medium, agitated by means of a standardized device; a test was also carried out with an alternative technique to the European Pharmacopoeia, using the continuous-flow cell method.
The process of EP-A-0330532 leads to a new dosage form in which the active ingredient, co-micronized with a solid surfactant, has improved fenofibrate dissolution, and thus increased bioavailability, which makes it possible, for a given level of effectiveness, to decrease the daily dose of the medicament: respective 67 mg and 200 mg instead of 100 mg and 300 mg.
However, the preparation method in that patent is not completely satisfactory inasmuch as it does not lead to complete bioavailability of the active ingredient, and suffers from several disadvantages. The technique of co-micronizing fenofibrate with a solid surfactant does, it is true, improve dissolution of the active ingredient, but this dissolution remains, however, incomplete.
There is thus a need to improve fenofibrate bioavailability in order to attain, over very short periods of time, a level close to 100% (or, in any case, better than the following limits: 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes in a medium consisting of 1200 ml water to which 2% Polysorbate 80 is added, or of 1000 ml of water to which 0.025M sodium lauryl sulfate sodium is added, with a blade rotation speed of 75 rpm), and this even when dissolution media having a low surfactant content are used.
Applicant has found that, surprisingly, it is possible to resolve this problem by a new method for preparing a pharmaceutical composition by spraying a suspension of the active ingredient onto an inert hydrosoluble carrier. The present invention also relates to pharmaceutical compositions thus prepared.
The use is already known of a polymer, such as polyvinylpyrrolidone for producing tablets, in concentrations of the order of 0.5 to 5% by weight, at a maximum 10% by weight. In this case, the polyvinylpyrrolidone is used as a binder. Similarly, the use of a polymer such as hydroxymethylpropylmethyl cellulose as a granulation binder is known. Thus, European patent application 0,519,144 discloses pellets of a poorly soluble substance, omeprazole, obtained by spraying a dispersion or suspension of the active ingredient in a solution containing said polymer onto inert pellets in a fluidized-bed granulator. However, here again, the polymer (HPMC and HPC) is only used as a granulation binder, in an amount of about 50% by weight, based on the weight of the active ingredient, which, bearing in mind the presence of the inert pellets of a large size (about 700 μm) and the overall final weight leads to final active ingredient and polymer contents which are very low, of the order of barely a few percent based on the weight of the final covered pellet. Finally, it will be noted that the size of the inert pellets in this documents is fairly large, which, in the case of fenofibrate, would lead to a final formulation having a volume which is much too large for ready oral administration.
The use of polymer, such as polyvinylpyrrolidone for manufacturing “solid dispersions” is also known, obtained in general by co-precipitation, co-fusion or liquid-phase mixing followed by drying. What we have here is fixation of the active ingredient in isolated microparticles on the polyvinylpyrrolidone, which avoids problems of poor wetting of the solid and re-agglomeration of the particles. The article “Stable Solid Dispersion System Against Humidity” by Kuchiki et al., Yakuzaigaku, 44 No. 1, 31-37 (1984) describes such a technique for preparing solid dispersions using polyvinylpyrrolidone. The amounts of PVP here are very high, and the ratio between the active ingredient and PVP are comprised between 1/1 and 1/20. In the case however there is no inert carrier.
WO-A-96 01621 further discloses a sustained release composition, comprising an inert core (silica in all examples) coated with a layer which contains the active ingredient in admixture with a hydrophilic polymer, the weight ratio active ingredient/polymer being comprised between 10/1 and 1/2 and the weight ratio active ingredient/inert core being comprised between 5/1 and 1/2, with an outer layer to impart the sustained release property. These compositions can be compressed. The hydrophilic polymer can be polyvinylpyrrolidone. This document also discloses a process for preparing said composition; for example in a fluidized-bed granulator one will spray a dispersion of active ingredient in a polymer solution onto the inert cores. This document solely relates to sustained release compositions, the technical problem to be solved being the compression, without damages, of the outer layer imparting the sustained release property.
Nevertheless, nothing in the state of the art teaches nor suggest the present invention.
SUMMARY OF THE INVENTION
Thus, the present invention provides an immediate-release fenofibrate composition comprising:
(a) an inert hydrosoluble carrier covered with at least one layer containing a fenofibrate active ingredient in a micronized form having a size less than 20 μm, a hydrophilic polymer and, optionally, a surfactant; said hydrophilic polymer making up at least 20% by weight of (a); and
(b) optionally one or several outer phase(s) or layer(s).
In one embodiment, a surfactant is present with the active ingredient and the hydrophilic polymer.
The invention also provides a composition comprising fenofibrate having a dissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes, as measured using the rotating blade method at 75 rpm according to the European Pharmacopoeia, in a dissolution medium constituted by water with 2% by weight polysorbate 80 or in a dissolution medium constituted by water with 0.025M sodium lauryl sulfate.
A method for preparing a pharmaceutical composition is also provided, comprising the steps of:
(a) preparing a fenofibrate suspension in micronized form with a particle size below 20 μm, in a solution of hydrophilic polymer and, optionally surfactant;
(b) applying the suspension from step (a) to an inert hydrosoluble carrier;
(c) optionally, coating granules thus obtained with one or several phase(s) or layer(s).
Step (b) is preferably carried out in a fluidized-bed granulator.
The method can comprise a step in which products obtained from step (b) or (c) are compressed, with or without additional excipients.
The invention also provides a suspension of fenofibrate in micronized form having a size less than 10 μm, in a solution of hydrophilic polymer and, optionally, surfactant.
The invention will be described in more detail in the description which follows, with reference to the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of a comparative study of the dissolution profile of a composition according to the invention, compared to that of Lipanthyl® 200M;
FIG. 2 is a graph illustrating a comparative study of the dissolution profile of a composition according to the invention and that of pharmaceutical products commercially available on the German market.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The expression “in micronized form” in this invention means a substance in a particulate form, the dimensions of the particles being less than or equal to about 20 μm.
Advantageously, this dimension is less than or equal to 10 μm.
In the framework of this invention, the expression “inert hydrosoluble carrier” means any excipient, generally hydrophilic, pharmaceutically inert, crystalline or amorphous, in a particulate form, not leading to a chemical reaction under the operating conditions employed, and which is soluble in an aqueous medium, notably in a gastric acid medium. Examples of such excipients are derivatives of sugars, such as lactose, saccharose, hydrolyzed starch (malto-dextrine), etc. Mixture are also suitable. The individual particle size of the inert hydrosoluble carrier can be, for example, between 50 and 500 micron.
The expression “hydrophilic polymer” in the invention should be taken to mean any high molecular weight substance (greater, for example, than 300) having sufficient affinity towards water to dissolve therein and form a gel. Examples of such polymers are polyvinylpyrrolidone, poly(vinyl alcohol), hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, etc. Polymer blends are also suitable.
The preferred hydrophilic polymer is polyvinylpyrrolidone (PVP). The PVP used in this invention has, for example, a molecular weight comprised between 10,000 and 100,000, preferably for example between 20,000 and 55,000.
The term “surfactant” is used in its conventional sense in this invention. Any surfactant is suitable, whether it be amphoteric, non-ionic, cationic or anionic. Examples of such surfactants are: sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, Poloxamer®, etc. Mixtures of surfactants are also suitable.
The preferred surfactant is sodium laurylsulfate, which can be co-micronized with fenofibrate.
The compositions according to the invention can additionally contain any excipient conventionally used in the pharmaceutical and chemical fields which is compatible with the active ingredient, such as binders, fillers, pigments, disintegrating agents, lubricants, wetting agents, buffers, etc. As examples, excipients able to be used in this invention we can cite: microcrystalline cellulose, lactose, starch, colloidal silica, talc, glycerol esters, sodium stearyl fumarate, titanium dioxide, magnesium stearate, stearic acid, cross-linked polyvinyl pyrrolidone (AC DI SOL®), carboxymethyl starch (Explotab®, Primojel®), hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, etc.
Here, the expression “outer phase or layer” should be taken to mean any coating on the element (a) with the active ingredient (forming a “core”). Indeed, it can be useful to have available one or several phase(s) or layer(s) on top of the coated core. The invention thus covers a single core with one layer, but also several cores in a phase, as is the case of tablets which are formed from “cores” mixed with a phase.
This outer layer comprises conventional excipients.
It is also possible to provide a layer comprising additives, for the manufacture of tablets. In this embodiment, the outer layer comprises a disintegration agent and, for example, a lubricant; the thus covered and mixed granules can then be readily compressed and easily disintegrate in water.
The compositions according to the invention comprise, in general, based on the total composition weight excluding the outer phase or layer, an inert hydrosoluble carrier making up from 10 to 80% by weight, preferably 20 to 50% by weight, the fenofibrate representing from 5 to 50% by weight, preferably from 20 to 45% by weight, the hydrophilic polymer representing from 20 to 60% by weight, preferably 25 to 45% by weight, the surfactant making up from 0 to 10% by weight, preferably 0.1 to 3% by weight.
The outer layer or phase if present, can make up to 80% by weight of the total weight, preferably up to 50% by weight.
The hydrophilic polymer represents preferably more than 25% by weight, based on the weight of (a).
The weight ratio of fenofibrate/hydrophilic polymer can for example be comprised between 1/10 and 4/1, preferably, for example, between 1/2 and 2/1.
When a surfactant is employed, the weight ratio surfactant/hydrophilic polymer can be comprised for example between 1/500 and 1/10, preferably, for example, between 1/100 and 5/100.
In one embodiment, the composition according to the invention takes the form of tablets.
This tablet preferably results from the compression of elements (a) (under the form of granules) together with an outer phase.
In another embodiment, the composition of the invention takes the form of granules enclosed inside a capsule, for example in gelatin, or inside a bag.
The compositions of the invention are particularly suitable for administering active ingredients by oral route.
The composition according to the invention is prepared by a novel process comprising spraying a suspension of the active ingredient in a micronized form in a solution of a hydrophilic polymer and, optionally, a surfactant, onto the inert core.
When a surfactant is present, the active ingredient can be co-micronized with the surfactant. One will then use with advantage the teachings of EP-A-0330532.
The method according to the invention consists in using the fluidized bed granulation principle, but with specific starting materials, in order to arrive at an improved dissolution profile and thus, at elevated bioavailability. In particular, the invention employs a suspension of the micronized active ingredient in a solution of a hydrophilic polymer and, optionally, a surfactant.
The fluidized-bed granulation technique is widely used in the pharmaceutical industry for preparing capsules or tablets. Conventionally, according to the prior art, a powder or a mixture of powders (active ingredient+excipients) is put into suspension in the fluidized bed in a granulator, and a solution containing a binder and, optionally, a surfactant, is sprayed onto this bed to form granules. The fluidized-bed granulation technique is well known to those skilled in the art and reference should be made to standard works such as for example “Die Tablette”, by Ritschel, Ed. Cantor Aulendorf, pages 211-212.
The invention, as has been indicated, comprises spraying a suspension of an active ingredient micronized with a hydrophilic polymer onto an inert carrier. Following granulation, the granulate formed consists of crystals of, for example, lactose, which are isolated (or possibly agglomerated together by the spray solution) and particles of active ingredient and PVP adhering to the crystal surface. The granule could similarly be constituted of coated crystals which are agglomerated, or even of such an agglomerate having received a coating.
The compositions according to the invention can also be prepared by other methods, for example by spraying a solution of the micronized active ingredient onto the hydrosoluble inert carrier.
The granulates thus obtained can, if desired, be provided with an outer coating or compressed into tablets, or form agglomerates.
The outer layer or layer is/are applied using conventional coating techniques such as coating in a pan or fluidized bed coater.
When the granulate obtained (whether subsequently coated or not) is compressed to form tablets, this step can be implemented using any conventional technique which is suitable, for example using an alternating or rotating compressing equipment.
The significant starting product is the suspension of the active ingredient. This suspension is prepared by putting the micronized active ingredient into suspension in a solution comprising the hydrophilic polymer and, optionally, a surfactant, in solution in a solvent. If a surfactant is employed, it is put into solution in the solvent (beaker+magnetic or vane stirrer). Next, the hydrophilic polymer (PVP) is dispersed, while stirring, in the solution previously obtained. Depending on polymer solubility, this either dissolves in the solution or forms a gel or a suspension having varying degrees of thickness. While still stirring, the micronized active ingredient is dispersed in the form of a fine shower into the above solution or suspension, to form a homogeneous suspension. The order of these steps can be reversed. The solvent employed can be aqueous or organic (for example ethanol). For example demineralized water can be used.
The active ingredient concentration in the suspension is from 1 to 40% by weight, preferably from 10 to 25%.
The hydrophilic polymer concentration in the suspension is from 5 to 40% by weight, preferably 10 to 25%.
The surfactant concentration in the suspension is from 0 to 10% by weight, preferably below 5%.
The invention also covers this novel suspension.
Without wishing to be tied down to a specific theory, applicant believes that this novel method, through the use of a micronized active ingredient suspension in a hydrophilic polymer solution, enabled a novel composition to be obtained in which the active ingredient is in a non-re-agglomerated form.
The following examples illustrate the invention without limiting it.
EXAMPLE 1
Preparation of a pharmaceutical composition of fenofibrate according to the invention.
A composition containing, as the element a), micronized fenofibrate, Plasdone®, Capsulac® and sodium lauryl sulfate was prepared.
The micronized fenofibrate had a particle size of about 5 μm, as measured using a Coulter counter.
The Plasdone K25® corresponds to a polyvinylpyrrolidone PVP ISP and the Capsulac 60® corresponds to a coarse crystal lactose monohydrate (Meggle) (particle size between 100 and 400 μm).
The sodium laurylsulfate (7 g) is dissolved in water (demineralized water, 1750 g) and the micronized fenofibrate (350 g) is put into suspension in the mixture obtained (for example using a helix stirrer at 300 rpm for 10 minutes, then using an Ultra Turrax agitator at 10,000 rpm, for 10 minutes). Following this, the PVP (350 g) is added while still agitating, stirring (helix stirrer) being continued until the latter had dissolved (30 minutes). It is all passed through a sieve (350 μm) to eliminate possible agglomerates.
Separately, the lactose (400 g) is put into suspension in a fluidized air bed granulator (of the Glatt® GPCG1—Top Spray type or equivalent) and heated to a temperature of 40° C.
The fenofibrate suspension is sprayed onto the lactose. This step is carried out under the following conditions: spraying pressure: 2.1 bar, air throughput 70 m3/h, air inlet temperature: 45° C.; air outlet temperature: 33° C.; product temperature 34° C.; duration of spraying: 3 h.
The granulate thus obtained can be put inside capsules or transformed into tablets. Any suitable conventional technique for preparing such dosage forms can be used.
For transformation to tablet form, one will mix 191 g of the granulate obtained (using for example a mixer-grinder type mixing apparatus, a planetary mixer or turn-over mixer), with the outer phase having the following composition:
56 g Polyplasdone XL® (cross-linked polyvinylpyrrolidone ISP, as described in the USA Pharmacopoeia “USP-NF” under the name of crospovidone, mean molecular weight>1,000,000);
88 g Avicel® PH200 (microcrystalline cellulose);
3.5 g sodium stearyl fumarate (Mendell, U.S.A.); and
2 g Aerosil® 200 (colloidal silica).
The cross-linked polyvinylpyrrolidone, the microcrystalline cellulose, the sodium stearyl fumarate and the colloidal silica are respectively, disintegration agents, binders, lubricating and flow enhancing agents.
The tablet can be obtained on an alternating compression machine (for example Korsch EKO) or a rotary machine (for example Fette Perfecta 2).
One thus obtains tablets having the following composition, expressed in mg:
element (a):
micronized fenofibrate
100.0
PVP
100.0
Lactose
114.3
sodium laurylsulfate
2.0
outer phase (or layer):
cross-linked PVP
92.7
microcrystalline cellulose
145.7
sodium stearyl fumarate
5.8
colloidal silica
3.3
EXAMPLE 2
Dissolution of a composition according to the invention and a composition according to the prior art.
a) dissolution medium and procedure for measuring dissolution.
A dissolution medium which is discriminating, in other words one in which two products having very different dissolution profiles in gastric juices will have very different dissolution curves is looked for.
For this, an aqueous medium containing a surfactant, this being Polysorbate 80 (polyoxyethylene sorbitane mono-oleate) is used. This surfactant is readily available from various suppliers, is the object of a monograph in the Pharmacopoeias, and is thus easy to implement (being also a water-soluble liquid product). Other surfactants can also be used.
The rotating blade method (European Pharmacopoeia) is used under the following conditions: volume of medium: 1200 ml; medium temperature: 37° C.; blade rotation speed: 75 rpm; samples taken: every 2.5 minutes. Determination of the amount dissolved is carried out by spectrophotometry. Test are repeated 6 times over.
b) Results
The composition according to the invention consisted of two tablets containing about 100 mg fenofibrate prepared according to Example 1.
The prior art composition was Lipanthyl® 200M from Laboratoires Fournier, containing 200 mg fenofibrate (corresponding to capsules of 200 mg fenofibrate, co-micronized with sodium laurylsulfate, and containing lactose, pre-gelatinized starch, cross-linked polyvinylpyrrolidone and magnesium stearate, in line with the teachings of EP-A-0330532).
The results obtained are shown graphically in FIG. 1, on which the percentage of dissolution is shown, the observed standard deviation being indicated between brackets.
These results clearly show that the compositions according to the invention have a dissolution profile which is distinctly better than that of the prior art compositions.
These results also clearly show that with the compositions of the invention, the standard deviation observed is distinctly lower than is the case with prior art compositions.
EXAMPLE 3
Study of bioavailability of compositions according to the invention and prior art compositions.
A test of bioavailability on healthy volunteers was carried out.
The following compositions were tested:
composition according to the invention: capsules containing granules prepared according to example 1, containing 200 mg fenofibrate.
first composition according to the prior art: Lipanthyl® 200M from Laboratoires Fournier, containing 200 mg fenofibrate, identical to that in the previous example.
second prior art composition: Secalip® in capsule form (300 mg fenofibrate in the form of three 100 mg capsules).
The study was carried out on 6 healthy volunteers receiving a single dose of fenofibrate, with a minimum 6-day rest period between administrations. The samples for pharmaco-kinetic analysis were collected after each administration at the following times: 0.5 h; 1 h; 2 h; 3 h; 4 h; 5 h; 6 h; 8 h; 10 h; 12 h; 24 h; 36 h; 48 h; 72 h; and 96 hours following administration of the medicament. Fenofibric acid content in plasma was measured for each sample.
The results obtained are given in table 1 below.
TABLE 1
dose
Cmax
tmax
t ½
AUC 0–t
AUC 0–∞
Product
(mg)
(μg/ml)
(h)
(h)
(μg · h/ml)
(μg · h/ml)
Invention
200
5.4
6
23
148
162
Secalip ® 100
3 × 100
1.1
25
39
53
56
Lipanthyl ®
200
1.6
8.3
41
71
92
200M
Cmax: maximum plasma concentration
tmax: time to reach Cmax
t ½: plasma halflife
AUC 0–t: area under the curve from 0 to t
AUC 0–∞: area under the curve from 0 to ∞.
The results clearly show that the compositions of the present invention have a dissolution profile that is an improvement over compositions of the prior art, leading to a considerably enhanced bioavailability of the active ingredient compared to that obtained with compositions of the prior art.
EXAMPLE 4
Comparison of the dissolution profile of compositions according to the invention and that of products currently on the German market.
On the German market, immediate or sustained-release fenofibrate formulations exist. Like in France, the 100 mg and 300 mg (conventional) forms coexist with 67 and 200 mg forms (having enhanced bioavailability, according to the teaching of EP-A-0330532). These products are as follows:
Fenofibrate—ratiopharm; Ratiopharm—Ulm;
Capsules;
Composition: 100 mg fenofibrate;
Excipients: lactose, corn starch, magnesium stearate, E 171 colorant, gelatine.
Durafenat; Durachemie—Wolfratshausen Capsules;
Composition: 100 mg fenofibrate;
Excipients: lactose, corn starch, magnesium stearate, E 171 colorant, gelatine.
Normalip pro; Knoll—Ludwigshafen;
Capsules;
Composition: 200 mg Fenofibrate;
Excipients: Crospovidone, gelatine, monohydrate lactose, magnesium stearate, corn starch, sodium laurylsulfate, E 132 and E 171 colorants.
A comparison was made between:
the tablet of the invention as prepared using example 1 (2×100 mg)
Normalip Pro® (200 mg);
Lipanthyl® 200M (200 mg) (according to the preceding example);
Fenofibrate by Ratiopharm® (2×100 mg);
Durafenat® (2×100 mg)
The tests were implemented under the same conditions as in the previous examples. FIG. 2 summarizes the results.
These results clearly show that the compositions of the invention have a distinctly improved dissolution compared to prior art compositions.
Obviously, the present invention is not limited to the embodiments described but may be subject to numerous variations readily accessible to those skilled in the art.
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11723645
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laboratories fournier s.a.
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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424/455
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Mar 31st, 2022 02:21PM
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Mar 31st, 2022 02:21PM
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AbbVie
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:abbv
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AbbVie
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Oct 1st, 2013 12:00AM
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Jan 7th, 2011 12:00AM
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https://www.uspto.gov?id=US08546385-20131001
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Benzoic pyrrolopyridine derivatives
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The present invention relates to compounds of formula:
in which A, Cy, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in the description.
The compounds of the invention are modulators of the NURR-1 nuclear receptors.
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8546385
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1. A compound corresponding to formula (I):
wherein:
one of the groups A represents a nitrogen atom and the other groups A represent a carbon atom;
Cy represents a phenyl or a 5- or 6-membered heteroaromatic ring;
R1 represents a hydrogen atom, a halogen atom, a group (C1-C4)alkyl that is optionally totally or partially halogenated, or a group (C1-C4)alkoxy;
R2 and R3 represent, independently of each other, a hydrogen atom, a halogen atom, a group (C1-C4)alkyl, a hydroxyl group or a group (C1-C4)alkoxy;
R4 and R5 represent, independently of each other, a hydrogen atom, a halogen atom, a group (C1-C4)alkyl or a hydroxyl group; or
R4 and R5 form, together with the carbon atoms to which they are attached, an ethylene group (C═CH2) or a carbonyl group (C═O);
R6 represents a group —COOR9 or a group —SO2NHR10, —CONHNH—COOR11, —CONR12R13 or —CONHSO2R14, or a group
R7 represents a phenyl optionally substituted with a group (C1-C4)alkyl, or a 6- to 10-membered heteroaromatic ring optionally substituted with a group (C1-C4)alkyl;
R8 represents a hydrogen atom, a group (C1-C4)alkyl or a halogen atom;
R9 represents a hydrogen atom or a group (C1-C4)alkyl;
R10, R11, R12, R13 and R14 represent, independently of each other, a hydrogen atom or a group (C1-C4)alkyl;
or a pharmaceutically acceptable salt of the compound of formula (I);
with the exception of the following compounds:
2-(1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl-carbonyl)benzoic acid;
N,N-diethyl-4-[hydroxy[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-2-methoxy-3-pyridinecarboxamide;
N,N-diethyl-2-methoxy-4-[[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]-3-pyridinecarboxamide;
N,N-diethyl-4-[1-hydroxy-1-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethyl]-2-methoxy-3-pyridinecarboxamide.
2. A compound according to claim 1, wherein R8 represents a hydrogen atom;
or a pharmaceutically acceptable salt of such a compound.
3. A compound according to claim 1, wherein:
Cy represents a phenyl or a 5- or 6-membered heteroaromatic ring;
R1 represents a halogen atom or a group (C1-C4)alkyl that is optionally totally or partially halogenated;
R2 and R3 represent, independently of each other, a hydrogen atom or a halogen atom;
R4 and R5 represent, independently of each other, a hydrogen atom, a halogen atom or a hydroxyl group; or
R4 and R5 form, together with the carbon atom to which they are attached, a carbonyl group (C═O);
R6 represents a group —COOR9;
R7 represents a phenyl optionally substituted with a group (C1-C4)alkyl;
R8 represents a hydrogen atom;
R9 represents a hydrogen atom or a group (C1-C4)alkyl;
or a pharmaceutically acceptable salt of such a compound.
4. A compound according to claim 1, wherein Cy represents a phenyl, thienyl, thiazolyl, furyl or pyridyl;
or a pharmaceutically acceptable salt of such a compound.
5. A compound according to claim 1, wherein R2 and R3 each represent a hydrogen atom;
or a pharmaceutically acceptable salt of such a compound.
6. A compound according to claim 1, wherein R4 and R5 each represent a hydrogen atom;
or a pharmaceutically acceptable salt of such a compound.
7. A compound according to claim 1, selected from the group consisting of:
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-thiophene-2-carboxylic acid,
3-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-2-benzoic acid,
2-chloro-4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-furane-3-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-pyridine-3-carboxylic acid,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-thiophene-2-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-2-fluoro-benzoic acid,
2-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-thiazole-4-carboxylic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoate,
4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[4-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2, 3 -c]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]-benzoate,
4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]-benzoic acid,
Methyl 4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoate,
4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-chloro-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl]-benzoate,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[1-(3-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[1-(3-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[5-chloro-1-(4-(1-methylethyl)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[5-Chloro-1-(4-(1-methylethyl)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo-[2,3-b]pyridin-2-yl]methyl]benzoic acid,
5-{hydroxy[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl}thiophene-2-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]fluoromethyl]-N,N-diethyl-2-thiophenecarboxamide,
5-{1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carbonyl}thiophene-2-carboxylic acid,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid, sodium salt,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid, piperazine salt,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-3-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]benzoic acid,
5-[[1-[[4-(1,1-methylethyl)phenyl]sulfonyl]-5-chloro-1H-pyrrolo[2,3-b]pyridin-2-yllmethyl]thiophene-2-carboxylic acid,
N-{4-[1-(3-tert-butylbenzenesulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethylThenzoyl}methanesulfonamide; and
pharmaceutically acceptable salts of any of the foregoing compounds.
8. A method of treating Parkinson's disease by agonizing the NURR-1 nuclear receptors which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) . . . ″
wherein:
one of the groups A represents a nitrogen atom and the other groups A represent a carbon atom;
Cy represents a phenyl or a 5- or 6-membered heteroaromatic ring;
R1 represents a hydrogen atom, a halogen atom, a group (C1-C4)alkyl that is optionally totally or partially halogenated, or a group (Cl-C4)alkoxy;
R2 and R3 represent, independently of each other, a hydrogen atom, a halogen atom, a group (C1-C4)alkyl, a hydroxyl group or a group (C1-C4)alkoxy;
R4 and R5 represent, independently of each other, a hydrogen atom, a halogen atom, a group (C1-C4)alkyl or a hydroxyl group; or
R4 and R5 form, together with the carbon atoms to which they are attached, an ethylene group (C═CH2) or a carbonyl group (C═O);
R6 represents a group —COOR9 or a group —SO2NHR10, —CONHNH—COOR11, —CONR12R13 or —CONHSO2R14, or a group
R7 represents a phenyl optionally substituted with a group (C1-C4)alkyl, or a 6- to 10-membered heteroaromatic ring optionally substituted with a group (C1-C4)alkyl;
R8 represents a hydrogen atom, a group (C1-C4)alkyl or a halogen atom;
R9 represents a hydrogen atom or a group (C1-C4)alkyl;
R10, R11, R12, R13 and R14 represent, independently of each other, a hydrogen atom or a group (C1-C4)alkyl;
or a pharmaceutically acceptable salt thereof.
9. A method according to claim 8, wherein in the formula (I) compound R8 represents a hydrogen atom.
10. A method according to claim 8, wherein in the formula (I) compound:
Cy represents a phenyl or a 5- or 6-membered heteroaromatic ring;
R1 represents a halogen atom or a group (C1-C4)alkyl that is optionally totally or partially halogenated;
R2 and R3 represent, independently of each other, a hydrogen atom or a halogen atom;
R4 and R5 represent, independently of each other, a hydrogen atom, a halogen atom or a hydroxyl group; or R4 and R5 form, together with the carbon atom to which they are attached, a carbonyl group (C═O);
R6 represents a group —COOR9;
R7 represents a phenyl optionally substituted with a group (C1-C4)alkyl;
R8 represents a hydrogen atom;
R9 represents a hydrogen atom or a group (C1-C4)alkyl.
11. A method according to claim 8, wherein in the formula (I) compound Cy represents a phenyl, thienyl, thiazolyl, furyl or pyridyl.
12. A method according to claim 8, wherein in the formula (I) compound R2 and R3 each represent a hydrogen atom.
13. A method according to claim 8, wherein in the formula (I) compound R4 and R5 each represent a hydrogen atom.
14. A method according to claim 8, wherein the formula (I) compound is selected from the group consisting of:
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-thiophene-2-carboxylic acid,
3-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-2-benzoic acid,
2-chloro-4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-furane-3-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-pyridine-3-carboxylic acid,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-thiophene-2-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-2-fluoro-benzoic acid,
2-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-thiazole-4-carboxylic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoate,
4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[4-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]-benzoate,
4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyll-benzoic acid,
Methyl 4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoate,
4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-chloro-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl]-benzoate,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[1-(3-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[1-(3-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyThbenzoic acid,
Methyl 4-{Hydroxy-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[5-chloro-1-(4-(1-methylethyl)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[5-Chloro-1-(4-(1-methylethyl)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo-[2,3-b]pyridin-2-yl]methyThbenzoic acid,
5-{hydroxy[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl}thiophene-2-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]fluoromethyl]-N,N-diethyl-2-thiophenecarboxamide,
5-{1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carbonyl}thiophene-2-carboxylic acid,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid, sodium salt,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid, piperazine salt,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-3-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methylbenzoic acid,
5-[[1-[[4-(1,1-methylethyl)phenyl]sulfonyl]-5-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]thiophene-2-carboxylic acid,
N-{4-[1-(3-tert-butylbenzenesulfonyl)-5-trffluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]benzoyl}methanesulfonamide; and
pharmaceutically acceptable salts of these compounds.
15. A pharmaceutical composition comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (ii) at least one pharmaceutically acceptable excipient:
wherein:
one of the groups A represents a nitrogen atom and the other groups A represent a carbon atom;
Cy represents a phenyl or a 5- or 6-membered heteroaromatic ring;
R1 represents a hydrogen atom, a halogen atom, a group (C1-C4)alkyl that is optionally totally or partially halogenated, or a group (C1-C4)alkoxy;
R2 and R3 represent, independently of each other, a hydrogen atom, a halogen atom, a group (C1-C4)alkyl, a hydroxyl group or a group (C1-C4)alkoxy;
R4 and R5 represent, independently of each other, a hydrogen atom, a halogen atom, a group (C1-C4)alkyl or a hydroxyl group; or R4 and R5 form, together with the carbon atoms to which they are attached, an ethylene group (C═CH2) or a carbonyl group (C═O);
R6 represents a group —COOR9 or a group —SO2NHR10, —CONHNH—COOR11, —CONR12R13 or —CONHSO2R14, or a group
R7 represents a phenyl optionally substituted with a group (C1-C4)alkyl, or a 6- to 10-membered heteroaromatic ring optionally substituted with a group (C1-C4)alkyl;
R8 represents a hydrogen atom, a group (C1-C4)alkyl or a halogen atom;
R9 represents a hydrogen atom or a group (C1-C4)alkyl;
R10, R11, R12, R13 and R14 represent, independently of each other, a hydrogen atom or a group (C1-C4)alkyl;
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition according to claim 15, wherein in the formula (I) compound R8 represents a hydrogen atom.
17. A pharmaceutical composition according to claim 15, wherein in the formula (I) compound:
Cy represents a phenyl or a 5- or 6-membered heteroaromatic ring;
R1 represents a halogen atom or a group (C1-C4)alkyl that is optionally totally or partially halogenated;
R2 and R3 represent, independently of each other, a hydrogen atom or a halogen atom;
R4 and R5 represent, independently of each other, a hydrogen atom, a halogen atom or a hydroxyl group; or R4 and R5 form, together with the carbon atom to which they are attached, a carbonyl group (C═O);
R6 represents a group —COOR9;
R7 represents a phenyl optionally substituted with a group (C1-C4)alkyl;
R8 represents a hydrogen atom;
R9 represents a hydrogen atom or a group (C1-C4)alkyl.
18. A pharmaceutical composition according to claim 15, wherein in the formula (I) compound Cy represents a phenyl, thienyl, thiazolyl, furyl or pyridyl.
19. A pharmaceutical composition according to claim 15, wherein in the formula (I) compound R2 and R3 each represent a hydrogen atom.
20. A pharmaceutical composition according to claim 15, wherein in the formula (I) compound R4 and R5 each represent a hydrogen atom.
21. A pharmaceutical composition according to claim 15, wherein the formula (I) compound is selected from the group consisting of:
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-thiophene-2-carboxylic acid,
3-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-2-benzoic acid,
2-chloro -4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-furane-3-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-pyridine-3-carboxylic acid,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-thiophene-2-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-2-fluoro-benzoic acid,
2-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-thiazole-4-carboxylic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2, 3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoate,
4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[4-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]-benzoate,
4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyThbenzoic acid,
Methyl 4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoate,
4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-chloro-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl] -benzoate,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-c]pyridin-2-yl]methyThbenzoic acid,
Methyl 4-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[1-(3-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[1-(3-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1,1-dimethylethyl)phonyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[5-chloro-1-(4-(1-methylethyl)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl]l-benzoate,
Methyl 4-[5-Chloro-1-(4-(1-methylethyl)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo-[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
5-{hydroxy[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl}thiophene-2-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]fluoromethyl]-N,N-diethyl-2-thiophenecarboxamide,
5-{1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carbonyl}thiophene-2-carboxylic acid,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid, sodium salt,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid, piperazine salt,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-3-methyl-5-(trifluoromethyl)-1H-pyrrolo[3, 2-b]pyridin-2-yl]methyl]benzoic acid,
5-[[1-[[4-(1,1-methylethyl)phenyl]sulfonyl]-5-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]thiophene-2-carboxylic acid,
N-{4-[1-(3-tert-butylbenzenesulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]benzoyl}methanesulfonamide; and
pharmaceutically acceptable salts of these compounds.
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The present invention relates to novel compounds of pyrrolopyridine type, preferentially derivatives of benzoic pyrrolopyridine type, and also to the process for preparing them and to their use as active principles of medicaments, especially for treating and/or preventing diseases involving the NURR-1 nuclear receptors. More specifically, this invention relates to the use of these compounds for the manufacture of a medicament for treating and/or preventing neurodegenerative diseases and in particular Parkinson's disease.
PRIOR ART
Neurodegenerative diseases are defined as diseases characterized by progressive dysfunction of the nervous system. They are often associated with atrophy of the affected structures of the central or peripheral nervous system. They include, inter alia, diseases such as Alzheimer's disease, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, lysosomal diseases, progressive supranuclear paralysis, multiple sclerosis and amyotrophic lateral sclerosis. Among these neurodegenerative diseases, Parkinson's disease is a complaint that affects about four million people worldwide. Although it affects individuals of all ages, it is more common among the elderly (with 2% of people over the age of 65 affected by this disease). It is characterized by neurodegeneration of the dopaminergic neurons of the substantia nigra. These types of neuron synthesize dopamine and use it as a neurotransmitter.
A relationship has been able to be established between dopamine deficiency and nervous disorders. Dopamine exerts a central role in controlling voluntary movements, cognitive functions and the development of emotion-related behaviour.
The current therapeutic strategy for treating Parkinson's disease is based on attenuating the symptoms, by compensating for the dopamine deficiency via the administration of a metabolic precursor such as L-DOPA.
However, presently, the increase in prevalence of this pathology has made it necessary to develop novel therapeutic agents that exert a beneficial role in neuronal survival and differentiation.
This development has led to the identification of compounds that are capable of activating the nuclear receptors involved in the pathogenesis of Parkinson's disease.
The transcription factor NURR-1, a member of the superfamily of orphan nuclear receptors, which is strongly expressed in the brain, was identified as having an essential role in the development and maintenance of the dopaminergic neurons of the mesencephalon (Zetterstrom et al. 1997, Science 276 (5310): 248-50).
The NURR-1 nuclear receptor is involved in maintaining the dopaminergic phenotype via regulation of the specific genes of the dopaminergic neurons (DA). It also promotes the survival of the DA neurons by protecting them against toxic attack. The NURR-1 nuclear receptor thus serves as a specific transcription factor for the dopaminergic neurons, the activities of which might be regulated by modulating the dopaminergic neurotransmission in Parkinson's disease.
This receptor binds to DNA in the form of monomers, homodimers or heterodimers with RXR (retinoid X receptor), a nuclear receptor that is the heteropartner of many other members of the family of nuclear receptors. RXR is involved in many physiological processes, such as fat and glucose metabolism, development and differentiation. NURR-1 thus interacts with the α and γ isoforms of RXR. RXRα is ubiquitously expressed, whereas the expression of RXRγ is concentrated mainly in the brain and especially in the striatum, the hypothalamus and the pituitary.
The formed complexes NURR-1/RXRα and NURR-1/RXRγ are capable of regulating transcription in response to an RXR ligand. RXR thus positively modulates the transcription activation potential of NURR-1.
The identification of compounds capable of inducing the activity of the NURR-1/RXRα and NURR-1/RXRγ complexes should consequently make it possible to provide novel routes for treating Parkinson's disease.
Document WO 2003/015 780 discloses heterocyclic compounds that are active for treating Parkinson's disease. Heterocyclic compounds with affinity for the PPAR receptors are described in document WO 2005/009 958.
Moreover, documents FR 2 903 105, FR 2 903 106 and FR 2 903 107 describe compounds that are activators of the NURR-1 receptor, while the use of heterocyclic compounds that modulate the activity of receptors of the NGFI-B family (of which NURR-1 is a member) is described in document WO 2005/047 268.
Heterocyclic compounds presented as being factor Xa inhibitors are described in document WO 98/25611. Other heterocyclic compounds presented as 5-HT6 receptor modulators are described in documents WO 2008/101 247 and WO 2010/002 802.
The following 1H-pyrrolo[2,3-b]pyridine derivatives are described in document: Tetrahedron, vol. 53, No. 10, pp. 3637-3648, 1997:
2-[[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]benzoic acid;
N,N-diethyl-4-[hydroxy[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-2-methoxy-3-pyridinecarboxamide;
N,N-diethyl-2-methoxy-4-[[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]-3-pyridinecarboxamide;
N,N-diethyl-4-[1-hydroxy-1-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethyl]-2-methoxy-3-pyridinecarboxamide.
These compounds are intermediates in the synthesis of polyazatetracyclic compounds.
SUBJECT OF THE INVENTION
According to a first aspect, the present invention relates to novel compounds of pyrrolopyridine type that are NURR-1/RXRα and NURR-1/RXRγ agonists, capable of inhibiting the neuronal degeneration observed in Parkinson's disease, chosen from:
(i) the compounds of formula (I):
in which:
one of the groups A represents a nitrogen atom and the other groups A represent a carbon atom;
Cy represents a phenyl or a 5- or 6-membered heteroaromatic ring;
R1 represents a hydrogen atom, a halogen atom, a group (C1-C4)alkyl that is optionally totally or partially halogenated, or a group (C1-C4)alkoxy;
R2 and R3 represent, independently of each other, a hydrogen atom, a halogen atom, a group (C1-C4)alkyl, a hydroxyl group or a group (C1-C4)alkoxy;
R4 and R5 represent, independently of each other, a hydrogen atom, a halogen atom, a group (C1-C4)alkyl or a hydroxyl group;
or R4 and R5 form, together with the carbon atoms to which they are attached, an ethylene group (C═CH2) or a carbonyl group (C═O);
R6 represents a group —COOR9 or a carboxylic acid bioisostere group, preferably a group —COOR9;
R7 represents a phenyl optionally substituted with a group (C1-C4)alkyl, or a 6- to 10-membered heteroaromatic ring optionally substituted with a group (C1-C4)alkyl;
R8 represents a hydrogen atom, a group (C1-C4)alkyl or a halogen atom;
R9 represents a hydrogen atom or a group (C1-C4)alkyl; and
(ii) the pharmaceutically acceptable salts of the said compounds of formula (I).
According to a second aspect, the invention relates to the above-mentioned compounds for their use as therapeutically active substances, especially in the treatment and/or prevention of neurodegenerative diseases, in particular Parkinson's disease, and also to pharmaceutical compositions containing them.
According to a third aspect, the invention relates to the use of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, as an active principle for the preparation of a medicament for treating diseases in which the NURR-1 receptor is involved, especially neurodegeneration, in particular such as Parkinson's disease.
According to a fourth aspect, the invention relates to a method for preventing and/or treating diseases in which the NURR-1 receptor is involved, especially neurodegenerative diseases, and more particularly Parkinson's disease, which consists in administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of the said compound, or a pharmaceutical composition containing such a compound.
DETAILED DESCRIPTION
The term “alkyl group” means a saturated hydrocarbon-based chain which may be linear or branched. For example, and without limitation, an alkyl group containing from 1 to 6 carbon atoms may be a methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 1,1-dimethylpropyl, 1-methylpentyl or 1,1-dimethylbutyl group.
The term “halogen” means a bromine, fluorine or chlorine atom.
The term “partially or totally halogenated alkyl group” means an alkyl group as defined above in which one or more hydrogen atoms are replaced with one or more halogen atoms. Examples that may be mentioned include difluoromethyl and trifluoromethyl groups.
The term “alkoxy group” means a group OR in which R is an alkyl group as defined above. Examples of alkoxy groups containing from 1 to 4 carbon atoms that may be mentioned include methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy, 1,1-dimethylethoxy, 1-methylpropoxy and 2-methylpropoxy groups.
The term “5- or 6-membered heteroaromatic ring” means an aromatic monocycle comprising from 1 to 3 heteroatoms and preferably 1 or 2 heteroatoms, chosen from nitrogen, oxygen and sulfur. Examples that may be mentioned include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, furyl, thienyl thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl groups.
The term “6- to 10-membered heteroaromatic ring” means an unsaturated or partially unsaturated monocyclic or bicyclic group comprising from 1 to 4 heteroatoms, preferably from 1 to 3 heteroatoms and more preferably 1 or 2 heteroatoms, chosen from nitrogen, oxygen and sulfur, the said group being optionally substituted with a (C1-C4)alkyl. Examples that may be mentioned include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, 1,2,3,4-isoquinolinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, benzimidazolyl, benzopyrazinyl, indolyl, 2,3-dihydroindolyl, benzofuryl, 2,3-dihydrobenzofuryl, benzothiazolyl, benzothiadiazolyl, benzisoxazolyl, 3,4-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzodioxinyl, imidazothiazolyl and benzoxazolyl groups.
The term “carboxylic acid bioisostere group” means a group with chemical and physical similarities and that produces biological properties broadly similar to a carboxylic group, as described in Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p. 283 “Bioisosterism In Drug Design”; Graham, Theochem., 1995, 343, pp. 105-109 “Theoretical Studies Applied To Drug Design: ab initio Electronic Distributions In Bioisosteres”.
Examples of carboxylic acid bioisostere groups that may be mentioned include optionally substituted acylhydrazine groups, optionally substituted acylhydrazine carboxylates, optionally substituted alkyl and aryl sulfonylcarbamoyls, carboxamides, optionally substituted sulfonamides, oxadiazolones, optionally substituted phosphonates, optionally substituted isothiazoles, optionally substituted isoxazoles, optionally substituted isoxazolones, tetrazoles, optionally substituted thiazolidinediones and optionally substituted thioxothiazolidinones. Advantageously, the carboxylic acid bioisostere group is chosen from the groups —SO2NHR10, —CONHNHCOOR11, —CONR12R13 and —CONHSO2R14, in which R10, R11, R12, R13 and R14 represent, independently of each other, a hydrogen atom or a group (C1-C4)alkyl, and preferably from the groups —CONR12R13 and —CONHSO2R14. The carboxylic acid bioisostere group may also be chosen from the groups
in which the symbol * denotes the point of attachment to the ring Cy.
The compounds of formula (I) in which the substituents R4 and R5 are different have an asymmetric centre. For these compounds, the invention covers both the racemic compound and each of the optical isomers considered separately.
The compounds of formula (I) in which R6 represents a group COOH are carboxylic acids that may be used in the form of free acids or in the form of salts, the said salts being obtained by combining the acid with a non-toxic and preferably pharmaceutically acceptable mineral or organic base. Among the mineral bases, use may be made, for example, of sodium, potassium, magnesium or calcium hydroxide. Among the organic bases, use may be made, for example, of amines, amino alcohols, basic amino acids such as lysine or arginine, or alternatively compounds bearing a quaternary ammonium function, for instance betaine or choline. The salts of the acids of formula (I) with a mineral or organic base may be obtained conventionally by using the methods that are well known to those skilled in the art, for example by mixing stoichiometric amounts of the acid of formula (I) in which R6=COOH and of the base in a solvent, for instance water or an aqueous-alcoholic mixture, and then freeze-drying the solution obtained.
According to one embodiment of the invention, the said invention concerns the compounds of formula (I) with the exception of the following compounds:
2-[[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]benzoic acid;
N,N-diethyl-4-[hydroxy[1-(phenylsulfonyl)-1′-1-pyrrolo[2,3-b]pyridin-2-yl]methyl]-2-methoxy-3-pyridine carboxamide;
N,N-diethyl-2-methoxy-4-[[1-(phenylsulfonyl)-1,4-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]-3-pyridinecarboxamide;
N,N-diethyl-4-[1-hydroxy-1-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethyl]-2-methoxy-3-pyridinecarboxamide.
A preferred family of compounds according to the invention corresponds to formula (I) in which R1 represents a halogen atom or a totally or partially halogenated group (C1-C4)alkyl and/or R8 represents a hydrogen atom.
Another preferred family of compounds according to the invention corresponds to formula (I) in which:
Cy represents a phenyl or a 5- or 6-membered heteroaromatic ring;
R1 represents a halogen atom or an optionally totally or partially halogenated group (C1-C4)alkyl;
R2 and R3 represent, independently of each other, a hydrogen atom or a halogen atom;
R4 and R5 represent, independently of each other, a hydrogen atom, a halogen atom or a hydroxyl group,
or R4 and R5 form, together with the carbon atom to which they are attached, a carbonyl group (C═O);
R6 represents a group —COOR9;
R7 represents a phenyl optionally substituted with a group (C1-C4)alkyl;
R8 represents a hydrogen atom;
R9 represents a hydrogen atom or a group (C1-C4)alkyl.
Among this family, the preferred compounds are those of formula (I) in which R4 and R5 represent, independently of each other, a hydrogen atom or a hydroxyl group.
Among the compounds described above, the ones that are preferred are those that satisfy at least one of the following conditions:
Cy represents a phenyl, thienyl, thiazolyl, furyl or pyridyl, preferably a phenyl or a thienyl;
R2 and R3 each represent a hydrogen atom;
R4 and R5 each represent a hydrogen atom.
As compounds that are most particularly preferred, mention may be made of:
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-thiophene-2-carboxylic acid,
3-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-2-benzoic acid,
2-chloro-4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-furane-3-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-pyridine-3-carboxylic acid,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-thiophene-2-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-2-fluoro-benzoic acid,
2-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-thiazole-4-carboxylic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoate,
4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[4-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]-benzoate,
4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]-benzoic acid,
Methyl 4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoate,
4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-chloro-1H-pyrrolo[2,3-e]pyridin-2-ylmethyl]-benzoate,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[1-(3-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[1-(3-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
Methyl 4-{Hydroxy-[5-chloro-1-(4-(1-methylethyl)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methyl}-benzoate,
Methyl 4-[5-Chloro-1-(4-(1-methylethyl)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo-[2,3-b]pyridin-2-yl]methyl]-benzoic acid,
5-{hydroxy[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl}thiophene-2-carboxylic acid,
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]fluoromethyl]-N,N-diethyl-2-thiophenecarboxamide,
5-{1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carbonyl}thiophene-2-carboxylic acid,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid, sodium salt,
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid, piperazine salt,
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-3-methyl-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]-benzoic acid,
5-[[1-[[4-(1,1-methylethyl)phenyl]sulfonyl]-5-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]thiophene-2-carboxylic acid,
N-{4-[1-(3-tert-butylbenzenesulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]benzoyl}methanesulfonamide.
The syntheses described below, including those in the preparations and the examples, illustrate methods for preparing the compounds of formula (I). In these syntheses, the substituents A, Cy, R1, R2, R3, R4, R5, R6, R7 and R8 have the meaning indicated above for the compounds of formula (I), unless otherwise indicated.
According to a first embodiment, the compounds of formula (I) in which R4 represents H, OH or (C1-C4)alkyl and R5 represents H may be prepared as described in Scheme 1.
Step (a)
An amine of formula (II), in which LG is preferably iodine, is reacted with a sulfonyl chloride R7SO2Cl in the presence of a suitable base, for instance pyridine, at room temperature for about 2 to 24 hours. The reaction medium thus obtained is then reacted with a suitable base, for instance potassium hydroxide, in a suitable solvent, for instance dioxane, at a temperature between room temperature and the reflux temperature of the solvent, for a period of about 1 to 6 hours. The compound of formula (III) is thus obtained.
Step (b)
The compound of formula (III) is reacted with 2-propyn-1-ol in the presence of copper iodide and a palladium-based catalyst, for instance bis(triphenylphosphine)palladium(II) chloride, in a suitable solvent, for instance N,N-dimethylformamide
(DMF). A suitable base is then added, for instance diethylamine or triethylamine, and the reaction mixture is heated for a period of about 1 to 6 hours at a temperature between room temperature and the reflux temperature of the solvent. According to one variant, the heating may be performed in a microwave oven for a period of about 5 to 30 minutes. The compound of formula (IV) is thus obtained where R8 represents a hydrogen atom.
Step (b′)
The compound of formula (III) is reacted with an alkyne of formula (XXII) in the presence of a palladium-based catalyst, for instance palladium acetate, and lithium chloride in a suitable solvent, for instance N,N-dimethylformamide (DMF). A suitable base is then added, for instance potassium carbonate, and the reaction mixture is heated for a period of about 1 to 24 hours at a temperature between room temperature and the reflux temperature of the solvent. According to one variant, the heating may be performed in a microwave oven for a period of about 5 to 30 minutes. The compound of formula (IV') is thus obtained where R8 represents a group (C1-C4)alkyl,
Step (c)
The compound of formula (IV) or (IV') is reacted with a source of bromine, for instance phosphorus tribromide, in a suitable solvent, for instance dichloromethane (DCM), at 0° C. or at room temperature for a period of about 1 hour to 4 days, or N-bromosuccinimide (NBS) in the presence of azobisisobutyronitrile (AIBN) in a suitable solvent, for instance refluxing carbon tetrachloride, for 24 hours. The compound of formula (V) is thus obtained.
Step (d)
The compound of formula (V) dissolved in a suitable solvent, for instance an ethanol/dioxane mixture, is reacted with a compound of formula (HO)2μ-Cy(R2,R3)-R6 in the presence of a palladium-based catalyst, for instance the complex Pd(dppf)Cl2.CH2Cl2, and of a suitable base, for instance potassium carbonate, and the reaction mixture is heated for a period of about 1 to 6 hours at a temperature between room temperature and the reflux temperature of the solvent. According to one variant, the heating may be performed in a microwave oven for a period of about 5 to 30 minutes. The compound of formula (I) is thus obtained. If necessary (when R6=COOR9 and R9=(C1-C4)alkyl), the ester function of the compound of formula (I) is hydrolysed, for example via the action of a mineral base such as lithium hydroxide, according to procedures that are well known to those skilled in the art, to obtain a compound of formula (I) in which R6=COOH.
According to a second embodiment, the compounds of formula (I) in which R4 and R5 represent H may be prepared as described in Scheme 2.
Step (e)
The compound of formula (VI) is reacted with diethyl oxalate in the presence of a suitable base, for instance 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), at room temperature, for a period of about 1 to 6 hours. If necessary, the compound obtained is reacted with a halogenating agent, for instance 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), in a suitable solvent, for instance acetonitrile, at a temperature of between 0 and 50° C., for a period of about 1 to 96 hours. The compound of formula (VII) is thus obtained.
Step (f)
The compound of formula (VII) is treated with a suitable base, for instance sodium hydride, in a suitable solvent, for instance tetrahydrofuran (THF), at room temperature for a period of about 1 to 6 hours, and is then reacted with a sulfonyl chloride R7SO2Cl at room temperature for a period of about 2 to 24 hours. The compound of formula (VIII) is thus obtained.
Step (g)
The compound of formula (VIII) is treated with a suitable reducing agent, for instance DIBAL-H or LiAlH4, in a suitable solvent, for instance toluene, at a temperature of between about −78° C. and room temperature, for a period of about 1 to 24 hours. The compound of formula (IV) is thus obtained.
Step (c)
This step is identical to step (c) described for Scheme 1, and leads to the production of the compound of formula (V).
Step (d)
This step is identical to step (d) described for Scheme 1, and leads to the production of the compound of formula (I). If necessary (when R6=COOR9 and R9=(C1-C4)alkyl), the ester function of the compound of formula (I) is hydrolysed, for example via the action of a mineral base such as lithium hydroxide, according to procedures that are well known to those skilled in the art, to obtain a compound of formula (I) in which R6=COOH.
According to a third embodiment, the compounds of formula (I) in which R2, R3, R4, R5 and R8 represent H, Cy represents a thiazolyl and R6 represents COOH may be prepared as described in Scheme 3.
Step (a)
This step is identical to step (a) described for Scheme 1, and leads to the production of the compound of formula (III).
Step (b)
This step is identical to step (b) described for Scheme 1, and leads to the production of the compound of formula (IV).
Step (c)
This step is identical to step (c) described for Scheme 1, and leads to the production of the compound of formula (V).
Step (h)
The compound of formula (V) is reacted with potassium cyanide in a suitable solvent, for instance DCM, in the presence of a phase-transfer catalyst, for instance tetrabutylammonium bromide, at room temperature for a period of about 1 to 4 days. The compound of formula (IX) is thus obtained.
Step (i)
The compound of formula (IX) dissolved in a suitable solvent, for instance a THF/water mixture, is reacted with diethyl dithiophosphate at a temperature of about 80 to 120° C. for a period of about 1 to 6 hours. The compound of formula (X) is thus obtained.
Step (j)
The compound of formula (X) is reacted with bromopyruvic acid in a suitable solvent, for instance ethanol, at room temperature for a period of about 12 to 36 hours. The compound of formula (I) is thus obtained.
According to a fourth embodiment, the compounds of formula (I) in which R4 and R8 represent H and Cy represents a phenyl may be prepared as described in Scheme 4.
Step (a)
This step is identical to step (a) described for Scheme 1, and leads to the production of the compound of formula (III).
Step (k)
The acetylenic derivative of formula (XV) is reduced in the presence of a trialkylsilane, for instance triethylsilane, and an optional catalytic amount of an acid, for instance trifluoroacetic acid, in a suitable solvent, for instance DCM, at room temperature for a period of about 4 to 8 days. The compound of formula (XIV) is thus obtained.
Step (l)
The compounds of formulae (III) and (XIV) are reacted in the presence of copper iodide and of a palladium-based catalyst, for instance bis(triphenylphosphine)palladium(II) chloride, in a suitable solvent, for instance N,N-dimethylformamide (DMF). A suitable base, for instance diethylamine or triethylamine, is then added and the reaction mixture is heated for a period of about 1 to 6 hours at a temperature between room temperature and the reflux temperature of the solvent. According to one variant, the heating may be performed in a microwave oven for a period of about 5 to 30 minutes. The compound of formula (XII) is thus obtained.
Step (m)
When R9 is other than H, the ester function of the compound of formula (XII) is hydrolysed according to procedures that are well known to those skilled in the art, for example via the action of a mineral base such as lithium hydroxide, in a suitable solvent, for instance THF or a THF/water mixture, at a temperature between room temperature and the reflux temperature of the solvent. The compound of formula (I) is thus obtained.
According to a fifth embodiment, the compounds of formula (I) in which R8 represents H may be prepared as described in Scheme 5.
Step (a)
This step is identical to step (a) described for Scheme 1, and leads to the production of the compound of formula (III).
Step (n)
The compounds of formulae (III) and (XV) are reacted in the presence of copper iodide and a palladium-based catalyst, for instance bis(triphenylphosphine)palladium(II) chloride, in a suitable solvent, for instance DMF. A suitable base, for instance diethylamine or triethylamine, is then added, and the reaction mixture is heated for a period of about 1 to 6 hours at a temperature between room temperature and the reflux temperature of the solvent. According to one variant, the heating may be performed in a microwave oven for a period of about 5 to 30 minutes. The compound of formula (XIII) is thus obtained.
Step (o)
The compound of formula (XIII) is reduced in the presence of a trialkylsilane, for instance triethylsilane, boron trifluoride diethyl etherate and an optional catalytic amount of an acid, for instance trifluoroacetic acid, in a suitable solvent, for instance DCM, at room temperature for a period of about 6 to 18 hours. The compound of formula (XII) is thus obtained.
Step (m)
This step is identical to step (m) described for Scheme 4, and leads to the production of the compound of formula (I).
According to a sixth embodiment, the compounds of formula (I) in which R4 and R5 form, together with the carbon atom to which they are attached, an ethylene group (C═CH2), R6 represents COOH and R8 represents H may be prepared as described in Scheme 6.
Step (a)
This step is identical to step (a) described for Scheme 1, and leads to the production of the compound of formula (III).
Step (n)
This step is identical to step (n) described for Scheme 5, and leads to the production of the compound of formula (XVIII).
Step (o)
This step is identical to step (o) described for Scheme 5, and leads to the production of the compound of formula (XVII).
Step (m)
This step is identical to step (m) described for Scheme 4, and leads to the production of the compound of formula (I).
According to a seventh embodiment, the compounds of formula (I) in which R4 and R5 form, together with the carbon atoms to which they are attached, a carbonyl group and R8 represents H may be prepared as described in Scheme 7.
Step (a)
This step is identical to step (a) described for Scheme 1, and leads to the production of the compound of formula (III).
Step (n)
This step is identical to step (n) described for Scheme 5, and leads to the production of the compound of formula (XXI).
Step (p)
The compound of formula (XXI) is treated with a suitable oxidizing agent, for instance pyridinium dichromate, in a suitable solvent, for instance DCM, at room temperature for a period of about 6 to 18 hours. The compound of formula (XX) is thus obtained.
Step (m)
This step is identical to step (m) described for Scheme 4, and leads to the production of the compound of formula (I).
According to an eighth embodiment, the compounds of formula (I) in which R4 represents a halogen atom and R5 represents a hydrogen atom may be prepared as described in Scheme 8.
Step (a)
This step is identical to step (a) described for Scheme 1, and leads to the production of the compound of formula (III).
Step (n)
This step is identical to step (n) described for Scheme 5, and leads to the production of the compound of formula (XIII′).
Step (q)
The compound of formula (XIII′) is reacted with a halogenating agent, for instance 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), at room temperature for about 30 minutes to 2 hours, to obtain the compound of formula I.
In general, the carboxylic acid function of the compounds of formula (I) in which R6 represents COOH may be advantageously replaced with a carboxylic acid bioisostere group according to methods that are well known to those skilled in the art, such as the methods described below.
The compounds of formula (I) according to the invention, in which R6 represents an acylhydrazine, acylhydrazine carboxylate or oxadiazolone bioisostere group, may be prepared according to a process that consists in:
a) reacting the compound of formula (I) in which R6 represents COOH with a carbazate in the presence of a coupling agent especially such as the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI)/1-hydroxy-7-azabenzotriazole (HOAT) reagent pair, in an organic solvent in particular such as toluene, at room temperature for 2 to 24 hours, to give an acylhydrazine carboxylate compound of formula (I) in which R6 represents CONHNHCOOR11 and R11 represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms;
b) if necessary, deprotecting the abovementioned compound of formula (I) according to a procedure that is well known to those skilled in the art, for instance by treating the said compound of formula (I) with an acid such as trifluoroacetic acid in a solvent in particular such as dichloromethane, to obtain an acylhydrazine;
c) if necessary, cyclizing the acylhydrazine in the presence of a coupling agent such as carbonyldiimidazole (CDI) in an organic solvent such as dichloromethane, at room temperature for 2 to 15 hours to obtain the oxadiazolone of formula (I) in which R6 represents:
The compounds of formula (I) according to the invention, in which R6 represents a carboxamide bioisostere group, may be prepared according to a process that consists in reacting the compound of formula (I) in which R6 represents COOH with an amine in the presence of a coupling agent especially such as the 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDCI)/1-hydroxy-7-azabenzotriazole (HOAT) reagent pair, in an organic solvent in particular such as dichloromethane, at room temperature for 2 to 24 hours to give a carboxamide compound of formula (I) in which R6 represents CONR12R13 and R12 and R13 independently represent a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms.
The compounds of formula (I) according to the invention, in which R6 represents a sulfonylcarbamoyl bioisostere group or a derived group may be prepared according to a process that consists in coupling the compound of formula I in which R6 represents COOH with a sulfonamide in the presence of a coupling agent in particular such as the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro chloride/4-dimethylaminopyridine (EDCI/DMAP) reagent pair in an organic solvent such as dichloromethane at room temperature for 12 to 24 hours.
The compounds of formula (I) according to the invention, in which R6 represents an isoxazole bioisostere group or a derived group such as an isoxazolone group, may be prepared according to the process that consists in:
a) activating the acid function of the compound of formula (I) in which R6 represents COOH using carbonyldiimidazole (CDI) and in reacting it with the magnesium salt of ethyl monomalonate;
b) cyclizing in the presence of hydroxylamine and in basic medium at room temperature for 2 to 4 days to obtain the compound of formula I in which R6 represents:
The compounds of formulae R7SO2Cl, (HO)2B-Cy(R2,R3)-R6, (II), (VI), (XV), (XV′), (XVI), (XIX) and (XXII) are commercially available or may be prepared according to procedures that are well known to those skilled in the art. The present invention relates to the preparation processes described above, and also to the intermediates used in these processes. In particular, a subject of the invention is the compounds of formulae (IV), (IV′), (V), (VII), (VIII), (IX), (X), (XII), (XIII), (XIII′), (XVII), (XVIII), (XX) and (XXI), and also the possible salts of these compounds.
The examples that follow, of the preparation of compounds according to formula (I), will allow the invention to be understood more clearly.
In these examples, which do not limit the scope of the invention, the term “preparation” denotes the examples describing the synthesis of intermediate compounds, and the term “examples” denotes the examples describing the synthesis of compounds of formula (I) according to the invention.
The following abbreviations have been used:
CuI copper iodide
DAST diethylaminosulfur trifluoride
DIBAL-H diisobutylaluminium hydride
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
eq. equivalent
h hours
HCl hydrochloric acid
min minutes
mM millimoles
RT room temperature
TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl
TFA trifluoroacetic acid
THF tetrahydrofuran
The melting points (m.p.) were measured using an automatic machine (Optimelt) and the nuclear magnetic resonance spectral values were characterized by means of the chemical shift (δ) calculated relative to TMS (tetramethylsilane), by the number of protons associated with the signal and by the shape of the signal (s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, dd for doublet of doublets). The working frequency (in megahertz) and the solvent used are indicated for each compound.
Room temperature is 20° C.±5° C.
PREPARATION 1
3-(1,1-dimethylethyl)-N-(2-iodo-6-trifluoromethylpyridin-3-yl)benzenesulfonamide
9.07 g (38.96 mM) of 3-tert-butylbenzenesulfonyl chloride were added to a solution of 6.60 g (22.92 mM) of 2-iodo-6-trifluoromethylpyridin-3-ylamine in 10.0 mL of pyridine. This reaction mixture was stirred at room temperature overnight. The medium was diluted with water and then extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid solution and then dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 14.40 g of the evaporation residue were dissolved in 50.0 mL of 1,4-dioxane, 56.4 mL (169.28 mM) of 3M potassium hydroxide were added, and the reaction mixture was then refluxed for 1 hour. The medium was concentrated under reduced pressure. The residue was dissolved in water, and the solution was acidified with concentrated hydrochloric acid and then extracted twice with DCM. The organic phase was dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was washed with petroleum ether and then filtered on a Büchner funnel. The title product was obtained in the form of a white solid (8.80 g, yield=86%). m.p.=125° C.
PREPARATION 2
[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]methanol
A solution of 2.00 g (4.13 mM) of 3-tert-butyl-N-(2-iodo-6-trifluoromethylpyridin-3-yl)benzenesulfonamide (Preparation 1) in 10.0 mL of DMF was prepared. 0.04 g (0.21 mM) of CuI, 0.14 g (6.19 mM) of bis(triphenylphosphine)palladium(II) chloride and 0.35 g (6.19 mM) of 2-propyn-1-ol were added. 5.0 mL of triethylamine were added to this mixture and this reaction mixture was then irradiated with microwaves for 10 minutes at 120° C. The medium was concentrated under reduced pressure, and the evaporation residue was purified by chromatography on silica gel using 90/10 and then 80/20 (v/v) cyclohexane/ethyl acetate as eluent. The title product was obtained in the form of a beige-coloured solid (1.29 g; yield=76%). m.p.=118° C.
PREPARATION 3
2-bromomethyl-1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoro-methyl-1H-pyrrolo[3,2-b]pyridine
A solution of 1.29 g (3.13 mM) of [1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]methanol (Preparation 2) in 25.0 mL of DCM was prepared. 1.69 g (6.26 mM) of phosphorus tribromide were added dropwise. This reaction mixture was stirred for 4 days at room temperature. 100 mL of saturated potassium carbonate solution and 100 mL of water were added, and the mixture was then extracted twice with DCM (50 mL). The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The title product was obtained in the form of a beige-coloured solid (1.62 g, yield=100%). m.p.=124° C.
EXAMPLE 1
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]thiophene-2-carboxylic acid
A solution of 230 mg (0.48 mM) of 2-bromomethyl-1-(3-tert-butylbenzene-sulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine (Preparation 3) in 4.0 ml of ethanol and 1.0 mL of 1,4-dioxane was prepared. 99.8 mg (0.58 mM) of 5-(dihydroxyboryl)-2-thiophenecarboxylic acid, 39.5 mg (0.58 mM) of Pd(dppf)Cl2.DCM complex and 80 mg (0.58 mM) of potassium carbonate were added to this solution. This reaction mixture was irradiated with microwaves for 20 minutes at 120° C. The medium was diluted with water and then extracted with ethyl acetate. The organic phase was washed with saturated saline solution and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue was purified by liquid chromatography with UV detection (LC-UV) (on a SunFire® C18 column) eluting with a water/methanol/0.1% TFA mixture. The fractions containing the expected product were combined and concentrated under reduced pressure. The title product was obtained in the form of an orange oil (25 mg, yield=10%).
1H NMR (400 MHz, DMSO) δ=13.00 (s, 1H), 8.68 (d, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 7.67-7.70 (m, 2H), 7.55 (d, 1H), 7.48 (t, 1H), 7.00 (d, 2H), 4.77 (s, 2H), 1.18 (s, 9H).
PREPARATION 4
4-methyl-5-nitro-2-trifluoromethylpyridine
25.0 g (115.2 mM) of 2-bromo-4-methyl-5-nitropyridine, 44.3 g (230 mM) of methyl fluorosulfonyldifluoroacetate and 17.6 g (92.2 mM) of CuI were suspended in 250 mL of DMF. This reaction mixture was stirred at 120° C. for 48 hours. The medium was cooled and then diluted with 1000 mL of saturated ammonium chloride solution and 100 mL of ammonium hydroxide, and then stirred until homogenized. The product was extracted three times with ethyl acetate. The residue was purified by chromatography on silica gel, using 95/5 and then 90/10 (v/v) cyclohexane/ethyl acetate as eluent. The fractions containing the expected product were combined and concentrated under reduced pressure. The title product was obtained in the form of a brown oil (8.0 g, yield=34%).
1H NMR (300 MHz, DMSO) δ=9.29 (s, 1H), 8.21 (s, 1H), 2.68 (s, 3H).
PREPARATION 5
ethyl 5-trifluoromethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
A solution of 6.0 g (23.29 mM) of 4-methyl-5-nitro-2-trifluoromethylpyridine (Preparation 4) in 14.8 mL (109.45 mM) diethyl oxalate was prepared. 8.65 g (56.8 mM) of DBU were added and the mixture was stirred for 4 hours at room temperature. The medium was concentrated under reduced pressure and the residue was then dissolved in 120 mL of acetic acid. This mixture was brought to 60° C. and 2.60 g (46.6 mM) of iron were added. The medium was heated at 70° C. overnight. The medium was diluted with water and the precipitate formed was filtered off and washed three times with water. The solid was dissolved in ethyl acetate, and the solution was filtered. The filtrate obtained was concentrated under reduced pressure. The title product was obtained in the form of a brown solid (5.70 g, yield=95%). m.p.=142° C.
PREPARATION 6
ethyl 1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate
1.55 g (38.7 mM) of sodium hydride at 60% in oil were suspended in 20.0 mL of THF under argon. A solution of 5.0 g (19.36 mM) of ethyl 5-trifluoromethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Preparation 5) in 20.0 mL of THF was prepared and this solution was then added slowly to the reaction mixture. The medium was stirred for 1 hour at room temperature, followed by addition of 6.76 g (29.0 mM) of 3-tert-butylbenzenesulfonyl chloride, and this reaction mixture was stirred at room temperature overnight. The medium was diluted with water and then extracted with ethyl acetate. The organic phase was washed with saturated saline solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue was purified by chromatography on silica gel using 90/10 (v/v) cyclohexane/ethyl acetate as eluent. The fractions containing the expected product were combined and concentrated under reduced pressure. The title product was obtained in the form of a white solid (7.25 g, yield=82%). m.p.=70° C.
PREPARATION 7
[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-e]pyridin-2-yl]methanol
A solution of 7.25 g (15.9 mM) of ethyl 1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Preparation 6) in 140 mL of toluene was prepared, under argon. This solution was cooled to −78° C. and 40 mL of DIBAL-H at 1.0 mol/L in toluene were added dropwise. This reaction mixture was stirred for 3 hours at −70° C. The medium was diluted with 300 mL of water, and sodium hydrogen carbonate solution and ethyl acetate were then added. This mixture was stirred for 2 days at room temperature. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue was purified by chromatography on silica gel using a 90/10 to 70/30 (v/v) cyclohexane/ethyl acetate gradient. The fractions containing the expected product were combined and concentrated under reduced pressure. The title product was obtained in the form of a beige-coloured solid (4.08 g, yield=62%).
1H NMR (300 MHz, DMSO) δ=9.43 (s, 1H), 8.19 (s, 1H), 8.00 (d, 1H), 7.93 (d, 1H), 7.80 (d, 1H), 7.57 (t, 1H), 6.99 (s, 1H), 5.85 (m, 1H), 4.92 (d, 2H), 1.23 (s, 9H)
PREPARATION 8
2-bromomethyl-1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoro-methyl-1H-pyrrolo[2,3-c]pyridine
This compound was obtained in the form of a white solid from the compound of Preparation 7, by following the procedure described in Preparation 3 (yield=68%). m.p.=115° C.
EXAMPLE 2
3-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-2-benzoic acid
This compound was obtained in the form of a white solid by following the procedure described in Example 1, from the compound of Preparation 8 and 3-(dihydroxyboryl)benzoic acid (yield=36%). m.p.=196° C.
EXAMPLE 3
2-chloro-4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]benzoic acid
This compound was obtained in the form of a white solid by following the procedure described in Example 1, from the compound of Preparation 8 and 4-(dihydroxyboryl)-2-chlorobenzoic acid (yield=21%).
1H NMR (500 MHz, DMSO) δ=13.35 (s, 1H), 9.45 (s, 1H), 8.15 (s, 1H), 7.78 (m, 4H), 7.52 (t, 1H), 7.39 (s, 1H), 7.26 (d, 1H), 6.70 (s, 1H), 4.56 (s, 2H), 1.20 (s, 9H).
EXAMPLE 4
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]furan-3-carboxylic acid
This compound was obtained in the form of a brown solid by following the procedure described in Example 1, from the compound of Preparation 8 and 5-(dihydroxyboryl)-3-furancarboxylic acid (yield=8%).
1H NMR (500 MHz, DMSO) δ=12.70 (s, 1H), 9.45 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.82 (m, 3H), 7.54 (t, 1H), 6.72 (s, 1H), 6.49 (s, 1H), 4.59 (s, 2H), 1.20 (s, 9H).
EXAMPLE 5
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]pyridine-3-carboxylic acid
This compound was obtained in the form of a brown-black solid by following the procedure described in Example 1, from the compound of Preparation 8 and 5-(dihydroxyboryl)-3-pyridinecarboxylic acid (yield=7%).
1H NMR (500 MHz, DMSO) δ=13.50 (s, 1H), 9.45 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.77 (m, 3H), 7.51 (t, 1H), 6.72 (s, 1H), 4.63 (s, 2H), 1.19 (s, 9H).
EXAMPLE 6
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]thiophene-2-carboxylic acid
This compound was obtained in the form of a brown solid by following the procedure described in Example 1, from the compound of Preparation 8 and 4-(dihydroxyboryl)-2-thiophenecarboxylic acid (yield=11%).
1H NMR (500 MHz, DMSO) δ=13.15 (s, 1H), 9.45 (s, 1H), 8.14 (s, 1H), 7.78 (m, 3H), 7.64 (s, 1H), 7.57 (s, 1H), 7.52 (t, 1H), 6.69 (s, 1H), 4.50 (s, 2H), 1.20 (s, 9H).
EXAMPLE 7
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]-2-fluorobenzoic acid
This compound was obtained in the form of a brown solid by following the procedure described in Example 1, from the compound of Preparation 8 and 5-(dihydroxyboryl)-2-fluorobenzoic acid (yield=18%).
1H NMR (500 MHz, DMSO) δ=13.25 (s, 1H), 9.40 (s, 1H), 8.13 (s, 1H), 7.77 (m, 3H), 7.69 (m, 1H), 7.51 (m, 2H), 7.27 (t, 1H), 6.62 (s, 1H), 4.53 (s, 2H), 1.20 (s, 9H).
PREPARATION 9
[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]acetonitrile
A solution of 1.62 g (3.41 mM) of 2-bromomethyl-1-(3-tert-butylbenzenesulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine (Preparation 3) in 13 ml of DCM was prepared. 3.24 mL of water, 0.11 g (0.34 mM) of tetrabutylammonium bromide and 0.33 g (5.11 mM) of potassium cyanide were added. This reaction mixture was stirred at room temperature for three days. 100 mL of 10% sodium thiosulfate solution were added to the medium and the resulting mixture was extracted with 100 mL of DCM three times. The organic phases were dried over magnesium sulfate and combined, and then concentrated under reduced pressure. The evaporation residue was purified by chromatography on silica gel using 95/5 and then 90/10 (v/v) cyclohexane/ethyl acetate as eluent. The fractions containing the expected product were combined and concentrated under reduced pressure. The title product was obtained in the form of a yellow resin (280 mg, yield=19%).
1H NMR (300 MHz, DMSO) δ=8.67 (d, 1H), 7.92-7.50 (m, 4H), 7.20 (s, 1H), 4.68 (s, 2H), 1.22 (s, 9H).
PREPARATION 10
2-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]thioacetamide
A solution of 280 mg (0.66 mM) of [1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]acetonitrile (Preparation 9) in 5.6 mL of THF and 11.2 mL of water was prepared. 494 mg (2.66 mM) of diethyl dithiophosphate were added, and this reaction mixture was then stirred overnight at 100° C. 2000 mg (10.74 mM) of diethyl dithiophosphate were added and stirring was continued at 100° C. for 4 hours. The medium was diluted with 100 mL of water and the mixture was then extracted 4 times with 50 mL of DCM. The organic phases were dried over magnesium sulfate, combined and concentrated under reduced pressure. The evaporation residue was purified by chromatography on silica gel using 90/10, then 80/20 and 70/30 cyclohexane/ethyl acetate as eluent. The fractions containing the expected product were combined and concentrated under reduced pressure. The title product was obtained in the form of a yellow solid (280.00 mg, yield=92%).
1H NMR (300 MHz, DMSO) δ=8.62 (d, 1H), 7.76-7.83 (m, 4H), 7.57 (t, 1H), 6.95 (s, 1H), 4.40 (s, 2H), 1.22 (s, 9H).
EXAMPLE 8
2-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]thiazole-4-carboxylic acid
A solution of 200 mg (0.44 mM) of 2-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]thioacetamide (Preparation 10) in 2.0 mL of ethanol was prepared, and 110 mg (0.66 mM) of bromopyruvic acid were then added. This reaction mixture was stirred for 24 hours at room temperature. 150 mL of ethyl acetate were added to the medium, and the resulting mixture was then washed three times with 50 mL of 10% sodium carbonate and then with 50 mL of 0.2 M hydrochloric acid. The organic phase was dried over magnesium sulfate and then filtered and concentrated under reduced pressure. The title product was obtained in the form of a white solid (94 mg, yield=41%). m.p.=180° C.
PREPARATION 11
N-(3-iodo-5-trifluoromethylpyridin-2-yl)-4-(1-methylethyl)benzenesulfonamide
This compound was obtained in the form of a yellow solid, by following the procedure described in Preparation 1, starting with 3-iodo-5-trifluoromethylpyridin-2-ylamine and 4-isopropylbenzenesulfonyl chloride (yield=52%). m.p.=124° C.
PREPARATION 12
methyl 4-prop-2-ynylbenzoate
A solution of 5.97 g (31.4 mM) of methyl 4-(1-hydroxyprop-2-ynyl)benzoate in 40 mL of DCM was prepared. 20 mL (62.9 mM) of trifluoroacetic acid and then 10.0 mL (62.9 mM) of triethylsilane were added. This reaction mixture was stirred at room temperature for 7 days. The medium was concentrated under reduced pressure. The evaporation residue was purified by chromatography on silica gel using 95/5 (v/v) cyclohexane/ethyl acetate as eluent. The fractions containing the expected product were combined and concentrated under reduced pressure. The title product was obtained in the form of a white solid (3.23 g, yield=61%). m.p.=78° C.
EXAMPLE 9
methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]benzoate
This compound was obtained in the form of a beige-coloured solid by following the procedure described in Preparation 2, starting with the compounds of Preparations 11 and 12 (yield=56%). m.p.=123° C.
EXAMPLE 10
4-[[1-[[3-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid
A solution of 140 mg (0.27 mM) of methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]-benzoate (Example 9) in 16.0 mL of THF and 4.0 mL of water was prepared. 13.65 mg (0.33 mM) of lithium hydroxide were added, and this reaction mixture was stirred at room temperature for 22 hours. The medium was diluted with water and then acidified with concentrated hydrochloric acid and extracted twice with DCM. The organic phase was dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue was purified by liquid chromatography with UV detection (LC-UV) (on a SunFire® C18 column) with a water/acetonitrile/0.1% TFA mixture as eluent. The fractions containing the expected product were combined and concentrated under reduced pressure. The title product was obtained in the form of a white solid (113 mg, yield=83%). m.p.=218° C.
PREPARATION 13
4-iodo-6-trifluoromethylpyridin-3-ylamine
a) tert-butyl (6-trifluoromethylpyridin-3-yl)carbamate
A solution of 5.0 g (30.84 mM) of 3-amino-6-(trifluoromethyl)pyridine and 6.73 g (30.84 mM) of di-tert-butyl dicarbonate in 30 mL of 1,4-dioxane was prepared. This reaction mixture was stirred at reflux for 19 hours. 8.08 g (37.01 mM) of di-tert-butyl dicarbonate were added and the medium was stirred at reflux for 24 hours. 6.73 g (30.84 mM) of di-tert-butyl dicarbonate were added and the medium was stirred at reflux for 24 hours. The medium was concentrated under reduced pressure and the evaporation residue was purified by chromatography on silica gel using 90/10 (v/v) cyclohexane/ethyl acetate as eluent. The fractions containing the expected product were combined and concentrated under reduced pressure. The protected product was obtained in the form of a beige-coloured solid (10.9 g, yield=100%). m.p.=117° C.
b) tert-butyl (4-iodo-6-trifluoromethylpyridin-3-yl)carbamate
A solution of 10.80 g (41.19 mM) of tert-butyl (6-trifluoromethylpyridin-3-yl)carbamate in 300 mL of diethyl ether was prepared. 15.5 mL of N,N,N′,N′tetramethylethylenediamine were added. This reaction mixture was cooled to −78° C. in a bath of cardice-acetone, followed by dropwise addition over 5 minutes of 64.3 mL (103 mM) of 1.60 M n-butyllithium in hexane. The medium was stirred for 30 minutes at −10° C. and then cooled to −78° C. A solution of 13.59 g (53.5 mM) of iodine in 16.0 mL of THF was added rapidly. The reaction mixture was allowed to warm to room temperature, and was stirred at room temperature for 16 hours. The medium was hydrolysed with 200 mL of water and then with 400 mL of saturated sodium bisulfite solution. It was then extracted with ether. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue was purified by chromatography on silica gel using 100/0 and then 95/5 (v/v) cyclohexane/ethyl acetate as eluent. The fractions containing the expected product were combined and concentrated under reduced pressure. The iodo product was obtained in the form of a yellow oil (5.04 g, yield=37%).
1H NMR (250 MHz, DMSO) δ=9.05 (broad s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 1.40 (s, 9H).
c) 4-iodo-6-trifluoromethylpyridin-3-ylamine
A solution of 5.04 g (13 mM) of tert-butyl (4-iodo-6-trifluoromethylpyridin-3-yl)carbamate in 100 mL of DCM was prepared. 10 mL of trifluoroacetic acid were added to this solution. This reaction mixture was stirred at room temperature for 18 hours. The medium was diluted with water and then extracted with DCM. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue was purified by chromatography on silica gel using 100/0 then 95/5 and 90/10 (v/v) cyclohexane/ethyl acetate as eluent. The fractions containing the expected product were combined and concentrated under reduced pressure. The title product was obtained in the form of a beige-coloured solid (620.00 mg, yield=16%). m.p.=116° C.
PREPARATION 14
N-(2-iodo-4-trifluoromethylpyridin-3-yl)(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonamide
This compound was obtained in the form of a yellow oil by following the procedure described in Preparation 1, starting with 4-iodo-6-trifluoromethylpyridin-3-ylamine (Preparation 13) and 3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-ylsulfonyl chloride (yield=68%).
1H NMR (300 MHz, DMSO) δ=10.14 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 6.95 (m, 2H), 6.80 (d, 1H), 4.29 (t, 2H), 3.29 (t, 2H), 2.80 (s, 3H).
EXAMPLE 11
methyl 4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]benzoate
This compound was obtained in the form of a white solid by following the procedure described in Preparation 2, starting with the compounds of Preparations 12 and 14 (yield=25%). m.p.=207° C.
EXAMPLE 12
4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]benzoic acid
This compound was obtained in the form of a white solid by following the procedure described in Example 10, starting with the compound of Example 11 (yield=43%). m.p.=192° C.
PREPARATION 15
N-(4-trifluoromethyl-6-iodopyridin-3-yl)-4-(1-methylethyl)benzenesulfonamide
This compound was obtained in the form of a beige-coloured solid, by following the procedure described in Preparation 1, starting with 4-iodo-6-trifluoromethylpyridin-3-ylamine (Preparation 13) and 4-(1-methylethyl)benzenesulfonyl chloride (yield=95%). m.p.=156° C.
EXAMPLE 13
methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl]benzoate
This compound was obtained in the form of a beige-coloured solid by following the procedure described in Preparation 2, starting with the compounds of Preparations 12 and 15 (yield=33%). m.p.=160° C.
EXAMPLE 14
4-[[1-[[4-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]benzoic acid
This compound was obtained in the form of a white solid by following the procedure described in Example 10, starting with the compound of Example 13 (yield=24%). m.p.=218° C.
PREPARATION 16
N-(2-iodo-6-trifluoromethylpyridin-3-yl)-4-(1-methylethyl)benzenesulfonamide
This compound was obtained in the form of a pale yellow solid, by following the procedure described in Preparation 1, starting with 2-iodo-6-trifluoromethylpyridin-3-ylamine and 4-isopropylbenzenesulfonyl chloride (yield=98%).
1H NMR (300 MHz, DMSO) δ=10.35 (s, 1H), 7.87 (d, 1H), 7.72 (dd, 2H), 7.62 (d, 1H), 7.48 (d, 2H), 2.98 (m, 1H), 1.20 (d, 6H).
EXAMPLE 15
methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]benzoate
This compound was obtained in the form of a beige-coloured solid by following the procedure described in Preparation 2, starting with the compounds of Preparations 12 and 16 (yield=15%). m.p.=98.5° C.
EXAMPLE 16
4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]benzoic acid
This compound was obtained in the form of a white solid by following the procedure described in Example 10, starting with the compound of Example 15 (yield=14%).
1H NMR (500 MHz, DMSO) δ=12.89 (s, 1H), 8.66 (d, 1H), 7.83 (d, 3H), 7.72 (d, 2H), 7.36 (d, 2H), 7.30 (d, 2H), 6.84 (s, 1H), 4.58 (s, 2H), 2.91 (m, 1H), 1.13 (d, 6H).
PREPARATION 17
N-(3-iodo-5-trifluoromethylpyridin-2-yl)(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonamide
This compound was obtained in the form of a brown oil by following the procedure described in Preparation 1, starting with 3-iodo-5-trifluoromethylpyridin-2-ylamine and 3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-ylsulfonyl chloride (yield=66%).
1H NMR (300 MHz, DMSO) δ=10.43 (s, 1H), 8.54 (s, 2H), 7.33 (s, 1H), 7.24 (d, 1H), 6.80 (d, 1H), 4.28 (t, 2H), 3.28 (t, 2H), 2.88 (s, 3H).
EXAMPLE 17
methyl 4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoate
This compound was obtained in the form of an orange solid by following the procedure described in Preparation 2, starting with the compounds of Preparations 12 and 17 (yield=30%). m.p.=202° C.
EXAMPLE 18
4-[[1-[(3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-yl)sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid
This compound was obtained in the form of a white solid by following the procedure described in Example 10, starting with the compound of Example 17 (yield=21%). m.p.=234° C.
PREPARATION 18
N-(6-chloro-4-iodopyridin-3-yl)-4-(1-methylethyl)benzenesulfonamide
This compound was obtained in the form of an orange solid, by following the procedure described in Preparation 1, starting with 6-chloro-4-iodopyridin-3-ylamine and 4-isopropylbenzenesulfonyl chloride (yield=97%). m.p.=160° C.
EXAMPLE 19
methyl 4-[1-(4-(1-methylethyl)phenylsulfonyl)-5-chloro-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl]benzoate
This compound was obtained in the form of a brown solid by following the procedure described in Preparation 2, starting with the compounds of Preparations 12 and 18 (yield=44%). m.p.=123° C.
EXAMPLE 20
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-c]pyridin-2-yl]methyl]benzoic acid
This compound was obtained in the form of a beige-coloured solid by following the procedure described in Example 10, starting with the compound of Example 19 (yield=13%). m.p.=228° C.
EXAMPLE 21
methyl 4-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]benzoate
This compound was obtained in the form of an orange paste by following the procedure described in Preparation 2, starting with the compounds of Preparations 1 and 12 (yield=4%).
1H NMR (300 MHz, DMSO) δ=8.67 (d, 1H), 7.86 (m, 3H), 7.73 (d, 1H), 7.71 (d, 1H), 7.62 (d, 1H), 7.46 (t, 1H), 7.36 (d, 2H), 6.85 (s, 1H), 4.60 (s, 2H), 3.45 (s, 3H), 1.18 (s, 9H).
EXAMPLE 22
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]benzoic acid
This compound was obtained in the form of a white solid by following the procedure described in Example 10, starting with the compound of Example 21 (yield=33%). m.p.=240° C.
PREPARATION 19
N-(3-iodo-5-trifluoromethylpyridin-2-yl)-3-(1-methylethyl)benzenesulfonamide
This compound was obtained in the form of a yellow oil by following the procedure described in Preparation 1, starting with 3-iodo-5-trifluoromethylpyridin-2-ylamine and 3-isopropylbenzenesulfonyl chloride (yield=84%).
1H NMR (300 MHz, DMSO) δ=10.70 (s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 7.91 (s, 1H), 7.62 (d, 1H), 7.51 (m, 2H), 3.00 (m, 1H), 1.23 (d, 6H).
EXAMPLE 23
methyl 4-{hydroxy[1-(3-(1-methylethyl)phenylsulfonyl)-5-trifluoro-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl}benzoate
This compound was obtained in the form of a yellow oil by following the procedure described in Preparation 2, from the compound of Preparation 19 and methyl 4-(1-Hydroxyprop-2-ynyl)benzoate (yield=60%).
1H NMR (300 MHz, DMSO) δ=8.72 (s, 1H), 8.49 (s, 1H), 7.98 (d, 2H), 7.79 (d, 1H), 7.54 (m, 4H), 7.43 (t, 1H), 6.86 (s, 1H), 6.57 (m, 2H), 3.87 (s, 3H), 2.74 (m, 1H), 1.08 (dd, 6H).
EXAMPLE 24
methyl 4-[1-(3-(1-methylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]benzoate
A solution of 220 mg (0.41 mM) of methyl 4-{hydroxy[1-(3-isopropylbenzenesulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl}-benzoate (Example 23) in 10 mL of DCM was prepared. This solution was cooled to 0° C. with an ice bath, and 4.19 mL (33.05 mM) of boron trifluoride diethyl etherate (4.19 mL; 33.05 mM; 80.00 eq.) and 2.0 mL (12.39 mM) of triethylsilane were then added. This reaction mixture was stirred at room temperature overnight. The medium was hydrolysed slowly with saturated sodium carbonate solution and then extracted with DCM. The organic phase was washed with water and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue was purified by chromatography on silica gel using 95/5 and then 90/10 (v/v) cyclohexane/ethyl acetate as eluent. The fractions containing the expected product were combined and concentrated under reduced pressure. The product obtained was washed with cyclohexane and then filtered through Whatman filter paper. The title product was obtained in the form of a white solid (90 mg, yield=42%). m.p.=110° C.
EXAMPLE 25
4-[[1-[[3-(1-methylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid
This compound was obtained in the form of a white solid by following the procedure described in Example 10, starting with the compound of Example 24 (yield=17%). m.p.=203° C.
PREPARATION 20
N-(3-iodo-5-trifluoromethylpyridin-2-yl)-3-(1,1-dimethylethyl)-benzenesulfonamide
This compound was obtained in the form of a beige-coloured solid by following the procedure described in Preparation 1, starting with 3-iodo-5-trifluoromethylpyridin-2-ylamine and 3-tert-butylbenzensulfonyl chloride (yield=72%). m.p.=135° C.
EXAMPLE 26
methyl 4-{hydroxy[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl}benzoate
This compound was obtained in the form of a yellow oil by following the procedure described in Preparation 2, from the compound of Preparation 20 and methyl 4-(1-hydroxyprop-2-ynyl)benzoate (yield=92%).
1H NMR (300 MHz, DMSO) δ=8.73 (d, 1H), 8.47 (d, 1H), 8.12 (d, 1H), 7.97 (d, 2H), 7.65-7.73 (m, 2H), 7.52 (d, 2H), 7.42 (t, 1H), 6.75 (s, 1H), 6.57 (m, 2H), 3.87 (s, 3H), 1.21 (s, 9H).
EXAMPLE 27
methyl 4-[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]benzoate
This compound was obtained in the form of a yellow oil by following the procedure described in Example 24, starting with the compound of Example 26 (yield=92%). This compound was used as obtained in the following example.
EXAMPLE 28
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid
This compound was obtained in the form of a white solid by following the procedure described in Example 10, starting with the compound of Example 27 (yield=22%). m.p.=209° C.
PREPARATION 21
N-(5-chloro-3-iodopyridin-2-yl)-4-(1-methylethyl)benzene-sulfonamide
This compound was obtained in the form of an orange solid, by following the procedure described in Preparation 1, starting with 5-chloro-3-iodopyridin-3-ylamine and 4-isopropylbenzenesulfonyl chloride (yield=15%).
1H NMR (250 MHz, DMSO) δ=10.42 (s, 1H), 8.40 (d, 1H), 8.23 (s, 1H), 7.91 (d, 2H), 7.44 (d, 2H), 2.97 (m, 1H), 1.21 (d, 6H).
EXAMPLE 29
methyl 4-{hydroxy[5-chloro-1-(4-(1-methylethyl)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl}benzoate
This compound was obtained in the form of a yellow solid by following the procedure described in Preparation 2, from the compound of Preparation 21 and methyl 4-(1-hydroxyprop-2-ynyl)benzoate (yield=58%). m.p.=77° C.
EXAMPLE 30
methyl 4-[5-chloro-1-(4-(1-methylethyl)phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl]benzoate
This compound was obtained in the form of a beige-coloured solid by following the procedure described in Example 24, starting with the compound of Example 29 (yield=77%). m.p.=186° C.
EXAMPLE 31
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid
This compound was obtained in the form of a white solid by following the procedure described in Example 10, starting with the compound of Example 30 (yield=100%). m.p.=227° C.
PREPARATION 22
5-(1-hydroxyprop-2-ynyl)thiophene-2-carboxylic acid
A solution of 2.342 g (15.0 mM) of 5-formyl-2-thiophenecarboxylic acid in 23.4 mL of distilled THF was prepared. 60.0 mL of a solution of ethylmagnesium bromide (0.50 mol/1; 30.0 mM) were added dropwise. The medium was stirred at room temperature for two hours. It was then poured into a mixture of 200 mL of ice and 70 mL of 1 M HCl and extracted with 100 mL of DCM and then twice 50 mL. The organic phases were dried over magnesium sulfate and combined, and then concentrated under reduced pressure. The title product was obtained in the form of a beige-coloured solid (2.6 g, yield=100%). m.p.=128° C.
EXAMPLE 32
5-{hydroxy[1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl}thiophene-2-carboxylic acid
This compound was obtained in the form of a white solid by following the procedure described in Preparation 2, from the compound of Preparation 1 and Preparation 22 (yield=5%). m.p.=100° C.
EXAMPLE 33
5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]fluoromethyl]-N,N-diethyl-2-thiophenecarboxamide
A solution of 160 mg (0.30 mM) of 5-{hydroxy[1-(3-(1,1-dimethylethyl)-phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl}thiophene-2-carboxylic acid (Example 32) in 10 mL of DCM was prepared. 238.55 μl of (n-Bu)3N (1.0 mM) were added and the medium was then stirred for 5 minutes. The solvent and the excess reagent were evaporated off. The amorphous solid obtained was redissolved in 10 mL of DCM. This solution was cooled to −78° C. under an argon atmosphere. 238.75 μl of DAST (1.78 mM) were added dropwise. The medium was stirred for 1 hour at −78° C., and was then allowed to warm to room temperature and was stirred for a further 1 hour. 100 mL of sodium carbonate solution were added, followed by 40 mL of 10 M HCl solution, and the mixture was extracted with 100 mL of DCM and then twice with 50 mL. The organic phases were combined and dried over magnesium sulfate, and the solvent was evaporated off. The evaporation residue was purified by semi-preparative LC-MS liquid chromatography (on a SunFire® C18 column) eluting with a water/acetonitrile mixture. The fractions containing the expected product were combined and concentrated to dryness. The title product was obtained in the form of a brown solid (19.85 mg, yield=11%).
1H NMR (500 MHz, DMSO) δ=8.75 (d, 1H), 7.93 (d, 1H), 7.81 (t, 1H), 7.76 (d, 1H), 7.72 (d, 1H), 7.69 (d, 1H), 7.49 (t, 1H), 7.32 (dd, 2H), 7.30 (d, 1H), 3.46 (broad s, 4H), 1.18 (m, 15H).
EXAMPLE 34
5-{1-(3-(1,1-dimethylethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carbonyl}thiophene-2-carboxylic acid
A solution of 110.00 mg (0.20 mM) of 5-{hydroxy[1-(3-(1,1-dimethyl-ethyl)phenylsulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl}thiophene-2-carboxylic acid (Example 32) in 5 mL of acetonitrile and 5 mL of water was prepared. 260.95 mg (1.84 mM) of sodium hydrogen phosphate were added. The medium was stirred for 15 minutes at room temperature. 110.83 mg of sodium chlorite (1.22 mM), 0.24 mL (13.0 g/1; 0.04 mM) of a sodium hypochlorite solution and 3.19 mg of 2,2,6,6-tetramethylpiperidine-1-oxyl (0.02 mM) were added. The medium was stirred for 5 hours at room temperature. 25 mL of 10% thiosulfate solution, 50 mL of water and 25 mL of M HCl were added and the mixture was then extracted four times with 50 mL of DCM. The organic phases were combined and dried over magnesium sulfate, and the solvent was evaporated off. The evaporation residue was purified by semi-preparative LC-MS liquid chromatography (on a SunFire® C18 column) eluting with a water/acetonitrile mixture. The fractions containing the expected product were combined and concentrated to dryness. The title product was obtained in the form of a white solid (12 mg, yield=11%). m.p.=108° C.
EXAMPLE 35
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid, sodium salt
A solution of 50 mg (0.11 mM) of 4-[[5-chloro-1-[[4-(1-methylethyl)-phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid (Example 31) in 2.5 mL of THF was prepared. 0.21 mL of sodium hydroxide (0.50 mol/1; 0.11 mM) was added. The reaction medium was stirred overnight at room temperature and then evaporated under vacuum to obtain 31 mg of sodium salt in the form of a white solid (yield=63%). m.p.=218° C.
1H NMR (400 MHz, DMSO) δ=8.32 (d, 1H), 8.05 (d, 1H), 7.82 (d, 2H), 7.79 (d, 2H), 7.36 (d, 2H), 7.15 (d, 2H), 6.30 (s, 1H), 4.47 (s, 2H), 2.91 (m, 1H), 1.15 (d, 6H).
EXAMPLE 36
4-[[5-chloro-1-[[4-(1-methylethyl)phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid, piperazine salt
A solution of 46.20 mg (0.10 mM) of 4-[[5-chloro-1-[[4-(1-methylethyl)-phenyl]sulfonyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]benzoic acid (Example 31) in 4 mL of THF was prepared. 8.49 mg of piperazine (0.10 mM) were added. The reaction medium was stirred for 24 hours at room temperature and then evaporated under vacuum to obtain 40 mg of piperazine salt in the form of a white solid (yield=80%). m.p.=105° C.
1H NMR (400 MHz, DMSO) δ=8.34 (d, 1H), 8.08 (d, 1H), 7.86 (d, 2H), 7.79 (d, 2H), 7.36 (d, 2H), 7.27 (d, 2H), 6.37 (s, 1H), 4.53 (s, 2H), 2.91 (m, 1H), 2.79 (s, 8H), 1.14 (d, 6H).
PREPARATION 23
1-(3-(1,1-dimethylethyl)phenylsulfonyl)-2,3-dimethyl-5-trifluoro-methyl-1H-pyrrolo[3,2-b]pyridine
A solution of 242.14 mg (0.50 mM) of the compound of Preparation 1 in 10 mL of DMF was prepared. 11.22 mg (0.04 mM) of palladium acetate, 21.20 mg (0.50 mM) of anhydrous lithium chloride, 345.51 mg (2.50 mM) of potassium carbonate and then 135.23 mg (2.5 mM) of 2-butyne were added. The medium was irradiated with microwaves for 30 minutes at 100° C. 100 mL of water were added. The resulting mixture was extracted with four times 100 mL of DCM and then with four times 100 mL of ethyl acetate. The organic phases were dried over magnesium sulfate. The medium was concentrated under reduced pressure and the evaporation residue was purified by chromatography on silica gel using 95/5 (v/v) cyclohexane/ethyl acetate as eluent. 220 mg of title product were obtained in the form of a yellow oil (yield=91.5%).
1H NMR (300 MHz, DMSO) δ=8.66 (d, 1H), 7.81 (d, 1H), 7.77 (m, 2H), 7.69 (dt, 1H), 7.53 (t, 1H), 2.61 (s, 3H), 2.18 (s, 3H), 1.21 (s, 9H).
EXAMPLE 37
4-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-3-methyl-5-(trifluoro-methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]methyl]benzoic acid
A solution of 310.0 mg (0.76 mM) of 1-(3-(1,1-dimethylethyl)phenylsulfonyl)-2,3-dimethyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine (Preparation 23) in 5 mL of carbon tetrachloride was prepared. 180.0 mg (1.01 mM) of N-bromosuccinimide (NBS) were added and the medium was then brought to reflux. 12.40 mg (0.08 mM) of azobisisobutyronitrile (AIBN) were then added and the medium was then stirred at reflux for 24 hours. A degree of conversion of 50% was observed. A further 200.00 mg (1.12 mM) of NBS and then 24.8 mg (0.16 mM) of AIBN were added and stirring at reflux was continued for 24 hours. 25 mL of DCM were added to the medium and the solvents were evaporated off. The evaporation residue was purified by chromatography on silica gel using 95/5 (v/v) cyclohexane/ethyl acetate as eluent, to give 435 mg of 2-bromomethyl-1-(3-(1,1-dimethylethyl)phenylsulfonyl)-3-methyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine in the form of an orange solid (purity=58%).
A solution of 200.0 mg (0.41 mM) of the preceding compound in a mixture of 10 mL of dimethyl ether (DME) and 2 mL of water was prepared. 33.38 mg (0.04 mM) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichlorure-dichloromethane complex, 101.73 mg (0.61 mM) of 4-carboxyphenylboronic acid and 399.50 mg (1.23 mM) of caesium carbonate were added. The medium was stirred at reflux for 2 hours. 100 mL of water and 100 mL of M HCl were added and the resulting mixture was extracted with four times 100 mL of DCM. The organic phases were dried over magnesium sulfate and the solvent was evaporated off. The evaporation residue was purified by semi-preparative LC-MS liquid chromatography (on a Discovery® column), eluting with a water/acetonitrile/TFA mixture. The fractions containing the expected product were combined and concentrated to dryness. The target product was obtained in the form of a beige-coloured solid (20 mg, yield=9.6%).
PREPARATION 24
[1-(4-(1,1-methylethyl)phenylsulfonyl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl]methanol
This compound was obtained in the form of a beige-coloured solid by following the procedure described in Preparation 2, from the compound of Preparation 21 and 2-propyn-1-ol (yield=78%). m.p.=140° C.
PREPARATION 25
2-bromomethyl-[1-(4-(1,1-methylethyl)phenylsulfonyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine
This compound was obtained in the form of a white solid from the compound of Preparation 24, by following the procedure described in Preparation 3 (yield=65%). m.p.=138° C.
EXAMPLE 38
5-[[1-[[4-(1,1-methylethyl)phenyl]sulfonyl]-5-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]thiophene-2-carboxylic acid
This compound was obtained in the form of a beige-coloured solid by following the procedure described in Example 1, from the compound of Preparation 25 and 5-(dihydroxyboryl)-2-thiophenecarboxylic acid (yield=3%). m.p.=210-243° C.
EXAMPLE 39
N-{4-[1-(3-tert-butylbenzenesulfonyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl]benzoyl}methanesulfonamide
A solution of 240 mg (0.46 mM) of the compound of Example 22 in 12 mL of dichloromethane was prepared. 89.07 mg (0.46 mM) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), 56.76 mg (0.46 mM) of 4-dimethylaminopyridine and 88.839 mg (0.93 mM) of methanesulfonamide were added. The reaction medium was stirred for 20 hours at room temperature. It was then concentrated under reduced pressure and the evaporation residue was purified by preparative liquid chromatography (LC-MS), eluting with an H2O/CH3CN/0.1% TFA mixture. The fractions containing the expected product were combined and concentrated under reduced pressure to give the desired product in the form of a white solid (yield: 39%). m.p.=95° C.
Pharmacological Activity
The compounds of the invention underwent biological tests so as to evaluate their potential for treating or preventing certain neurodegenerative pathologies.
The ability of the compounds according to the invention to behave as activators of the heterodimers formed by the NURR-1 nuclear receptor and the RXR nuclear receptors was measured, by means of an in vitro test.
A transactivation test was used as a primary screening test. Cos-7 cells were co-transfected with a plasmid expressing a construct of the NURR-1-Ga14 human receptor, a plasmid expressing the RXR human receptor (RXRα or RXRγ receptor) and a reporter plasmid 5Gal4pGL3-TK-Luc. The transfections were performed using a chemical agent (Jet PEI).
The transfected cells were distributed into 384-well plates and left to stand for 24 hours.
After 24 hours, the culture medium was changed. The test products were added (final concentration of between 10−4 and 3×10−10 M) in the culture medium. After incubating overnight, the luciferase expression was measured after addition of “SteadyGlo” according to the manufacturer's instructions (Promega).
4-[[6-Methyl-2-phenyl-5-(2-propenyl)-4-pyrimidinyl]amino]benzoic acid (reference XCT0135908, described by Wallen-Mackenzie et al. 2003, Genes & Development 17: 3036-3047) at 2×10−5 M (RXR agonist) was used as reference.
The levels of induction were calculated relative to the basal activity of each heterodimer. The results were expressed as a percentage of the level of induction relative to the level of induction obtained with the reference (the level of induction of the reference is arbitrarily equal to 100%).
By way of example, among the compounds according to the invention, the following results are obtained expressed as a percentage relative to a reference activator compound NURR-1/RXR(XCT0135908):
hNurr1_RXRγFL
hNurr1_RXRαFL
Example
EC50 (nM)
Eff (%)
EC50 (nM)
Eff (%)
1
73
64
25
67
2
100
86
52
70
4
—
—
35
104
5
—
—
2344
94
6
—
—
17
137
7
—
—
11
119
8
1514
72
1023
103
10
576
82
337
68
12
761
75
310
81
14
771
54
541
64
16
1052
53
575
68
18
495
69
194
62
20
1189
27
731
42
22
93
68
42
92
25
nc
52
nc
57
28
803
51
634
66
31
1346
48
713
63
32
—
—
288
84
33
—
—
1820
92
34
—
—
1000
31
35
—
—
481
61
36
—
—
361
71
37
—
—
146
67
38
—
—
295
80
39
—
—
269
51
—: not tested
nc: not calculable
Eff: percentage efficacy relative to the reference XCT0135908
The compounds according to the invention show a level of induction that is up to 137% (NURR1/RXRα) and 86% (NURR1/RXRγ□□) and EC50 values that are up to 11 nM (NURR1/RXRα) and 73 nM (NURR1/RXRγ□□).
These in vitro results show that the compounds of the invention are capable of modifying the mechanisms of the disease on certain cell models, and of stopping the degenerative process by generating neuroprotective agents that can combat the cell death of dopaminergic neurons. They therefore confirm the advantage of these compounds for their use as active principles of medicaments for preventing and/or treating neurodegenerative diseases and more particularly Parkinson's disease.
The invention also relates to a pharmaceutical composition containing, as active principle, at least one compound of formula (I), or a pharmaceutically acceptable salt thereof.
According to another aspect, the present patent application is directed towards covering the use of a compound of formula (I) or of a pharmaceutical composition containing such a compound, for the prevention and/or treatment of diseases in which the NURR-1 receptor is involved, especially neurodegenerative diseases and more particularly Parkinson's disease.
According to another aspect, the present patent application is directed towards covering a method for preventing and/or treating diseases in which the NURR-1 receptor is involved, especially neurodegenerative diseases and more particularly Parkinson's disease, which consists in administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition containing such a compound.
The pharmaceutical compositions in accordance with the invention may be prepared conventionally, using pharmaceutically acceptable excipients, in order to obtain forms for parenteral or, preferably, oral administration, for example tablets or gel capsules.
In the case of injectable forms, the compounds of formula (I) will advantageously be used in the form of soluble salts in an aqueous medium. As indicated previously, the salts are preferentially formed between a compound of formula (I) and a pharmaceutically acceptable non-toxic base. The formulation may be either a solution of the compound in an isotonic aqueous medium in the presence of soluble excipients, or a lyophilizate of the compound to which the dilution solvent is extemporaneously added. These preparations may be injected in perfusion form or as a bolus, as a function of the patient's requirements.
In practice, in the case of parenteral administration of the compound, the daily dosage in man will preferably be between 2 and 250 mg.
The preparations for oral administration will preferably be in the form of a gel capsule or a tablet containing the finely ground or better still micronized compound of the invention, and mixed with excipients known to those skilled in the art, for instance lactose, pregelatinized starch and magnesium stearate.
By way of example, a mixture formed from 500 g of the finely ground compound of Example 2, 500 g of pregelatinized starch, 1250 g of lactose, 15 g of sodium lauryl sulfate and 235 g of polyvinylpyrrolidone was granulated. This granulated mixture was then added to 20 g of magnesium stearate and 80 g of microcrystalline cellulose, and the mixture obtained was divided, after milling and screening, into 260-mg gel capsules. Gel capsules each containing 50 mg of active principle were thus obtained.
In practice, in the case of oral administration of the compound, the daily dosage in man will preferably be between 5 and 500 mg. To this effect, unit doses comprising from 5 to 250 mg of active principle and preferably unit doses comprising from 5 to 100 mg of active principle may be used.
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13519774
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laboratoires fournier sa
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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514/230.5
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Mar 31st, 2022 02:21PM
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Mar 31st, 2022 02:21PM
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AbbVie
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:abbv
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AbbVie
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Apr 22nd, 2008 12:00AM
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Jun 12th, 2003 12:00AM
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https://www.uspto.gov?id=US07361687-20080422
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Arylsulphonamide derivatives and methods of preparing
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The present invention relates to novel arylsulphonamide compounds, defined by formula I and the description, as well as their method of preparation and their therapeutic use
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7361687
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1. A compound of formula I:
wherein:
R1 is aromatic group, where said aromatic is optionally substituted by one or more atoms or groups of atoms selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy;
R2 is hydrogen or C1-C4 alkyl, where said C1-C4 alkyl is optionally monosubstituted by a phenyl or —CONH2 or optionally substituted by one or more fluorine atoms;
R3 is hydrogen or hydroxy;
R4 is hydrogen;
or R4, together with R3, forms a —CH═N— or a straight or branched C2-C4 alkylene;
R5 is hydrogen or C1-C3 alkyl;
R6 is hydrogen or halogen;
Y is straight or branched saturated C2-C4 alkylene or straight or branched unsaturated C2-C4 alkylene, where said C2-C4 alkylene is optionally interrupted between two carbon atoms by an oxygen atom;
or an acid addition salt thereof.
2. A compound according to claim 1,
wherein R1 is chlorophenyl, dichlorophenyl, trichlorophenyl, chloro-methoxyphenyl, chloro-trifluoromethoxyphenyl, dichloro-trifluoromethyl-phenyl, chlorofluorophenyl, difluorophenyl, trifluoromethyl-phenyl, trifluoromethyl-methoxyphenyl, trifluoromethyl-chlorophenyl trifluoromethoxy-phenyl, tolyl, chlorotolyl, dichlorotolyl, dimethyltolyl, methoxytolyl, methoxy-methyltolyl, dichloromethoxy, trifluoromethoxy-tolyl, naphthyl, nitrophenyl, trifluoromethyl-nitrophenyl, cyanophenyl, or thienyl.
3. A compound according to claim 1,
wherein R1 is phenyl substituted by one or more atoms or groups of atoms selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 alkoxy.
4. A compound according to claim 1,
wherein R2 is C1-C4 alkyl.
5. A compound according to claim 1,
wherein R2 is hydrogen, methyl, cyclopropyl, trifluoroethyl, isopropyl, —CH2CONH, —(CH2)2CONH, or phenethyl.
6. A compound according to claim 1,
wherein R3 is hydrogen.
7. A compound according to claim 1,
wherein R3 is hydroxy.
8. A compound according to claim 1,
wherein R4 is hydrogen.
9. A compound according to claim 1,
wherein R3 and R4 together form a —N═CH— or C2-C3 alkylene.
10. A compound according to claim 1,
wherein R3 and R4 together form —N═CH—, —(CH2)2—, or —CH2—C(CH3)2—.
11. A compound according to claim 1,
wherein R5 is hydrogen, methyl, ethyl, or isopropyl.
12. A compound according to claim 1,
wherein R6 is hydrogen, difluoro, or dichloro.
13. A compound according to claim 1,
wherein R5 and R6 are hydrogen.
14. A compound according to claim 1,
wherein Y is saturated C2-C4 alkylene or saturated C2-C4 alkylene interrupted by an oxygen atom.
15. A compound according to claim 1,
wherein Y is —(CH2)2—, —(CH2)3—, —(CH2)4—, —CH2—CH═CH—, —(CH2)2—O—CH2—, or
16. A compound according to claim 1,
wherein Y is —(CH2)4—.
17. A compound according to claim 1,
wherein Y is —(CH2)2—O—CH2—.
18. A compound according to claim 1,
wherein said compound is:
5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-butanamide;
3-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide;
4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-(2E)-2-butenamide;
5-[[(2-chlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
(2E)-4-[[(2-chlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
3-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide;
4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-butanamide;
5-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
(2E)-4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
5-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
(2E)-4-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
5-[methyl[(1-naphthalenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
(2E)-4-[methyl[(1-naphthalenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
5-[[(2-chlorophenyl)sulphonyl]cyclopropylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
5-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
5-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
5-[[(2,6-dichlorophenyl)sulphonyl](1-methylethyl)amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
5-[(2-amino-2-oxoethyl)[(2,4-dichloro-3-methylphenyl)sulphonyl]-amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
5-[(3-amino-3-oxopropyl)[(2,4-dichloro-3-methylphenyl)sulphonyl]-amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
3-[[(2,3-dichlorophenyl)sulphonyl](1-methylethyl)amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide;
3-[[(2,6-dichlorophenyl)sulphonyl](1-methylethyl)amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide;
2-[2-[[(2-chlorophenyl)sulphonyl]cyclopropylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl](2-phenylethyl)-amino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
3-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide;
3-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide;
3-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide;
3-[(2,2,2-trifluoroethyl)[(2,3-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide;
3-[(2,2,2-trifluoroethyl)[(2,6-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide;
N-[[4-(4,5-dihydro-1H-imidazol-2yl)phenyl]methyl]-N-methyl-4-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-(2E)-2-butenamide;
4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-(2E)-2-butenamide;
5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(5,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(5,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-methyl-N-[[4-(1,4,5,6-tetrahydro-2-pyrimidinyl)phenyl]methyl]acetamide;
2-[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,6-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2-chlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[2-fluoro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]propoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-methyl-N-[[4-(1,4,5,6-tetrahydro-2-pyrimidinyl)phenyl]methyl]acetamide;
2-[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]ethoxy]-acetamide;
2-[2-[[(2,4-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,4-dichloro-5-methylphenyl)sulphonyl]methylamino]-ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[(2-nitrophenyl)sulphonyl]amino]ethoxy]acetamide;
2-[2-[[[2,6-dichloro-4-(trifluoromethyl)phenyl]sulphonyl]-methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2-chloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2-cyanophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[(2,3,4-trichlorophenyl)sulphonyl]amino]ethoxy]acetamide;
2-[2-[[(3-chloro-2-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2-chloro-4-cyanophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[2-nitro-4-(trifluoromethyl)phenyl]sulphonyl]amino]-ethoxy]acetamide;
2-[2-[[(2,6-difluorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[4-(trifluoromethoxy)phenyl]sulphonyl]amino]-ethoxy]acetamide;
2-[2-[[(2,5-dichlorothien-3-yl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[(3-methylphenyl)sulphonyl]amino]ethoxy]acetamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl(1-naphthalenylsulphonyl)amino]ethoxy]acetamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[3-(trifluoromethyl)phenyl]sulphonyl]amino]-ethoxy]acetamide;
2-[2-[[(4-chloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2,4-difluorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(3-chlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-5-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]pentanamide;
5-[[(2,4-dichloro-5-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl-N-methyl-5-[methyl[(3-methylphenyl)sulphonyl]amino]pentanamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-5-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-N-methyl-pentanamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl-N-methyl-5-[methyl[(2,3,4-trichlorophenyl)sulphonyl]amino]pentanamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl-N-methyl-5-[methyl[(2-nitrophenyl)sulphonyl]amino]pentanamide;
5-[[(2,4-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
5-[[(2-chloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
N-[[4-[amino(hydroxyimino)methyl]phenyl]methyl]-5-[[(2,4-dichloro-3-methyl)phenyl]sulphonyl]methylamino]-N-methyl-pentanamide
N-[[4-(aminoiminomethyl)phenyl]methyl]-5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-methyl-pentanamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]-N-methyl-acetamide;
N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-4-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-(2E)-2-butenamide;
N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-4-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-(2E)-2-butenamide;
4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)-2-fluorophenyl]methyl]-N-methyl-(2E)-2-butenamide;
4-[[(2-chlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)-2-fluorophenyl]methyl]-N-methyl-(2E)-2-butenamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-3-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-N-methyl-propanamide;
N-[[2-chloro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-5-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-N-methyl-pentanamide;
N-[[2-chloro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-5-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-N-methyl-pentanamide;
N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-ethoxy]acetamide;
N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-ethoxy]acetamide;
N-[[2-chloro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(2-chlorophenyl)sulphonyl]methylamino]ethoxy]-N-methyl-acetamide;
N-[[2-chloro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]-N-methyl-acetamide;
N-[[4-(4,5-dihydro-1-(1-methylethyl)-1H-imidazol-2-yl)phenyl]-methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methyl-amino]ethoxy]-N-methyl-acetamide;
N-[[2-chloro-4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]-methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methyl-amino]ethoxy]-N-methyl-acetamide;
N-[[2-chloro-4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]-methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methyl-amino]ethoxy]-N-methyl-acetamide;
N-[[2-chloro-4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]-methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]-sulphonyl]amino]ethoxy]acetamide;
N-[[2-chloro-4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]-methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]-sulphonyl]amino]ethoxy]acetamide;
2-[2-[[(2-cyanophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2-cyanophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl-N-methyl-3-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]propanamide;
N-[[4-(1-ethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]-amino]ethoxy]acetamide;
N-[[4-[1-(1-methylethyl)-4,5-dihydro-1H-imidazol-2-yl]phenyl]-methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]-sulphonyl]amino]ethoxy]acetamide;
N-[[4-(1H-1,2,4-triazol-5-yl)phenyl]methyl]-N-methyl-2-[2-[methyl-[(4-methoxy-2,6-dimethylphenyl)sulphonyl]amino]ethoxy]acetamide;
(2E)-4-[[(2-chloro-4-fluorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[[2,6-dichloro-4-(trifluoromethyl)phenyl]sulphonyl]methyl-amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(2,6-difluorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(2-nitrophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(2,4,6-trimethylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(2,5-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(2,4-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(3-chloro-2-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(2-cyanophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(2,4-dichloro-5-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(2,3,4-trichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[[2-chloro-4-(trifluoromethoxy)phenyl]sulphonyl]-methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[[4-methoxy-2-(trifluoromethyl)phenyl]sulphonyl]methyl-amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
(2E)-4-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide;
5-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
5-[[(4-methoxy-2-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
5-[[[2-methyl-4-(trifluoromethoxy)phenyl]sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
5-[[[4-methoxy-2-(trifluoromethyl)phenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide;
2-[2-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide;
2-[2-[[(4-methoxy-2-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide.
or an acid addition salt thereof.
19. A compound according to claim 18,
wherein said acid addition salt is hydrochloride, fumarate, or trifluoroacetate.
20. A method for preparing a compound according to claim 1 or an acid addition salt thereof, comprising the steps consisting of:
a) reacting an acid of formula II:
wherein
R1 is aryl, where said aryl is optionally substituted by one or more atoms or groups of atoms selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy;
R2 is hydrogen or C1-C4 alkyl, where said C1-C4 alkyl is optionally monosubstituted by a phenyl or —CONH2 or optionally substituted by one or more fluorine atoms;
Y is straight or branched saturated C2-C4 alkylene or straight or branched unsaturated C2-C4 alkylene, where said C2-C4 alkylene is optionally interrupted between two carbon atoms by an oxygen atom; R1 is an aromatic system that is non-substituted or substituted by one or more atoms or groups of atoms selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, cyano, trifluoromethyl and trifluoromethoxy;
with an amine of formula III:
wherein
R3 is hydrogen;
R4 is hydrogen;
or R4, together with R3, forms a —CH═N— or a straight or branched C2-C4 alkylene;
R′5 is hydrogen, C1-C3 alkyl, or an amino-protecting group;
R6 is hydrogen or halogen;
wherein the reaction being conducted in a solvent in the presence of at least one activator agent at a temperature of room temperature to 60° C. to obtain the amide of formula:
wherein
R1 is aryl, where said aryl is optionally substituted by one or more atoms or groups of atoms selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, cyano, trifluoromethyl, and trifluoromethoxy;
R2 is hydrogen or C1-C4 alkyl, where said C1-C4 alkyl is optionally monosubstituted by a phenyl or —CONH2 or optionally substituted by one or more fluorine atoms;
R3 is hydrogen;
R4 is hydrogen;
or R4, together with R3, forms a —CH═N— or a straight or branched C2-C4 alkylene;
R′5 is hydrogen, C1-C3 alkyl, or an amino-protecting group;
R6 is hydrogen or halogen; and
Y is straight or branched saturated C2-C4 alkylene or straight or branched unsaturated C2-C4 alkylene, where said C2-C4 alkylene is optionally interrupted between two carbon atoms by an oxygen atom; R1 is an aromatic system that is non-substituted or substituted by one or more atoms or groups of atoms selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, nitro, cyano, trifluoromethyl and trifluoromethoxy;
b) if necessary, when said R′5 is an amino-protecting group, reacting said compound of formula IV to remove said amino-protecting group and replace it by hydrogen, thereby obtaining said compound of formula I, where R5 is hydrogen;
c) if necessary, reacting said compound of formula IV or compound of formula I with a mineral or organic acid to obtain said acid addition salt of said compound of formula IV or said compound of formula I.
21. A composition, comprising:
at least one compound according to claim 1 or an acid addition salt thereof; and
at least one physiologically suitable excipient.
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21
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the National Stage of International Application No. PCT/FR03/01763, filed Jun. 12, 2003, which claims priority to French Patent Application No. 02 07387, filed Jun. 14, 2002, the entire disclosures of which are incorporated herein by reference.
The present invention relates to novel compounds of arylsulphonamide type, their method of preparation and their use to obtain pharmaceutical compositions.
These new compounds can be given therapeutic use, especially to treat pain.
PRIOR ART
Compounds are already known whose structure includes a group of arylsulphonamide type. For example, through EP 236 163 and EP 236 164, N-α-arylsulphonylaminoacyl-p-amidino-phenyl-alaninamide derivatives may be cited which are selective inhibitors of thrombin and can be used as anti-thrombotics. Also, according to EP 614 911, compounds are known whose structure is fairly close to the preceding compounds, simultaneously comprising an arylsulphamoyl group and a substituted phenylamidine group, which have the property of binding onto the receptors of the Y neuropeptide and which may be used to treat hypertension, angina pectoris, atherosclerosis, depression, anxiety, inflammation, allergy or excess fat.
EP 558 961 also suggests the use of arylsulphonamide-type compounds of substituted amino acids for the treatment of thrombosis on account of their anticoagulant properties.
Studies on the antithrombotic properties of compounds whose structure includes an arylsulphonamide group and a phenylamidine group, have also been published in Pharmazie 1984 vol. 39 (5) pages 315-317 and Pharmazie 1986 vol. 41 (4) p 233-235.
In the same area of pharmacological activity, WO 92/16549 A1 describes derivatives of phenylalanine comprising an arylsulphonamide group, which are proteinase inhibitors, in particular thrombin inhibitors.
Compounds are also known, from WO 97/25315, having N-(arylsulphonyl)amino-acid structure, which can be used to treate inflammatory diseases.
In a different therapeutic domain, WO 00/34313 describes peptides which may have an end-chain arylsulphonyl group and which are claimed for their ability to inhibit procollagen-C-proteinase. Also, through the publication in J. Chem. Soc., Perkin Trans. 1(1986), (9) p 1655-64 compounds are known with closely similar structure which are presented as inhibitors of porcine pancreatic elastase.
Among the prior art documents proposing elements with a structure of arylsulphonamide type, mention may be made of WO 96/40639, WO 97/24349, WO 98/03503, WO 98/24783 and WO 99/00387, pertaining to antagonist compounds of the B2 receptor of bradykinin.
OBJECT OF THE INVENTION
The invention concerns novel compounds comprising the substituted arylsulphonamide chain, said compounds being useful in particular as active ingredients for medicinal products intended to treat pain, in particular hyperalgesia and major algesia.
DESCRIPTION
According to the present invention, as a novel industrial product, an arylsulphonamide compound is proposed, characterized in that it chosen from among the group formed by:
i) compounds having the formula:
in which
R1 represents a aromatic system which is non-substituted or substituted by one or more atoms or groups of atoms chosen from among halogens, C1-C3 alkyl groups, C1-C3 alcoxy groups, nitro, cyano, trifluoromethyl or trifluoromethoxy,
R2 represents a hydrogen atom or a C1-C4 alkyl group optionally substituted by a phenyl group, by a CONH2 group or by one or more fluorine atoms,
R3 represents a hydrogen atom, a hydroxy group, or with R4 forms a —CH═N— group or a straight or branched C2-C4 alkylene group,
R4 represents a hydrogen atom or with R3 forms a —CH═N— group or a straight or branched C2-C4 alkylene group,
R5 represents a hydrogen atom or a C1-C3 alkyl group,
R6 represents a hydrogen atom or a halogen,
Y represents a C2-C4 alkylene group that is saturated or unsaturated, straight or branched, optionally interrupted between two carbon atoms by an oxygen atom,
ii) the addition salts of the above formula I compounds with an acid.
According to the invention, a method is also advocated for preparing compounds having formula I and their addition salts.
The use is also proposed of a substance chosen from among the formula I compounds and their non-toxic addition salts, to prepare a medicinal product which can be used for human or animal therapy intended for the prevention or treatment of pain-related pathologies, in particular hyperalgesia subsequent to an inflammatory condition, or major algesia related to other pathologies such as cancer for example.
DETAILED DESCRIPTION
In formula I, by C1-C4 alkyl group is meant a hydrocarbon chain having 1 to 4 carbon atoms, whether straight, branched or cyclic. Said group is in particular a methyl, ethyl, propyl, butyl, 1-methyl-ethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, cyclopropyl and cyclopropylmethyl group.
By C1-C4 alkyl group substituted by a phenyl group is meant a C1-C4 alkyl group of which one of the hydrogen atoms is replaced by a phenyl group. Said group is in particular a phenylmethyl group, a 2-(phenyl)-ethyl group, a 1-(phenyl)ethyl group, a phenylpropyl group or a phenylbutyl group.
By C1-C4 alkyl group substituted by a CONH2 group is meant a C1-C4 alkyl group of which one of the carbon atoms is replaced by a CONH2 group. Said group may, for example, be a —CH2—CONH2 group, a —(CH2)2—CONH2 group, —CH(CH3)—CH2—CONH2 group or still further a —(CH2)4—CONH2 group.
By halogen is meant an atom of fluorine, chlorine or bromine, and preferably a fluorine or chlorine atom.
By aromatic system is meant a phenyl system, a 1- or 2-naphthyl system or a 2- or 3-thienyl system.
By C1-C3 alkoxy group is meant an OR group in which R is a C1-C3 alkyl group, the term alkyl having the denotation given above. Said group is for example a methoxy, ethoxy, propoxy or 1-methylethoxy group.
By saturated C2-C4 alkylene group is meant a —(CH2)n— group in which n is 2, 3 or 4 if it is a straight-chain group, or for example a —CH(CH3)—CH2—CH2— or —C(CH3)2—CH2— group if it is a branched group. By alkylene group interrupted by an oxygen atom is meant for example the groups—CH2—CH2—O—CH2—, —CH2—O—CH2—CH2— or —CH2—CH2—O—CH2—CH2—. By unsaturated C2-C4 alkylene group is meant a group comprising 2 to 4 carbon atoms of which 2 consecutive atoms are bound by an ethylene bond, for example the groups —CH2—CH═CH—CH2—, —CH═CH—CH2—, —CH═C(CH3)—CH2—, CH2—CH═CH— or —CH═CH—CH(CH3)—.
By addition salts is meant addition salts obtained by reaction of a formula 1 compound, containing at least one base function in its non-salified form, with a mineral or organic acid. Preferably, these are pharmaceutically acceptable salts.
Among the mineral acids suitable for salifying a formula 1 base compound, preference is given to hydrochloric, hydrobromic, phosphoric and sulphuric acids. Among the organic acids suitable for salifying a base compound of formula 1, preference is given to methanesulphonic, benzenesulphonic, toluenesulphonic, maleic, fumaric, oxalic, citric, tartaric, lactic and trifluoroacetic acids.
According to one preferred aspect, the subject of the invention is compounds of formula:
in which
R1, R2, R5, R6 and Y are as defined for the compounds of formula I,
R3 represents a hydrogen atom, a hydroxy group, or with R4 forms an C2-C4 alkylene group, straight or branched,
R4 represents a hydrogen atom or with R3 forms a C2-C4 straight or branched alkylene group.
Among the compounds of fomula I or Ia, preference is given to those in which R1 represents a phenyl ring substituted by one or more atoms or groups, of atoms chosen from among a halogen atom, preferably chlorine, and the C1-C3 alkyl groups and C1-C3 alkoxy groups.
Preference is also given to:
those in which R2 represents a C1-C4 alkyl group;
those in which R3 et R4 together form a C2-C3 alkylene group;
those in which R5 et R6 each represent a hydrogen atom; and
those in which Y represents a saturated C2-C4 alkylene chain, optionally interrupted by an oxygen atom, in particular a —(CH2)4— group or a —(CH2)2—O—CH2— group.
According to the invention, a general method is proposed for preparing compounds of their invention and their addition salts, comprising the steps consisting of:
1) reacting an acid of formula:
in which
R1 represents an aromatic system that is non-substituted or substituted by one or more atoms or groups of atoms chosen from among the halogens, C1-C3, alkyl groups, C1-C3 alkoxy groups, nitro, cyano, trifluoromethyl or trifluoromethoxy,
R2 represents a hydrogen atom, a C1-C4 alkyl group optionally substituted by a phenyl group, by a CONH2 group or by one or more fluorine atoms,
and Y represents a saturated or unsaturated C2-C4 alkylene group, straight or branched, optionally interrupted between two carbon atoms by an oxygen atom,
with an amine of formula:
in which
R3 represents a hydrogen atom or with R4 forms a straight or branched C2-C4 alkylene group,
R4 represents a hydrogen atom or with R3 forms a straight or branched C2-C4 alkylene group,
R′5 represents a C1-C3 alkyl group, a hydrogen atom or an amino-protecting group, for example the Boc group (1,1-dimethyl-ethoxycarbonyl),
R6 represents a hydrogen atom or a halogen,
the reaction being conducted in a solvent, dichloromethane for example, in the presence of at least one activator agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) in particular and 1-hydroxy-7-azabenzotriazole (HOAT), at a temperature generally lying between room temperature (approximately 15° C.) and 60° C. preferably for around 2 to 15 hours to obtain the amide having the formula:
in which R1, R2, R3, R4, R′5, R6 and Y maintain the same meanings as in the starting products,
2) if necessary, when the substituent R′5 is an amino-protecting group, to react the compound of formula IV so as to remove the amino-protecting group and replace it by a hydrogen atom, for example if R′5 represents the Boc group, through the action of trifluoroacetic acid in the presence of anisole, thereby obtaining the compound of formula I in which R5 represents a hydrogen atom,
3) if necessary, to react the compound of formula IV or I obtained above with a mineral or organic acid, to obtain an addition salt of the compound of formula IV or I.
According to another preparation method, the formula I compounds of the invention in which R3, R4 and R5 represent a hydrogen atom, may be obtained by conducting the steps consisting of:
1) reacting an acid of formula:
in which
R1 represents an aromatic system that is non-substituted or substituted by one or more atoms or groups of atoms chosen from among the halogens, C1-C3, alkyl groups, C1-C3 alkoxy groups, trifluoromethyl or trifluoromethoxy,
R2 represents a hydrogen atom, a C1-C4 alkyl group optionally substituted by a phenyl group, by a CONH2 group or by one or more fluorine atoms,
and Y represents a C2-C4 alkylene group, saturated or unsaturated, straight or branched, optionally interrupted between two carbon atoms by an oxygen atom,
with an amine of formula:
the reaction being conducted under similar conditions to those described previously (step 1 of the general method), to obtain the compound of formula:
in which R1, R2, and Y maintain the same meanings as in the initial acid,
2) reacting the above formula VI compound with hydroxylamine, in a solvent such as dimethylsulphoxide (DMSO) for example in the presence of triethylamine, at a temperature generally close to room temperature, for approximately 2 to 15 hours, to obtain the compound of formula:
in which R1, R2 and Y remain unchanged,
3) reacting the formula VII compound with acetic anhydride, in a solvent such as dichloromethane for example, at a temperature generally close to room temperature for approximately 2 to 15 hours, to obtain the compound of formula:
4) conducting reduction by catalytic hydrogenation of the formula VIII compound, for example in the presence of palladium black, in a solvent such as methanol for example, at a temperature close to room temperature, to obtain the compound of formula:
in which R1, R2 and Y remain unchanged,
5) if necessary, to obtain the salt of the formula IX compound through the addition of a suitable acid.
The compounds of formula (I) in which R3 and R4 together form a —CH═N— group can be obtained starting from the compound of formula VI, by successive reaction with:
1) hydrogen sulfide, for example by using pyridine as a solvent and operating at room temperature, in order to give rise to a thioamide (aminothioxomethyl) group at the site of and as a replacement for the original cyano group,
2) methyl iodide, in a solvent such as acetone, in order to give rise to an iminomethylthiomethyl group, at the site of and as a replacement for the thioamide group,
3) formylhydrazine, in a solvent such as ethanol, in order to give rise to triazole ring, at the site of and as a replacement for the previously present iminomethylthiomethyl group.
According to another method of preparation, the formula I compounds of the invention may be obtained by conducting the steps consisting of:
1) reacting an amine of formula:
in which
R2 represents a hydrogen atom, a C1-C4 alkyl group optionally substituted by a phenyl group, a CONH2 group or by one or more fluorine atoms,
R3 represents a hydrogen atom or with R4 forms a straight or branched C2-C4 alkylene group,
R4 represents a hydrogen atom or with R3 forms a straight or branched C2-C4 alkylene group,
R″5 represents an amino-protecting group, in particular the Boc group,
R6 represents a hydrogen atom or a halogen,
Y represents a straight or branched C2-C4 alkylene group, optionally interrupted by an oxygen atom,
with an arylsulphonyl chloride of formula:
R1—SO2Cl XI
in which R1 represents a non-substituted aromatic nucleus or substituted by one or more atoms or groups of atoms chosen from among the halogens, C1-C3 alkyl groups, C1-C3 alcoxy groups, nitro, cyano, trifluoromethyl or trifluoromethoxy,
the reaction being conducted in a solvent such as dichloromethane for example, in the presence of an aprotic base such as triethylamine, at room temperature and for approximately 1 to 12 hours, to obtain the compound of formula:
in which R1, R2, R3, R4, R″5, R6 and Y remain unchanged.
2) reacting the above formula IV compound, so as to remove the R″5 amino-protecting group and replace it by a hydrogen atom, for example if R″5 represents the Boc group, through action of trifluoroacetic aicd in the presence of anisole, thereby obtaining the compound of formula I in which R5 represents a hydrogen atom.
The compounds of formula II:
can be obtained in particular through the action of an arylsulphonyl chloride
R1—SO2Cl XI
with an amine
R2—NH2 XII,
followed by reaction of the amide obtained successively with sodium hydride and a halogenated acid of formula:
X—Y—COOH XIII
in which X represents a halogen, preferably bromine, and Y represents a C2-C4 alkylene group to obtain the acid of formula II.
The compounds of formula III:
may be obtained using a method consisting of:
1) reacting an amine of formula:
with the benzyl chloroformiate, in a solvent such as dichloromethane for example and in the presence of an aprotic base to obtain the compound of formula:
2) reacting the above formula XV compound with ethylenediamine, so as to obtain the compound of formula:
3) reacting the compound of formula XVI with the dicarbonate of di-tert-butyl, in a solvent and in the presence of an aprotic base so as to obtain the product of formula:
4) performing partial deprotection of the formula XVII compound, by catalytic hydrogenation for example in the presence of palladium black, so as to obtain the expected amine of formula III
in which R″5 is the Boc protector group
The invention will be more readily understood on reading the examples of preparation and the results of pharmacological tests conducted using compounds of the invention. These non-restrictive examples are solely intended to illustrate the invention and cannot be interpreted as limiting the scope thereof.
Among the abbreviations used in the following descriptions, M denotes mole, mM denotes millimole (10−3 mole). DCM denotes dichloromethane, DMSO denotes dimethylsulphoxide.
PREPARATION I
[(4-cyanophenyl)methyl]methylcarbamic acid, phenylmethyl ester
A mixture of 7 g (47.9 mM) of [(4-cyanophenyl)methyl]methanamine is prepared in 60 ml of DCM and 5.8 g (57.5 mM) of triethylamine are added. The mixture is cooled to 0° C. and a solution of 9.8 g (57.5 mM) of benzyl chloroformate in 20 ml of DCM is added dropwise. The mixture is then agitated for 20 hours at ambient temperature and then washed with a solution of 0.1 N hydrochloric acid, and then with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel in eluting with the aid of a mixture of toluene/ethyl acetate (95/5; v/v). 11.4 g of the desired product are thus obtained as an oil (yield=87%).
nD22=1.564
PREPARATION II
[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]methylcarbamic acid, phenylmethyl ester
A mixture of 11.3 g (40 mM) of the compound obtained according to preparation I is prepared in 40 ml of ethylenediamine and 0.64 g (20 mM) of flowers of sulphur are added. The reaction mixture is agitated for 2 hours at 100° C. and then cooled. Water is added and extraction is carried out with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel in eluting with the aid of a mixture of dichloromethane/methanol/aqueous ammonia (95/5/0.05; v/v/v). 11 g of the expected product are thus obtained as a white solid (yield=85%).
M.Pt.=84° C.
PREPARATION III
4,5-dihydro-2-[4-[[methyl[(phenylmethoxy)carbonyl]amino]methyl]-phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
A solution of 3.22 g (10 mM) of the compound obtained according to preparation II is prepared in 45 ml of DCM, and 1.34 g (11 mM) of N,N-dimethylaminopyridine are added. A solution of 2.4 g (11 mM) of di-tert-butyl dicarbonate in 45 ml of DCM is then added dropwise. The reaction mixture is agitated for 2 hours at ambient temperature and then washed with the aid of a solution of 0.5 N hydrochloric acid, and then with water. The organic phase is dried over sodium sulphate and then concentrated under reduced pressure. The residue is crystallised in isopropyl ether and then filtered and dried. 4 g of the desired product are thus obtained as fine white crystals (yield=94%).
M.Pt.=124° C.
PREPARATION IV
4,5-dihydro-2-[4-[(methylamino)methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
A mixture of 4.23 g (10 mM) of the compound obtained according to preparation III is prepared in 80 ml of methanol and 0.4 g of palladium on carbon (10% Pd) are added. The mixture is agitated under a hydrogen atmosphere at ambient temperature and atmospheric pressure for 2 hours. The catalyst is removed by filtration and the filtrate is then concentrated under reduced pressure. The residue is purified by chromatography on silica gel in eluting with the aid of a mixture of dichloromethane/methanol/aqueous ammonia (90/10/0.1; v/v/v). 2.5 g of the desired product are thus obtained as an off-white solid (yield=90%).
M.Pt.=65° C.
PREPARATION V
N-methyl-2,4-dichloro-3-methylbenzenesulphonamide
A suspension of 2.55 g (37.8 mM) of methanamine hydrochloride is prepared in 120 ml of dichloromethane (DCM) and 7.5 g of 2,4-dichloro-3-methylbenzenesulphonyl chloride in solution in 30 ml of DCM, and 10.5 ml of triethylamine, are added; the reaction mixture is kept under agitation for 15 hours at ambient temperature and then washed with a solution of 1N hydrochloric acid, with a solution of sodium bicarbonate, and then with water. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The solid residue obtained is purified by chromatography on silica gel in eluting with the aid of a mixture of cyclohexane/ethyl acetate (8/2, v/v). 6.2 g of the expected compound are thus obtained as a white solid (yield=85%).
M.Pt.=118° C.
PREPARATION VI
5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]pentanoic acid, ethyl ester
A solution of 1 g (3.9 mM) of the compound obtained according to Preparation V is prepared in 30 ml of dimethylformamide and 1.63 g (11.8 mM) of potassium carbonate, and then 987 mg (4.7 mM) of ethyl 5-bromopentanoate, are added. The reaction mixture is agitated at ambient temperature for 15 hours, and water is then added thereto, and extraction is carried out with ethyl acetate. The organic phase is washed with water several times and then dried over magnesium sulphate and concentrated under reduced pressure. 1.5 g of the desired product are thus obtained as a colourless oil (quantitative yield).
1H NMR (300 MHz, DMSO) δ: 7.83 (d, 1H); 7.65 (d, 1H); 4.04 (q, 2H); 3.19 (t, 2H); 2.80 (s, 3H); 2.49 (s, 3H); 2.28 (t, 2H); 1.49 (m, 4H); 1.17 (t, 3H).
PREPARATION VII
5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]pentanoic acid
A solution of 1.45 g (3.79 mM) of the ester obtained according to Preparation VI is prepared in 15 ml of tetrahydrofuran (THF) and 320 mg (7.56 mM) of lithia, and 30 ml of water, are added. The reaction mixture is agitated for 15 hours at ambient temperature. The THF is drawn off under reduced pressure and 50 ml of water are added to the residual aqueous phase, and the aqueous phase is acidified with the aid of an N solution of hydrochloric acid, and then extracted with the aid of ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. 1.3 g of the expected acid are thus obtained as a colourless oil (yield=97%).
1H NMR (300 MHz, DMSO) δ: 12.0 (broad s, 1H); 7.83 (d, 1H); 7.64 (d, 1H); 3.20 (t, 2H); 2.80 (s, 3H); 2.57 (s, 3H); 2.20 (t, 2H); 1.49 (m, 4H).
PREPARATION VIII
2-[4-[[[5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
A solution of 200 mg (0.565 mM) of the acid obtained according to Preparation VII is prepared in 15 ml of dichloromethane, and then 120 mg of EDCI and 90 mg of HOAT are added. The mixture is agitated at ambient temperature for 20 min and then 163 mg (0.565 mM) of the amine obtained according to the preparation IV, in solution in 3 ml of dichloromethane, is added. The reaction mixture is kept under agitation at ambient temperature for 15 hours, and then diluted with 40 ml of dichloromethane. This organic phase is washed with water and then dried and concentrated under reduced pressure. The oily product obtained is purified by chromatography on silica gel in eluting with the aid of a mixture of dichloromethane/methanol (98/2, v/v).
260 mg of the expected compound are thus obtained as a colourless oil (yield=73%)
1H NMR (300 MHz, DMSO) δ: 7.80 (t, 1H); 7.60 (m, 1H); 7.40 (m, 2H); 7.20 (m, 2H); 4.52 (d, 2H); 3.84 (m, 4H); 3.20 (m, 2H); 2.88 (s, 3H); 2.81 (s, 3H); 2.79 (m, 2H); 2.49 (s, 3H); 2.38 (m, 2H); 2.30 (m, 4H); 1.17 (s, 9H).
EXAMPLE 1
5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
A mixture of 240 mg of the compound obtained according to preparation VIII, 5 ml of trifluoroacetic acid, 5 ml of dichloromethane and 41 mg of anisole is prepared and this mixture is kept under agitation for 15 hours at ambient temperature. The solvents are drawn off under reduced pressure first of all, and then secondly in the presence of toluene. The residual oil is agitated with isopropyl ether which is then removed. The oily residue is taken up with pure water. The solution is filtered and the filtrate is lyophilised. 240 mg of the desired product are thus obtained as a cotton-like white solid (yield=97%).
M.Pt.=83° C.
In operating analogously to Preparation VI, the following compounds are obtained:
PREPARATION IX
4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]butanoic acid, ethyl ester
(non-isolated)
PREPARATION X
N-[(2,4-dichloro-3-methylphenyl)sulphonyl]-N-methyl-β-alanine, ethyl ester
(colourless oil, yield=43%)
1H NMR (300 MHz, DMSO) δ: 7.83 (d, 1H); 7.66 (d, 1H); 4.04 (q, 2H); 3.46 (t, 2H); 2.85 (s, 3H); 2.59 (t, 2H); 2.5 (s, 3H); 1.17 (t, 3H).
PREPARATION XI
4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-(2E)-2-butenoic acid, ethyl ester
(white solid, yield=53%)
M.Pt.=90° C.
In operating analogously to Preparation VII, the following compounds are obtained:
PREPARATION XII
4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]butanoic acid
(white solid, quantitative yield)
M.Pt.=104° C.
PREPARATION XIII
N-[(2,4-dichloro-3-methylphenyl)sulphonyl]-N-methyl-β-alanine
(white solid, yield=98%).
M.Pt.=119° C.
PREPARATION XIV
4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-(2E)-2-butenoic acid
(white solid, yield=47%).
M.Pt.=160° C.
In operating analogously to Preparation VIII, the following compounds are obtained:
PREPARATION XV
2-[4-[[[4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-1-oxobutyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(oil, yield=34%)
1H NMR (300 MHz, DMSO) δ: 7.95 (m, 1H); 7.82 (m, 1H); 7.41 (m, 2H); 7.21 (m, 2H); 4.52 (d, 2H); 3.84 (m, 4H); 3.22 (m, 2H); 2.85 (m, 6H); 2.49 (s, 3H); 2.24 (m, 2H); 1.79 (m, 2H); 1.17 (s, 9H).
PREPARATION XVI
2-[4-[[[3-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-1-oxopropyl]methylamino]methyl]phenyl]-4,5-dihydro-1H imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(ecru foam, yield=55%)
M.Pt.=50° C.
PREPARATION XVII
2-[4-[[[(2E)-4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester.
(white solid, yield=74%).
M.Pt.=65° C.
In operating analogously to Example 1, the following 3 compounds are obtained:
EXAMPLE 2
4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-butanamide, trifluoroacetate
(white solid, yield=92%)
M.Pt.=90° C.
EXAMPLE 3
3-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide, trifluoroacetate
(white solid, yield=87%)
M.Pt.=65° C.
EXAMPLE 4
4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-(2E)-2-butenamide, trifluoroacetate
(white solid, yield=100%)
M.Pt.=55° C.
In operating analogously to Preparation V, the following compounds are obtained:
PREPARATION XVIII
2-chloro-N-methyl-benzenesulphonamide
(yellow oil, yield=94%)
1H NMR (300 MHz, DMSO) δ: 7.95 (d, 1H); 7.65 (m, 3H); 7.54 (t, 1H); 2.47 (s, 3H).
PREPARATION XIX
2,3-dichloro-N-methylbenzenesulphonamide
(ecru solid, yield=76%)
M.Pt.=126° C.
PREPARATION XX
2,6-dichloro-N-methylbenzenesulphonamide
(white solid, yield=99%)
M.Pt.=110° C.
PREPARATION XXI
N-methyl-1-naphthalenesulphonamide
(beige solid, yield=94%)
1H NMR (250 MHz, DMSO) δ: 8.63 (m, 1H); 8.23 (d, 1H); 8.10 (m, 2H); 7.72 (q, 1H); 7.66 (m, 3H); 2.42 (d, 3H).
In operating analogously to Preparation VI, the following compounds are obtained:
PREPARATION XXII
5-[[(2-chlorophenyl)sulphonyl]methylamino]-pentanoic acid, ethyl ester
(non-isolated)
PREPARATION XXIII
4-[[(2-chlorophenyl)sulphonyl]methylamino]-(2E)-2-butenoic acid, ethyl ester
(colourless oil, yield=78%)
1H NMR (250 MHz, DMSO) δ: 8.02 (d, 1H); 7.71 (m, 2H); 7.60 (m, 1H); 6.79 (m, 1H); 6.04 (d, 1H); 4.08 (d, 2H); 3.67 (s, 3H); 2.80 (s, 3H).
PREPARATION XXIV
N-[(2,3-dichlorophenyl)sulphonyl]-N-methyl-β-alanine, ethyl ester
(oil, yield=74%)
1H NMR (250 MHz, DMSO) δ: 7.94 (m, 2H), 7.57 (m, 1H); 4.02 (q, 2H); 3.48 (t, 2H); 2.88 (s, 3H); 2.59 (t, 2H); 1.17 (t, 3H).
PREPARATION XXV
4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]butanoic acid, ethyl ester
(yellow oil, yield=69%)
1H NMR (250 MHz, DMSO) δ: 7.93 (m, 2H); 7.57 (t, 1H); 4.03 (q, 2H); 3.24 (t, 2H); 2.84 (s, 3H); 2.29 (t, 2H); 1.75 (m, 2H); 1.17 (t, 3H).
PREPARATION XXVI
5-[[(2,3-dichlorophenyl)sulphonyl]methylamino]pentanoic acid, ethyl ester
(non-isolated)
PREPARATION XXVII
4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-(2E)-2-butenoic acid, ethyl ester
(white solid, yield=72%)
M.Pt.=98° C.
PREPARATION XXVIII
5-[[(2,6-dichlorophenyl)sulphonyl]methylamino]pentanoic acid, ethyl ester
(non-isolated)
PREPARATION XXIX
4-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-(2E)-2-butenoic acid, ethyl ester
(white solid, yield=81%)
M.Pt.=84° C.
PREPARATION XXX
5-[methyl(1-naphthalenylsulphonyl)amino]pentanoic acid, ethyl ester
(colourless oil, yield=93%)
1H NMR (250 MHz, DMSO) δ: 8.58 (d, 1H); 8.27 (d, 1H); 8.08 (m, 2H); 7.69 (m, 3H); 4.04 (q, 2H); 3.16 (t, 2H); 2.77 (s, 3H); 2.25 (t, 2H); 1.45 (m, 4H); 1.16 (t, 3H).
PREPARATION XXXI
4-[methyl(1-naphthalenylsulphonyl)amino]-(2E)-2-butenoic acid, ethyl ester
(white solid, yield=54%)
M.Pt.=75° C.
In operating analogously to Preparation VII, the following compounds are obtained:
PREPARATION XXXII
5-[[(2-chlorophenyl)sulphonyl]methylamino]pentanoic acid
(white solid, yield=75%)
M.Pt.=120° C.
PREPARATION XXXIII
4-[[(2-chlorophenyl)sulphonyl]methylamino]-(2E)-2-butenoic acid
(white solid, yield=50%)
M.Pt.=136° C.
PREPARATION XXXIV
N-[(2,3-dichlorophenyl)sulphonyl]-N-methyl-β-alanine
(white solid, yield=74%)
M.Pt.=141° C.
PREPARATION XXXV
4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]butanoic acid
(white solid, yield=78%)
M.Pt.=114° C.
PREPARATION XXXVI
5-[[(2,3-dichlorophenyl)sulphonyl]methylamino]pentanoic acid
(colourless oil, yield=63%)
1H NMR (250 MHz, DMSO) δ: 12.0 (broad s, 1H); 7.94 (d, 2H); 7.56 (t, 1H); 3.25 (t, 2H); 2.73 (s, 3H); 2.24 (t, 2H); 1.50 (m, 4H).
PREPARATION XXXVII
4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-(2E)-2-butenoic acid
(colourless oil, yield=60%)
1H NMR (250 MHz, DMSO) δ: 7.96 (m, 2H); 7.58 (t, 1H); 6.58 (m, 1H); 5.90 (d, 1H); 4.04 (d, 2H); 2.81 (s, 3H).
PREPARATION XXXVIII
5-[[(2,6-dichlorophenyl)sulphonyl]methylamino]pentanoic acid
(white ecru solid, yield=59%)
M.Pt.=105° C.
PREPARATION XXXIX
4-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-(2E)-2-butenoic acid
(white solid, yield=48%)
M.Pt.=158° C.
PREPARATION XL
5-[methyl(1-naphthalenylsulphonyl)amino]pentanoic acid
(colourless oil, yield=74%)
1H NMR (300 MHz, DMSO) δ: 12.0 (broad s, 1H); 8.62 (d, 1H); 8.58 (d, 1H); 8.25 (m, 2H); 8.08 (m, 3H); 3.16 (t, 2H); 2.77 (s, 3H); 2.20 (t, 2H); 1.48 (m, 4H).
PREPARATION XLI
4-[methyl(1-naphthalenylsulphonyl)amino]-(2E)-2-butenoic acid
(white solid, yield=38%)
1H NMR (250 MHz, DMSO) δ: 12.5 (broad s, 1H); 8.60 (d, 1H); 8.29 (d, 1H); 8.13 (m, 2H); 7.75 (m, 3H); 6.64 (m, 1H); 5.90 (d, 1H); 4.03 (d, 2H); 2.78 (s, 3H).
In operating analogously to Preparation VIII, the following compounds are obtained:
PREPARATION XLII
2-[4-[[[5-[[(2-chlorophenyl)sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(oil, yield=65%)
1H NMR (300 MHz, DMSO) δ: 7.97 (t, 1H); 7.66 (m, 2H); 7.54 (m, 1H); 7.44 (m, 2H); 7.20 (m, 2H); 4.55 (d, 2H); 3.84 (m, 4H); 3.20 (m, 2H); 2.85 (m, 6H); 2.36 (m, 2H); 1.50 (m, 4H); 1.17 (d, 9H).
PREPARATION XLIII
2-[4-[[[(2E)-4-[[(2-chlorophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless paste, yield=82%)
1H NMR (300 MHz, DMSO) δ: 8.03 (t, 1H); 7.67 (m, 2H); 7.51 (m, 1H); 7.42 (m, 2H); 7.20 (m, 2H); 6.60 (m, 2H); 4.60 (d, 2H); 4.05 (m, 2H); 3.84 (m, 4H); 2.88 (m, 6H); 1.18 (s, 9H).
PREPARATION XLIV
2-[4-[[[3-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-1-oxopropyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=42%)
M.Pt.=65° C.
PREPARATION XLV
2-[4-[[[4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-1-oxobutyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=68%)
M.Pt.=50° C.
PREPARATION XLVI
2-[4-[[[5-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=47%)
M.Pt.=50° C.
PREPARATION XLVII
2-[4-[[[(2E)-4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white paste, yield=69%)
1H NMR (250 MHz, DMSO) δ: 8.02 (m, 2H); 7.59 (m, 1H); 7.43 (m, 2H); 7.21 (m, 2H); 6.60 (m, 2H); 4.70 (d, 2H); 4.00 (m, 2H); 3.82 (m, 4H); 2.86 (m, 6H); 1.18 (s, 9H).
PREPARATION XLVIII
2-[4-[[[5-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(oil, yield=51%)
1H NMR (250 MHz, DMSO) δ: 7.67 (m, 2H); 7.64 (m, 1H); 7.42 (m, 2H); 7.20 (m, 2H); 4.55 (d, 2H); 3.84 (m, 4H); 3.23 (m, 2H); 2.83 (m, 6H); 2.39 (m, 2H); 1.55 (m, 4H); 1.17 (s, 9H).
PREPARATION IL
2-[4-[[[(2E)-4-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=70%)
M.Pt.=70° C.
PREPARATION L
2-[4-[[[5-[methyl[(1-naphthalenyl)sulphonyl]amino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=70%)
1H NMR (300 MHz, DMSO) δ: 8.60 (m, 1H); 8.25 (d, 1H); 8.07 (m, 2H); 7.65 (m, 3H); 7.43 (m, 2H); 7.24 (m, 2H); 4.53 (d, 2H); 3.84 (m, 4H); 3.17 (m, 2H); 2.80 (m, 6H); 2.35 (m, 2H); 1.48 (m, 4H); 1.17 (s, 9H).
PREPARATION LI
2-[4-[[[(2E)-4-[methyl[(1-naphthalenyl)sulphonyl]amino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless paste, yield=79%)
1H NMR (300 MHz, DMSO) δ: 8.60 (t, 1H); 8.26 (d, 1H); 8.13 (m, 2H); 7.70 (m, 3H); 7.42 (d, 2H); 7.16 (m, 2H); 6.55 (m, 2H); 4.54 (s, 2H); 4.00 (m, 2H); 3.84 (m, 4H); 2.70 (m, 6H); 1.16 (d, 9H).
In operating analogously to Example 1, the following compounds are obtained:
EXAMPLE 5
5-[[(2-chlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(white solid, yield=98%)
M.Pt.=60° C.
EXAMPLE 6
(2E)-4-[[(2-chlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(white solid, yield=90%)
M.Pt.=72° C.
EXAMPLE 7
3-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide, trifluoroacetate
(white solid, yield=84%)
M.Pt.=60° C.
EXAMPLE 8
4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-butanamide, trifluoroacetate
(white solid, yield=91%)
M.Pt.=62° C.
EXAMPLE 9
5-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(white solid, yield=80%)
M.Pt.=64° C.
EXAMPLE 10
(2E)-4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(white solid, yield=94%)
M.Pt.=66° C.
EXAMPLE 11
5-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(ecru solid, yield=65%)
M.Pt.=50° C.
EXAMPLE 12
(2E)-4-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(beige solid, yield=98%)
M.Pt.=83° C.
EXAMPLE 13
5-[methyl[(1-naphthalenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(white solid, yield=97%)
1H NMR (250 MHz, DMSO) δ: 10.5 (d, 2H); 8.60 (t, 1H); 8.26 (d, 1H); 8.09 (m, 2H); 7.90 (m, 2H); 7.70 (m, 3H); 7.45 (d, 2H); 4.60 (d, 2H); 4.01 (s, 4H); 3.20 (m, 2H); 2.85 (m, 6H); 2.40 (m, 2H); 1.52 (m, 4H).
EXAMPLE 14
(2E)-4-[methyl[(1-naphthalenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(beige solid, yield=99%)
M.Pt.=77° C.
In operating analogously to Preparation V, the following compounds are obtained:
PREPARATION LII
2-chloro-N-cyclopropyl-benzenesulphonamide
(white solid, yield=82%)
M.Pt.=117° C.
PREPARATION LIII
N-cyclopropyl-2,3-dichloro-benzenesulphonamide
(ecru solid, yield=50%)
M.Pt.=140° C.
PREPARATION LIV
N-cyclopropyl-2,6-dichloro-benzenesulphonamide
(white solid, yield=99%)
M.Pt.=76° C.
PREPARATION LV
2,3-dichloro-N-(1-methylethyl)-benzenesulphonamide
(white solid, yield=93%)
M.Pt.=131° C.
PREPARATION LVI
2,6-dichloro-N-(1-methylethyl)-benzenesulphonamide
(white solid, yield=99%)
M.Pt.=105° C.
PREPARATION LVII
N-(2-amino-2-oxoethyl)-2,4-dichloro-3-methylbenzenesulphonamide
(oil, yield=95%)
1H NMR (300 MHz, DMSO) δ: 8.04 (s, 1H); 7.82 (d, 1H); 7.62 (d, 1H); 7.12 (s, 1H); 7.03 (s, 1H); 3.50 (s, 2H); 2.48 (s, 3H).
PREPARATION LVIII
N-(3-amino-3-oxopropyl)-2,4-dichloro-3-methylbenzenesulphonamide
(white solid, yield=81%)
M.Pt.=163° C.
PREPARATION LIX
2,3-dichloro-N-(2,2,2-trifluoroethyl)benzenesulphonamide
(ecru solid, yield=76%)
M.Pt.=107° C.
PREPARATION LX
2,6-dichloro-N-(2,2,2-trifluoroethyl)benzenesulphonamide
(white solid, yield=99%)
M.Pt.=106° C.
PREPARATION LXI
2,4-dichloro-3-methyl-N-(2-phenylethyl)benzenesulphonamide
(white solid, yield=81%)
M.Pt.=75° C.
In operating analogously to Preparation VI, the following compounds are obtained:
PREPARATION LXII
5-[[(2-chlorophenyl)sulphonyl]cyclopropylamino]pentanoic acid, ethyl ester
(white solid, yield=82%)
M.Pt.=117° C.
PREPARATION LXIII
5-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]pentanoic acid, ethyl ester
(yellow oil, yield=98%)
1H NMR (250 MHz, DMSO3) δ: 8.00 (m, 2H); 7.58 (t, 1H); 4.05 (q, 2H); 3.42 (t, 2H); 2.50 (m, 1H); 2.33 (t, 2H); 1.59 (m, 4H); 1.18 (t, 3H); 0.60 (m, 2H); 0.40 (m, 2H).
PREPARATION LXIV
5-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]pentanoic acid, ethyl ester
(non-isolated).
PREPARATION LXV
5-[[(2,6-dichlorophenyl)sulphonyl](1-methylethyl)amino]pentanoic acid, ethyl ester
(non-isolated).
PREPARATION LXVI
5-[(2-amino-2-oxoethyl)[(2,4-dichloro-3-methylphenyl)sulphonyl]amino]pentanoic acid, ethyl ester
(yellow oil, yield=95%)
1H NMR (300 MHz, DMSO) δ: 7.91 (d, 1H); 7.64 (d, 1H); 7.15 (s, 1H); 7.01 (s, 1H); 4.04 (m, 2H); 3.95 (s, 2H); 3.27 (t, 2H); 2.49 (s, 3H); 2.15 (t, 2H); 1.62 (m, 1H); 1.20 (m, 3H); 1.17 (t, 3H).
PREPARATION LXVII
5-[(3-amino-3-oxopropyl)[(2,4-dichlorophenyl)sulphonyl]amino]-pentanoic acid, ethyl ester
(colourless oil, yield=99%)
1H NMR (300 MHz, DMSO) δ: 7.84 (d, 1H); 7.65 (d, 1H); 7.34 (s, 1H); 6.84 (s, 1H); 4.04 (m, 2H); 3.51 (m, 2H); 3.25 (m, 2H); 2.50 (s, 3H); 2.30 (m, 2H); 2.22 (t, 2H); 1.44 (m, 4H); 1.17 (t, 3H).
In operating analogously to Preparation VI but by replacing the brominated ethyl ester by an iodinated t-butyl ester, the following compounds are obtained:
PREPARATION LXVIII
[2-[[(2-chlorophenyl)sulphonyl]cyclopropylamino]ethoxy]acetic acid, 1,1-dimethylethyl ester
(yellow oil, yield=52%)
1H NMR (250 MHz, DMSO) δ: 8.00 (d, 1H); 7.68 (d, 2H); 7.57 (m, 1H); 3.98 (s, 2H); 3.69 (t, 2H); 3.52 (t, 2H); 2.50 (m, 1H); 1.43 (s, 9H); 0.56 (m, 2H); 0.45 (m, 2H).
PREPARATION LXIX
[2-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]ethoxy]acetic acid, 1,1-dimethylethyl ester
(colourless oil, yield=78%)
1H NMR (250 MHz, DMSO) δ: 8.00 (m, 2H); 7.60 (t, 1H); 4.08 (s, 2H); 3.69 (t, 2H); 3.56 (t, 2H); 2.56 (m, 1H); 1.42 (s, 9H); 0.60 (m, 2H); 0.50 (m, 2H).
PREPARATION LXX
[2-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]ethoxy]acetic acid, 1,1-dimethylethyl ester
(ecru solid, yield=40%)
M.Pt.=76° C.
PREPARATION LXXI
[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl](2-phenylethyl)amino]-ethoxy]acetic acid, 1,1-dimethylethyl ester
(colourless oil, yield=77%)
1H NMR (250 MHz, DMSO) δ: 7.86 (m, 1H); 7.60 (m, 1H); 7.17 (m, 6H); 3.94 (s, 2H); 3.56 (m, 6H); 2.80 (m, 2H); 2.44 (d, 3H); 1.42 (s, 9H).
In operating analogously to Preparation VIII, the following compounds are obtained:
PREPARATION LXXII
5-[[(2-chlorophenyl)sulphonyl]cyclopropylamino]pentanoic acid
(white solid, yield=86%)
M.Pt.=104° C.
PREPARATION LXXIII
5-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]pentanoic acid
(ecru solid, yield=79%)
M.Pt.=115° C.
PREPARATION LXXIV
5-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]pentanoic acid
(yellow solid, yield=53%)
M.Pt.=146° C.
PREPARATION LXXV
5-[[(2,6-dichlorophenyl)sulphonyl](1-methylethyl)-amino]pentanoic acid
(oil, yield=36%)
1H NMR (300 MHz, DMSO) δ: 12.0 (broad s, 1H); 7.67 (d, 2H); 7.56 (t, 1H); 3.98 (m, 1H); 3.97 (t, 2H); 2.17 (t, 2H); 1.48 (m, 4H); 1.06 (d, 6H).
PREPARATION LXXVI
5-[(2-amino-2-oxoethyl)[(2,4-dichloro-3-methylphenyl)sulphonyl]-amino]pentanoic acid
(white solid, yield=63%)
M.Pt.=160° C.
PREPARATION LXXVII
5-[(3-amino-3-oxopropyl)[(2,4-dichlorophenyl)sulphonyl]-amino]pentanoic acid
(white solid, yield=93%)
M.Pt.=161° C.
PREPARATION LXXVIII
[2-[[(2-chlorophenyl)sulphonyl]cyclopropylamino]ethoxy]acetic acid
A solution of 210 mg (0.5 mM) of the ester obtained according to the preparation LXVIII is prepared in 10 ml of dichloromethane, and 3 ml of trifluoroacetic acid are added. This reaction mixture is kept under agitation for 16 hours, at ambient temperature. The reaction medium is then concentrated under reduced pressure, taken up by 30 ml of toluene and once again concentrated under reduced pressure. The residue crystallised during drying. The expected product is thus obtained as a white solid (yield=99%).
M.Pt.=115° C.
In operating analogously to Preparation LXXVIII, the following compounds are obtained:
PREPARATION LXXIX
[2-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]ethoxy]acetic acid
(yellow solid, yield=99%)
M.Pt.=96° C.
PREPARATION LXXX
[2-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]ethoxy]acetic acid
(white solid, yield=88%)
M.Pt.=98° C.
PREPARATION LXXXI
[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl](2-phenylethyl)amino]ethoxy]acetic acid
(yellow oil, yield=77%)
1H NMR (300 MHz, DMSO) δ: 12.0 (broad s, 1H); 7.87 (d, 1H); 7.60 (d, 1H); 7.15 (m, 5H); 3.91 (s, 2H); 3.56 (m, 6H); 2.81 (t, 2H); 2.43 (s, 3H).
PREPARATION LXXXII
N-[(2,6-dichlorophenyl)sulphonyl]-N-methyl-β-alanine
A solution of 480 mg (2 mM) of the compound obtained according to preparation XX is prepared in 7 ml of dimethylformamide and 120 mg (4 mM) 80% sodium hydride in oil are added. The mixture is agitated 2 min at ambient temperature and 306 mg (2 mM) of 3-bromopropanoic acid are then added. The reaction medium is kept under agitation for 1 hour at ambient temperature, and then 20 hours at 70° C. After cooling, the mixture is hydrolysed over 50 ml of iced water. This aqueous phase is extracted with ethyl acetate, and then acidified to pH 2 with the aid of N hydrochloric acid and extracted with ethyl acetate. This latter organic phase is washed with water and then dried over sodium sulphate, and then concentrated under reduced pressure. The expected acid is thus obtained as a white amorphous solid (yield=70%).
M.Pt.=115° C.
In operating analogously to Preparation LXXXII, the following compounds are obtained:
PREPARATION LXXXIII
N-[(2,3-dichlorophenyl)sulphonyl]-N-methyl-β-alanine
(white solid, yield=70%)
M.Pt.=115° C.
PREPARATION LXXXIV
N-cyclopropyl-N-[(2,6-dichlorophenyl)sulphonyl]-β-alanine
(ecru solid, yield=55%)
M.Pt.=190° C.
PREPARATION LXXXV
N-[(2,3-dichlorophenyl)sulphonyl]-N-(1-methylethyl)-β-alanine
(ecru solid, yield=47%)
M.Pt.=115° C.
PREPARATION LXXXVI
N-[(2,6-dichlorophenyl)sulphonyl]-N-(1-methylethyl)-β-alanine
(white solid, yield=53%)
M.Pt.=138° C.
PREPARATION LXXXVII
N-[(2,3-dichlorophenyl)sulphonyl]-N-(2,2,2-trifluoroethyl)-β-alanine
(ecru solid, yield=92%)
M.Pt.=125° C.
PREPARATION LXXXVIII
N-[(2,6-dichlorophenyl)sulphonyl]-N-(2,2,2-trifluoroethyl)-β-alanine
(white solid, yield=77%)
M.Pt.=100° C.
In operating analogously to Preparation V, the following compound is obtained:
PREPARATION LXXXIX
N-methyl-2-(trifluoromethyl)benzenesulphonamide
(white solid, yield=99%)
M.Pt.=107° C.
PREPARATION XC
2,4-dichloro-3-methylbenzenesulphonamide
A solution of 5 g (16.8 mM) of 2,4-dichloro-N-(1,1-dimethylethyl)-3-methylbenzenesulphonamide is prepared in 100 ml of dichloromethane and 50 ml of trifluoroacetic acid are added. The reaction mixture is agitated at ambient temperature for 20 hours. 20 ml of 10N hydrochloric acid are then added and agitation is maintained for 4 hours at ambient temperature. The mixture is then concentrated under reduced pressure. The solid residue is purified by chromatography on silica gel in eluting by means of a mixture of toluene-ethyl acetate (9/1; v/v). 3.74 g of the desired product are thus obtained (yield=92%).
M.Pt.=210° C.
In operating analogously to Preparation VI, the following compounds are obtained:
PREPARATION XCI
(2E)-4-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-2-butenoic acid, 1,1-dimethylethyl ester
(yellow oil, yield=44%)
1H NMR (250 MHz, DMSO) δ: 8.04 (m, 2H); 7.90 (m, 2H); 6.66 (dt, 1H); 5.88 (dt, 1H); 4.07 (dd, 2H); 2.84 (s, 3H); 1.44 (s, 9H).
PREPARATION XCII
(2E)-4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]amino]-2-butenoic acid, 1,1-dimethylethyl ester
(yellow oil, yield=20%)
1H NMR (300 MHz, DMSO) δ: 8.33 (s, 1H); 7.81 (d, 1H); 7.63 (d, 1H); 6.49 (dt, 1H); 5.69 (dt, 1H); 3.70 (dd, 2H); 2.48 (s, 3H); 1.38 (s, 9H).
In operating analogously to Preparation LXXVIII, the following compounds are obtained:
PREPARATION XCIII
(2E)-4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]amino]-2-butenoic acid
(white solid, yield=99%)
M.Pt.=154° C.
PREPARATION XCIV
4-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-2-butenoic acid
(white solid, yield=99%)
M.Pt.=184° C.
In operating analogously to Preparation VIII, the following compounds are obtained:
PREPARATION XCV
2-[4-[[[5-[[(2-chlorophenyl)sulphonyl]cyclopropylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(amorphous solid, yield=84%)
M.Pt.=50° C.
PREPARATION XCVI
2-[4-[[[5-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=65%)
1H NMR (300 MHz, DMSO) δ: 7.97 (m, 2H); 7.40 (m, 1H); 7.25 (m, 2H); 7.18 (m, 2H); 4.55 (d, 2H); 3.84 (m, 4H); 3.40 (m, 2H); 2.85 (d, 3H); 2.46 (m, 3H); 1.60 (m, 4H); 1.17 (s, 9H); 0.59 (m, 2H); 0.42 (m, 2H).
PREPARATION XCVII
2-[4-[[[5-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(amorphous solid, yield=59%)
M.Pt.=50° C.
PREPARATION XCVIII
2-[4-[[[5-[[(2,6-dichlorophenyl)sulphonyl](1-methylethyl)amino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=69%)
M.Pt.=50° C.
PREPARATION IC
2-[4-[[[5-[(2-amino-2-oxoethyl)[(2,4-dichloro-3-methylphenyl)-sulphonyl]amino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=69%)
M.Pt.=70° C.
PREPARATION C
2-[4-[[[5-[(3-amino-3-oxopropyl)[(2,4-dichloro-3-methylphenyl)-sulphonyl]amino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=76%)
M.Pt.=80° C.
PREPARATION CI
2-[4-[[[3-[[(2,3-dichlorophenyl)sulphonyl](1-methylethyl)amino]-1-oxopropyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=55%)
M.Pt.=60° C.
PREPARATION CII
2-[4-[[[3-[[(2,6-dichlorophenyl)sulphonyl](1-methylethyl)amino]-1-oxopropyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=54%)
M.Pt.=55° C.
PREPARATION CIII
2-[4-[[[[2-[[(2-chlorophenyl)sulphonyl]cyclopropylamino]-ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(amorphous solid, yield=96%)
M.Pt.=50° C.
PREPARATION CIV
2-[4-[[[[2-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]ethoxy]-acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=56%)
M.Pt.=62° C.
PREPARATION CV
2-[4-[[[[2-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]ethoxy]-acetyl]methylamino]-methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(amorphous solid, yield=64%)
M.Pt.=55° C.
PREPARATION CVI
2-[4-[[[[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl](2-phenylethyl)-amino]ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=63%)
1H NMR (250 MHz, DMSO) δ: 7.87 (m, 1H); 7.60 (m, 1H); 7.30 (m, 3H); 7.20 (m, 6H); 4.52 (s, 2H); 4.19 (d, 2H); 3.84 (m, 4H); 3.60 (m, 6H); 2.83 (s, 3H); 2.77 (t, 2H); 2.48 (d, 3H); 1.17 (s, 9H).
PREPARATION CVII
2-[4-[[[3-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-1-oxopropyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=60%)
M.Pt.=55° C.
PREPARATION CVIII
2-[4-[[[3-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]-1-oxopropyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=64%)
M.Pt.=60° C.
PREPARATION CIX
2-[4-[[[3-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]-1-oxopropyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=63%)
M.Pt.=64° C.
PREPARATION CX
2-[4-[[[3-[[(2,3-dichlorophenyl)sulphonyl](2,2,2-trifluoroethyl)-amino]-1-oxopropyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=33%)
M.Pt.=55° C.
PREPARATION CXI
2-[4-[[[3-[[(2,6-dichlorophenyl)sulphonyl](2,2,2-trifluoroethyl)-amino]-1-oxopropyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=36%)
M.Pt.=50° C.
PREPARATION CXII
4,5-dihydro-2-[4-[[methyl[(2E)-4-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-1-oxo-2-butenyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=62%)
1H NMR (250 MHz, DMSO) δ: 8.04 (m, 2H); 7.88 (m, 2H); 7.43 (m, 2H); 7.17 (m, 2H); 6.60 (m, 2H); 4.62 (d, 2H); 4.05 (dd, 2H); 3.83 (m, 4H); 2.86 (m, 6H); 1.17 (m, 9H).
PREPARATION CXIII
2-[4-[[[(2E)-4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]amino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=50%)
1H NMR (300 MHz, DMSO) δ: 8.31 (s, 1H); 7.82 (t, 1H); 7.62 (dd, 1H); 7.44 (dd, 2H); 7.22 (dd, 2H); 6.50 (m, 2H); 4.55 (d, 2H); 3.84 (m, 4H); 3.70 (m, 2H); 2.82 (d, 3H); 2.47 (m, 3H); 1.18 (s, 9H).
In operating analogously to Example 1, the following compounds are obtained:
EXAMPLE 15
5-[[(2-chlorophenyl)sulphonyl]cyclopropylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(white solid, yield=84%)
M.Pt.=55° C.
EXAMPLE 16
5-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(ecru solid, yield=99%)
M.Pt.=70° C.
EXAMPLE 17
5-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoreoacetate
(white solid, yield=86%)
M.Pt.=60° C.
EXAMPLE 18
5-[[(2,6-dichlorophenyl)sulphonyl](1-methylethyl)amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(white solid, yield=98%)
M.Pt.=60° C.
EXAMPLE 19
5-[(2-amino-2-oxoethyl)[(2,4-dichloro-3-methylphenyl)sulphonyl]-amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(white solid, yield=99%)
M.Pt.=90° C.
EXAMPLE 20
5-[(3-amino-3-oxopropyl)[(2,4-dichloro-3-methylphenyl)sulphonyl]-amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(white solid, yield=95%)
M.Pt.=85° C.
EXAMPLE 21
3-[[(2,3-dichlorophenyl)sulphonyl](1-methylethyl)amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide, trifluoroacetate
(white solid, yield=73%)
M.Pt.=92° C.
EXAMPLE 22
3-[[(2,6-dichlorophenyl)sulphonyl](1-methylethyl)amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide, trifluoroacetate
(white solid, yield=73%)
M.Pt.=75° C.
EXAMPLE 23
2-[2-[[(2-chlorophenyl)sulphonyl]cyclopropylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=71%)
M.Pt.=52° C.
EXAMPLE 24
2-[2-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=97%)
M.Pt.=65° C.
EXAMPLE 25
2-[2-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=99%)
M.Pt.=60° C.
EXAMPLE 26
2-[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl](2-phenylethyl)-amino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=81%)
M.Pt.=85° C.
EXAMPLE 27
3-[[(2,6-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide, trifluoroacetate
(white solid, yield=73%)
M.Pt.=75° C.
EXAMPLE 28
3-[cyclopropyl[(2,3-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide, trifluoroacetate
(white solid, yield=86%)
M.Pt.=80° C.
EXAMPLE 29
3-[cyclopropyl[(2,6-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide, trifluoroacetate
(white solid, yield=84%)
M.Pt.=65° C.
EXAMPLE 30
3-[(2,2,2-trifluoroethyl)[(2,3-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide, trifluoroacetate
(white solid, yield=90%)
M.Pt.=88° C.
EXAMPLE 31
3-[(2,2,2-trifluoroethyl)[(2,6-dichlorophenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-propanamide, trifluoroacetate
(white solid, yield=80%)
M.Pt.=80° C.
EXAMPLE 32
N-[[4-(4,5-dihydro-1H-imidazol-2yl)phenyl]methyl]-N-methyl-4-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-(2E)-2-butenamide, trifluoroacetate
(white solid, yield=99%)
M.Pt.=50° C.
EXAMPLE 33
4-[[(2,4-dichloro-3-methylphenyl)sulphonyl]amino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-(2E)-2-butenamide, trifluoroacetate
(white solid, yield=62%)
M.Pt.=99° C.
PREPARATION CXIV
[(4-cyanophenyl)methyl]methylcarbamic acid, 1,1-dimethylethyl ester
A solution of 1.94 g (13 mM) of [(4-cyanophenyl)methyl]methanamine is prepared in 100 ml of dichloromethane and 1.78 g (14.6 mM) of 4-dimethylaminopyridine, and then 3.19 g (14.6 mM) of di-t-butyl dicarbonate, are added. The reaction mixture is agitated at ambient temperature for 2 hours. The organic phase is washed with water and then with a solution of citric acid, and then with water, and then dried over magnesium sulphate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel in eluting with a mixture of toluene/isopropanol (9/1, v/v). 2.91 g of the desired product are thus obtained as a colourless oil
(yield=82%).
1H NMR (250 MHz, DMSO) δ: 7.82 (d, 2H); 7.39 (d, 2H); 4.45 (s, 2H); 2.79 (s, 3H); 1.38 (s, 9H).
PREPARATION CXV
[[4-(4,5-dihydro-5,5-dimethyl-1H-imidazol-2-yl)phenyl]methyl]methylcarbamic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation II, starting with the compound obtained according to Preparation CXIV and 1,2-diamino-2-methylpropane, the expected product is obtained as a colourless oil with a yield of 82%.
1H NMR (300 MHz, DMSO) δ: 7.78 (d, 2H); 7.25 (d, 2H); 4.39 (s, 2H); 3.36 (s, 2H); 2.76 (s, 3H); 1.39 (s, 9H); 1.23 (s, 6H).
PREPARATION CXVI
4-(4,5-dihydro-5,5-dimethyl-1H-imidazol-2-yl)-N-methyl-benzenemethanamine, dihydrochloride
A solution of 1.585 g (5 mM) of the compound obtained according to preparation CXV is prepared in 80 ml of ethyl acetate and 24 ml of a solution of hydrogen chloride in ethyl acetate are added slowly. The mixture is agitated at ambient temperature for 20 hours. The precipitate is separated off by filtration and then washed with ethyl acetate and then ethyl ether, and then dried in an anhydrous medium. 1.33 g of the desired product are thus obtained (yield 92%).
1H NMR (250 MHz, DMSO) δ: 7.73 (d, 2H); 7.33 (d, 2H); 3.65 (s, 2H); 3.35 (s, 2H); 2.24 (s, 3H); 1.22 (s, 6H).
In operating analogously to Preparation VIII, starting with the compound obtained according to preparation CXVI, the following compound is obtained:
EXAMPLE 34
5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(5,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methylpentanamide
(white solid, yield=38%)
M.Pt.=104° C.
EXAMPLE 35
5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(5,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methylpentanamide, hydrochloride
A solution of 62.6 mg (0.113 mM) of the compound obtained according to Example 34 is prepared in 10 ml of methanol and 225 μl of an N solution of hydrochloric acid are added. Mixing is carried out under agitation for 5 min and then concentration is carried out under reduced pressure. The residue is taken up in 5 ml of pure water and lyophilised. 48 mg of the expected compound are thus obtained as a white solid.
(yield=72%)
M.Pt.=104° C.
In operating analogously to Preparation V, the following compounds are obtained:
PREPARATION CXVII
2,4-dichloro-3,N-dimethyl-N-(2-hydroxyethyl)benzenesulphonamide
(non-isolated).
PREPARATION CXVIII
2,3-dichloro-N-(2-hydroxy-1-methylethyl)-N-methylbenzenesulphonamide
(colourless oil, yield=71%)
1H NMR (300 MHz, DMSO) δ: 8.05 (d, 1H); 8.01 (d, 1H); 7.55 (t, 1H); 4.76 (t, 1H); 3.79 (m, 1H); 3.40 (m, 2H); 2.81 (s, 3H); 1.04 (d, 3H).
PREPARATION CXIX
2,3-dichloro-N-(2-hydroxyethyl)-N-methylbenzenesulphonamide
(colourless oil, yield=99%)
1H NMR (300 MHz, DMSO) δ: 7.93 (m, 2H); 7.55 (t, 1H); 3.49 (m, 2H); 3.27 (t, 2H); 2.90 (s, 3H).
PREPARATION CXX
2,6-dichloro-N-(2-hydroxyethyl)-N-methylbenzenesulphonamide
(yellow oil, yield=99%)
1H NMR (300 MHz, DMSO) δ: 7.67 (d, 2H); 7.57 (m, 1H); 4.79 (t, 1H); 3.54 (q, 2H); 3.29 (t, 2H); 2.92 (s, 3H).
PREPARATION CXXI
2-chloro-N-(2-hydroxyethyl)-N-methylbenzenesulphonamide
(oil, yield=99%)
1H NMR (300 MHz, DMSO) δ: 7.95 (d, 1H); 7.66 (m, 2H); 7.60 (m, 1H); 4.79 (t, 1H); 3.53 (q, 2H); 3.25 (t, 2H); 2.88 (s, 3H).
PREPARATION CXXII
[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-ethoxy]acetic acid, 1,1-dimethylethyl ester
A solution of 100 mg (0.335 mM) of compound obtained according to the preparation CXVII is prepared in 4 ml of toluene and 30 mg (0.111 mM) of tetrabutylammonium chloride, and then 4 ml of a 35% solution of sodium hydroxide, are added. The reaction medium is cooled to 10° C. and 98 mg (0.5 mM) of t-butyl bromoacetate are then added. The mixture is agitated at ambient temperature for 30 min, and then hydrolysed over iced water. The mixture obtained is extracted with toluene and the organic phase obtained is dried over magnesium sulphate and concentrated under reduced pressure. The expected product is thus obtained as a colourless oil (yield=87%).
1H NMR (300 MHz, DMSO) δ: 7.84 (d, 1H); 7.63 (d, 1H); 3.93 (s, 2H); 3.59 (t, 2H); 3.39 (t, 2H); 2.91 (s, 3H); 2.49 (s, 3H); 1.41 (s, 9H).
In operating analogously to Preparation CXXII, the following compounds are obtained:
PREPARATION CXXIII
[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]propoxy]acetic acid, 1,1-dimethylethyl ester
(colourless oil, yield=88%)
1H NMR (250 MHz, DMSO) δ: 8.05 (d, 1H); 8.02 (d, 1H); 7.92 (t, 1H); 4.01 (m, 1H); 3.82 (s, 2H); 3.47 (m, 2H); 2.85 (s, 3H); 1.42 (s, 9H); 1.03 (d, 3H).
PREPARATION CXXIV
[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]acetic acid, 1,1-dimethylethyl ester
(colourless oil, yield=96%)
1H NMR (300 MHz, DMSO) δ: 7.94 (m, 2H); 7.56 (t, 1H); 3.93 (s, 2H); 3.60 (t, 2H); 3.40 (t, 2H); 2.94 (s, 3H); 1.42 (s, 9H).
PREPARATION CXXV
[2-[[(2,6-dichlorophenyl)sulphonyl]methylamino]ethoxy]acetic acid, 1,1-dimethylethyl ester
(yellow oil, yield=99%).
1H NMR (250 MHz, DMSO) δ: 7.67 (d, 2H); 7.55 (m, 1H); 3.93 (s, 2H); 3.62 (t, 2H); 3.43 (d, 2H); 2.94 (s, 3H); 1.41 (s, 9H).
PREPARATION CXXVI
[2-[[(2-chlorophenyl)sulphonyl]methylamino]ethoxy]acetic acid, 1,1-dimethylethyl ester
(oil, yield=99%).
1H NMR (300 MHz, DMSO) δ: 7.98 (d, 1H); 7.67 (m, 2H); 7.54 (m, 1H); 3.94 (s, 2H); 3.60 (t, 2H); 3.39 (t, 2H); 2.85 (s, 3H); 1.42 (s, 9H).
In operating analogously to Preparation VII, the following compounds are obtained:
PREPARATION CXXVII
[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-acetic acid
(colourless oil, yield=100%)
1H NMR (300 MHz, DMSO) δ: 12.5 (broad s, 1H); 7.86 (d, 1H); 7.64 (d, 1H); 4.02 (s, 2H); 3.61 (t, 2H); 3.40 (t, 2H); 2.91 (s, 3H); 2.51 (s, 3H).
PREPARATION CXXVIII
[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]propoxy]acetic acid
(colourless oil, yield=81%).
1H NMR (300 MHz, DMSO) δ: 12.6 (broad s, 1H); 8.06 (d, 1H); 7.92 (d, 1H); 7.53 (t, 1H); 3.98 (m, 1H); 3.82 (s, 2H); 3.50 (m, 2H); 2.85 (s, 3H); 1.05 (d, 3H).
In operating analogously to Preparation LXXVIII, the following compounds are obtained:
PREPARATION CXXIX
[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]acetic acid
(white ecru solid, yield=100%).
M.Pt.=80° C.
PREPARATION CXXX
[2-[[(2,6-dichlorophenyl)sulphonyl]methylamino]ethoxy]acetic acid
(yellow oil, yield=100%).
1H NMR (250 MHz, DMSO) δ: 12.6 (broad s, 1H); 7.67 (d, 2H); 7.55 (m, 1H); 3.97 (s, 2H); 3.63 (t, 2H); 3.44 (t, 2H); 2.94 (s, 3H).
PREPARATION CXXXI
[2-[[(2-chlorophenyl)sulphonyl]methylamino]ethoxy]acetic acid
(colourless oil, yield=99%).
1H NMR (300 MHz, DMSO) δ: 12.5 (broad s, 1H); 7.95 (d, 1H); 7.66 (m, 2H); 7.55 (m, 1H); 3.97 (s, 2H); 3.61 (t, 2H); 3.39 (t, 2H); 2.90 (s, 3H).
PREPARATION CXXXII
Methyl[[4-(1,4,5,6-tetrahydro-2-pyrimidinyl)phenyl]methyl]carbamic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation CXV, starting with 1,3-propanediamine, the expected product is obtained as a colourless oil with a yield of 30%.
1H NMR (250 MHz, DMSO) δ: 7.75 (d, 2H); 7.37 (d, 2H); 4.44 (s, 2H); 3.47 (t, 4H); 2.79 (s, 3H); 1.90 (m, 2H); 1.40 (s, 9H).
PREPARATION CXXXIII
N-methyl-4-(1,4,5,6-tetrahydro-2-pyrimidinyl)-benzenemethanamine, dihydrochloride
In operating analogously to Preparation CXVI, the expected product is obtained as a yellow oil (yield=100%).
1H NMR (250 MHz, DMSO) δ: 10.23 (s, 2H); 9.73 (broad s, 2H); 7.83 (m, 4H); 4.20 (t, 2H); 3.50 (s, 4H); 2.51 (m, 3H); 1.95 (m, 2H).
PREPARATION CXXXIV
[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]methylcarbamic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation CXV, starting with 1,2-propanediamine, the expected product is obtained as a yellow oil (yield=74%).
1H NMR (250 MHz, DMSO) δ: 7.49 (d, 2H); 7.26 (d, 2H); 4.4 (s, 2H); 3.68 (t, 2H); 3.34 (t, 2H); 2.78 (s, 3H); 2.70 (s, 3H); 1.40 (s, 9H).
PREPARATION CXXXV
N-methyl-4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)benzenemethanamine, dihydrochloride
In operating analogously to Preparation CXVI, the expected product is obtained as a beige oil (yield=100%).
1H NMR (250 MHz, DMSO) δ: 10.44 (s, 1H); 9.13 (s, 2H); 7.74 (m, 4H); 4.26 (s, 2H); 4.08 (m, 2H); 3.92 (m, 2H); 3.05 (s, 3H); 2.61 (s, 3H).
PREPARATION CXXXVI
4-cyano-2-fluoro-N-methylbenzenemethanamine
1 ml of a 16.5% solution of methanamine in ethanol is cooled by an ice bath and a solution of 120 mg (0.56 mM) of 4-(bromomethyl)-3-fluoro-benzonitrile in 1 ml of dichloromethane is added dropwise. The reaction medium is then agitated for 4 hours at ambient temperature and is then concentrated under reduced pressure. The residue is taken up with ethyl acetate and washed with a solution of sodium bicarbonate. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The crude product is purified by chromatography on silica gel in eluting with the aid of a mixture of dichloromethane/methanol (98/0.05; v/v). The expected amine is thus obtained as a colourless oil (yield=49%).
1H NMR (300 MHz, DMSO) δ: 7.78 (d, 1H); 7.64 (m, 2H); 3.73 (s, 2H); 2.33 (s, 1H); 2.26 (s, 3H).
In operating analogously to Preparations I to IV, the following compounds are obtained successively:
PREPARATION CXXXVII
[(2-fluoro-4-cyanophenyl)methyl]methylcarbamic acid, phenylmethyl ester
(yellow oil, yield=99%).
1H NMR (300 MHz, DMSO) δ: 7.84 (d, 1H); 7.67 (m, 1H); 7.36 (m, 8H); 5.16 (d, 2H); 4.57 (s, 2H); 2.91 (s, 3H).
PREPARATION CXXXVIII
[[2-fluoro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]methylcarbamic acid, phenylmethyl ester
(white solid, yield=70%).
M.Pt.=90° C.
PREPARATION CXXXIX
2-[3-fluoro-4-[[methyl[(phenylmethoxy)carbonyl]amino]-methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=99%).
M.Pt.=131° C.
PREPARATION CXL
2-[3-fluoro-4-[(methylamino)methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(yellow oil, yield=81%).
1H NMR (300 MHz, DMSO) δ: 7.44 (t, 1H); 7.23 (m, 3H); 3.84 (m, 4H); 3.69 (s, 2H); 2.25 (s, 3H); 1.21 (s, 9H).
In operating analogously to Preparation VIII, the following compounds are obtained:
PREPARATION CXLI
2-[4-[[[[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=81%).
1H NMR (250 MHz, DMSO) δ: 7.87 (t, 1H); 7.62 (m, 1H); 7.44 (m, 2H); 7.24 (d, 2H); 4.51 (s, 2H); 4.19 (d, 2H); 3.83 (m, 4H); 3.62 (m, 2H); 3.43 (m, 2H); 2.85 (m, 6H); 1.18 (s, 9H).
PREPARATION CXLII
2-[4-[[[[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]propoxy]-acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=52%).
1H NMR (250 MHz, DMSO) δ: 8.08 (m, 1H); 7.89 (m, 1H); 7.50 (m, 3H); 7.30 (m, 2H); 4.49 (d, 2H); 4.05 (d, 2H); 3.98 (m, 1H); 3.84 (m, 4H); 3.49 (m, 2H); 2.83 (m, 6H); 1.18 (s, 1H); 1.04 (t, 3H).
PREPARATION CXLIII
2-[4-[[[[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=73%).
1H NMR (300 MHz, DMSO) δ: 7.95 (m, 2H); 7.50 (m, 3H); 7.24 (d, 2H); 4.52 (s, 2H); 4.18 (d, 2H); 3.83 (m, 4H); 3.64 (m, 2H); 3.46 (m, 2H); 2.91 (m, 6H); 1.18 (s, 9H).
PREPARATION CXLIV
2-[4-[[[[2-[[(2,6-dichlorophenyl)sulphonyl]methylamino]ethoxy]-acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=58%).
1H NMR (300 MHz, DMSO) δ: 7.67 (m, 2H); 7.55 (m, 1H); 7.45 (m, 2H); 7.25 (d, 2H); 4.51 (s, 2H); 4.18 (d, 2H); 3.83 (m, 4H); 3.66 (m, 2H); 3.45 (m, 2H); 2.84 (m, 6H); 1.18 (s, 9H).
EXAMPLE 36
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-methyl-N-[[4-(1,4,5,6-tetrahydro-2-pyrimidinyl)phenyl]methyl]acetamide
(colourless oil, yield=25%).
1H NMR (300 MHz, DMSO) δ: 7.95 (m, 2H); 7.50 (m, 3H); 7.24 (d, 2H); 4.52 (s, 2H); 4.18 (d, 2H); 3.83 (m, 4H); 3.64 (m, 2H); 3.46 (m, 2H); 2.91 (m, 6H); 1.18 (s, 9H).
EXAMPLE 37
2-[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide
(yellow oil, yield=25%).
1H NMR (300 MHz, DMSO) δ: 7.84 (t, 1H); 7.63 (m, 1H); 7.49 (m, 2H); 7.28 (m, 2H); 4.53 (s, 2H); 4.20 (d, 2H); 3.65 (m, 4H); 3.42 (m, 4H); 2.78 (m, 9H); 2.51 (s, 3H).
EXAMPLE 38
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide
(oil, yield=20%).
1H NMR (250 MHz, DMSO) δ: 7.98 (m, 2H); 7.55 (m, 3H); 7.34 (m, 2H); 4.54 (s, 2H); 4.20 (d, 2H); 3.60 (m, 8H); 2.80 (m, 9H).
PREPARATION CXLV
2-[4-[[[[2-[[(2-chlorophenyl)sulphonyl]methylamino]ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=46%).
1H NMR (300 MHz, DMSO) δ: 7.97 (t, 1H); 7.65 (m, 2H); 7.56 (m, 1H); 7.47 (m, 2H); 7.24 (d, 2H); 4.52 (s, 2H); 4.20 (d, 2H); 3.83 (m, 4H); 3.63 (m, 2H); 3.40 (m, 2H); 2.84 (m, 6H); 1.18 (s, 9H).
PREPARATION CXLVI
2-[4-[[[[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-acetyl]methylamino]methyl]-3-fluorophenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=46%).
1H NMR (250 MHz, DMSO) δ: 7.94 (m, 2H); 7.55 (dd, 1H); 7.26 (m, 3H); 4.56 (s, 2H); 4.20 (d, 2H); 3.85 (m, 4H); 3.61 (m, 2H); 3.45 (m, 2H); 2.85 (m, 6H); 1.20 (s, 9H).
In operating analogously to Example 1, the following compounds are obtained:
EXAMPLE 39
2-[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=98%).
M.Pt.=75° C.
EXAMPLE 40
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=96%).
M.Pt.=60° C.
EXAMPLE 41
2-[2-[[(2,6-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=96%).
M.Pt.=60° C.
EXAMPLE 42
2-[2-[[(2-chlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=99%).
M.Pt.=60° C.
EXAMPLE 43
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[2-fluoro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=87%).
M.Pt.=80° C.
In operating analogously to Preparation CXVI starting with the compound obtained according to Preparation CXLII, the following compound is obtained:
EXAMPLE 44
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]propoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, hydrochloride
(white solid, yield=85%).
M.Pt.=104° C.
EXAMPLE 45
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-methyl-N-[[4-(1,4,5,6-tetrahydro-2-pyrimidinyl)phenyl]methyl]acetamide, trifluoroacetate
A solution of 40 mg (0.075 mM) of the compound obtained according to Example 36 is prepared in 10 ml of methanol and 5.9 μl of trifluoroacetic acid are added. The mixture is agitated 15 min at ambient temperature and then concentrated under reduced pressure. The residue is taken up in 3 ml of pure water and the solution obtained is filtered. The filtrate is lyophilised. 35 mg of the expected compound are thus obtained as a white powder (yield=73%).
1H NMR (250 MHz, DMSO) δ: 10.05 (broad s, 2H); 7.98 (m, 2H); 7.73 (m, 2H); 7.56 (m, 4H); 4.59 (s, 2H); 4.20 (d, 2H); 3.65 (m, 2H); 3.46 (m, 6H); 2.87 (m, 6H); 1.98 (m, 2H).
EXAMPLE 46
2-[2-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, hydrochloride
90 mg (0.166 mM) of the compound obtained according to Example 37 are dissolved in 3 ml of methanol and 1 ml of a saturated solution of hydrogen chloride in ethyl ether is added. The mixture is kept under agitation at ambient temperature for 1 hour. 10 ml of ethyl ether are added and the mixture is then concentrated under reduced pressure. The residue is taken up in 6 ml of pure water. The solution obtained is filtered and then lyophilised. 95 mg of the desired product are thus obtained as a white crystallised solid (yield=98%).
M.Pt.=60° C.
EXAMPLE 47
2-[2-[[(2,3-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, hydrochloride
In operating analogously to Example 46, starting with the compound obtained according to Example 38, the expected compound is obtained as a colourless oil
(yield=53%).
1H NMR (250 MHz, DMSO) δ: 10.20 (s, 1H); 7.98 (m, 2H); 7.65 (m, 2H); 7.53 (m, 3H); 4.60 (s, 2H); 4.20 (d, 2H); 3.95 (m, 4H); 3.70 (m, 4H); 3.06 (s, 3H); 2.90 (m, 6H).
PREPARATION CXLVII
(2-hydroxyethyl)methylcarbamic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation CXIV, starting with 2-(methylamino)ethanol, the expected compound is obtained as a colourless oil
(yield=87%).
1H NMR (300 MHz, DMSO) δ: 4.65 (t, 1H); 3.45 (q, 2H); 3.19 (t, 2H); 2.81 (s, 3H); 1.38 (s, 9H).
PREPARATION CXLVIII
[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]ethoxy]acetic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation CXXII, starting with the compound obtained according to preparation CXLVII, the expected product is obtained as a yellow oil (yield=99%).
1H NMR (250 MHz, DMSO) δ: 3.96 (s, 2H); 3.52 (t, 2H); 3.31 (t, 2H); 2.81 (s, 3H); 1.42 (s, 9H); 1.38 (s, 9H).
PREPARATION CIL
[2-(methylamino)ethoxy]acetic acid, trifluoroacetate
In operating analogously to Preparation LXXVIII, starting with the compound obtained according to Preparation CXLVIII, the expected product is obtained as a yellow oil (yield=99%).
1H NMR (250 MHz, DMSO) δ: 8.50 (broad s, 1H); 4.09 (s, 2H); 3.70 (m, 2H); 3.11 (m, 2H); 2.60 (m, 3H).
PREPARATION CL
[2-[methyl[(phenylmethoxy)carbonyl]amino]ethoxy]acetic acid
A solution of 25 g (0.101 mM) of the compound obtained according to Preparation CIL is prepared in 400 ml of dichloromethane. 35.2 ml (0.25 mM) of triethylamine and then, dropwise, 15.5 ml of benzyl chloroformate, are added at 0° C. The reaction mixture is agitated for 5 hours at ambient temperature. The reaction mixture is hydrolysed over 200 ml of iced water and 50 ml of N hydrochloric acid. The separated organic phase is washed with water and then dried over magnesium sulphate and concentrated under reduced pressure. The crude oily product is purified by chromatography on silica gel in eluting with a mixture of toluene/isopropanol/aquous ammonia (9/1/0.1; v/v/v). 13.7 g of the desired product are thus obtained as a colourless oil (yield=51%).
1H NMR (250 MHz, DMSO) δ: 7.33 (m, 5H); 5.06 (s, 2H); 4.10 (s, 2H); 3.58 (t, 2H); 3.49 (m, 2H); 2.90 (d, 3H).
PREPARATION CLI
2-[4-(2,8-dimethyl-3,9-dioxo-11-phenyl-5,10-dioxa-2,8-diazaundec-1-yl)phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation VIII, starting with the acid obtained according to the Preparation CL, the expected product is obtained as a yellow oil (yield=62%).
1H NMR (250 MHz, DMSO) δ: 7.42-7.22 (m, 9H); 5.05 (s, 2H); 4.51 (s, 2H); 4.21 (s, 2H); 3.84 (m, 4H); 3.58 (m, 2H); 3.45 (m, 2H); 2.88 (m, 6H); 1.17 (s, 9H).
PREPARATION CLII
4,5-dihydro-2-[4-[[methyl[[2-(methylamino)ethoxy]acetyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation IV, starting with the compound obtained according to Preparation CLI, the expected product is obtained as a yellow oil (yield=91%).
1H NMR (250 MHz, DMSO) δ: 7.41 (d, 2H); 7.26 (d, 2H); 4.53 (d, 2H); 4.20 (d, 2H); 3.84 (m, 4H); 3.50 (m, 2H); 2.86 (s, 3H); 2.63 (m, 2H); 2.26 (d, 3H); 1.18 (s, 9H).
In operating analogously to Preparation V, starting with the compound obtained according to Preparation CLII, the following compounds are obtained:
PREPARATION CLIII
4,5-dihydro-2-[4-[[methyl[[2-[methyl[[2-(trifluoromethyl)phenyl]-sulphonyl]amino]ethoxy]acetyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
1H NMR (300 MHz, DMSO) δ: 8.02 (m, 2H); 7.87 (m, 2H); 7.44 (m, 2H); 7.23 (d, 2H); 4.53 (s, 2H); 4.23 (d, 2H); 3.83 (m, 4H); 3.65 (m, 2H); 3.48 (m, 2H); 2.88 (m, 6H); 1.17 (s, 9H).
PREPARATION CLIV
4,5-dihydro-2-[4-[[[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]-methylamino]ethoxy]acetyl]methylamino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=74%).
1H NMR (300 MHz, DMSO) δ: 7.42 (m, 2H); 7.22 (d, 2H); 6.80 (d, 2H); 4.50 (s, 2H); 4.15 (d, 2H); 3.84 (m, 4H); 3.79 (s, 3H); 3.57 (m, 2H); 3.22 (m, 2H); 2.76 (m, 6H); 2.53 (s, 6H); 1.17 (s, 9H).
PREPARATION CLV
2-[[[[2-[[(2,4-dichlorophenyl)sulphonyl]methylamino]ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=70%).
1H NMR (250 MHz, DMSO) δ: 7.89 (m, 2H); 7.60 (m, 1H); 7.43 (m, 2H); 7.23 (d, 2H); 4.51 (s, 2H); 4.20 (d, 2H); 3.84 (m, 4H); 3.60 (m, 2H); 3.42 (m, 2H); 2.83 (m, 6H); 1.18 (s, 9H).
PREPARATION CLVI
2-[4-[[[[2-[[(2,4-dichloro-5-methylphenyl)sulphonyl]methylamino]ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=43%).
1H NMR (300 MHz, DMSO) δ: 7.94 (m, 1H); 7.82 (m, 1H); 7.42 (m, 2H); 7.23 (d, 2H); 4.52 (s, 2H); 4.20 (d, 2H); 3.83 (m, 4H); 3.60 (m, 2H); 3.42 (m, 2H); 2.85 (m, 6H); 2.38 (s, 3H); 1.18 (s, 9H).
PREPARATION CLVII
4,5-dihydro-2-[4-[[methyl[[2-[methyl[(2-nitrophenyl)sulphonyl]amino]ethoxy]acetyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white foam, yield=50%).
M.Pt.=60° C.
PREPARATION CLVIII
2-[4-[[[[2-[[[2,6-dichloro-4-(trifluoromethyl)phenyl]sulphonyl]methylamino]ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=55%).
1H NMR (300 MHz, DMSO) δ: 8.08 (d, 2H); 7.42 (m, 2H); 7.22 (d, 2H); 4.50 (s, 2H); 4.18 (d, 2H); 3.83 (m, 4H); 3.64 (m, 2H); 3.50 (m, 2H); 2.80 (m, 6H); 1.18 (s, 9H).
PREPARATION CLIX
2-[4-[[[[2-[[(2-chloro-3-methylphenyl)sulphonyl]methylamino]-ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=63%).
M.Pt.=50° C.
PREPARATION CLX
2-[4-[[[[2-[[(2-cyanophenyl)sulphonyl]methylamino]ethoxy]-acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=56%).
M.Pt.=60° C.
PREPARATION CLXI
4,5-dihydro-2-[4-[[methyl[[2-[methyl[(2,3,4-(trichlorophenyl)-sulphonyl]amino]ethoxy]acetyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=59%).
M.Pt.=60° C.
PREPARATION CLXII
2-[4-[[[[2-[[(3-chloro-2-methylphenyl)sulphonyl]methylamino]-ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=57%).
1H NMR (250 MHz, DMSO) δ: 7.78 (m, 2H); 7.41 (m, 3H); 7.23 (d, 2H); 4.52 (s, 2H); 4.20 (d, 2H); 3.82 (m, 4H); 3.59 (m, 2H); 3.39 (m, 2H); 2.83 (m, 6H); 2.59 (d, 3H); 1.18 (s, 9H).
PREPARATION CLXIII
2-[4-[[[[2-[[(2-chloro-4-cyanophenyl)sulphonyl]methylamino]-ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=51%).
M.Pt.=60° C.
PREPARATION CLXIV
4,5-dihydro-2-[4-[[methyl[[2-[methyl[[2-nitro-4-(trifluoromethyl)-phenyl]sulphonyl]amino]ethoxy]acetyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=47%)
1H NMR (300 MHz, DMSO) δ: 8.59 (s, 1H); 8.27 (m, 2H); 7.42 (m, 2H); 7.23 (d, 2H); 4.51 (s, 2H); 4.20 (d, 2H); 3.83 (m, 4H); 3.64 (m, 2H); 3.47 (m, 2H); 2.90 (m, 6H); 1.18 (s, 9H).
PREPARATION CLXV
2-[4-[[[[2-[[(2,6-difluorophenyl)sulphonyl]methylamino]-ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=49%).
1H NMR (250 MHz, DMSO) δ: 7.74 (m, 1H); 7.43 (m, 2H); 7.27 (m, 4H); 4.51 (s, 2H); 4.16 (d, 2H); 3.82 (m, 4H); 3.60 (m, 2H); 3.56 (m, 2H); 2.82 (m, 6H); 1.18 (s, 9H).
PREPARATION CLXVI
4,5-dihydro-2-[4-[[methyl[[2-[methyl[[4-(trifluoromethoxy)phenyl]-sulphonyl]amino]ethoxy]acetyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=63%).
1H NMR (250 MHz, DMSO) δ: 7.93 (m, 2H); 7.60 (d, 2H); 7.42 (m, 2H); 7.23 (d, 2H); 4.51 (s, 2H); 4.19 (d, 2H); 3.84 (m, 4H); 3.59 (m, 2H); 3.22 (m, 2H); 2.78 (m, 6H); 1.18 (s, 9H).
PREPARATION CLXVII
2-[4-[[[[2-[[(2,5-dichlorothien-3-yl)sulphonyl]methylamino]-ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=30%).
1H NMR (250 MHz, DMSO) δ: 7.41 (m, 3H); 7.23 (d, 2H); 4.52 (s, 2H); 4.21 (d, 2H); 3.84 (m, 4H); 3.62 (m, 2H); 3.37 (m, 2H); 2.84 (m, 6H); 1.18 (s, 9H).
PREPARATION CLXVIII
4,5-dihydro-2-[4-[[methyl[[2-[methyl[(3-methylphenyl)sulphonyl]amino]ethoxy]acetyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=33%).
1H NMR (300 MHz, DMSO) δ: 7.60 (m, 2H); 7.56 (m, 2H); 7.50 (m, 2H); 7.22 (d, 2H); 4.52 (s, 2H); 4.20 (d, 2H); 3.84 (m, 4H); 3.57 (m, 2H); 3.17 (m, 2H); 2.76 (m, 6H); 2.40 (s, 3H); 1.18 (s, 9H).
PREPARATION CLXIX
4,5-dihydro-2-[4-[[methyl[[2-[methyl(1-naphthalenylsulphonyl)amino]ethoxy]acetyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=33%).
1H NMR (300 MHz, DMSO) δ: 8.60 (m, 1H); 8.20 (m, 1H); 8.08 (m, 2H); 7.68 (m, 3H); 7.46 (m, 2H); 7.23 (d, 2H); 4.50 (d, 2H); 4.13 (d, 2H); 3.84 (m, 4H); 3.59 (m, 2H); 3.41 (m, 2H); 2.86 (m, 6H); 1.17 (s, 9H).
PREPARATION CLXX
4,5-dihydro-2-[4-[[methyl[[2-[methyl[[3-(trifluoromethyl)phenyl]-sulphonyl]amino]ethoxy]acetyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=66%).
1H NMR (300 MHz, DMSO) δ: 8.12 (m, 3H); 7.85 (m, 1H); 7.44 (m, 2H); 7.23 (d, 2H); 4.50 (s, 2H); 4.15 (d, 2H); 3.82 (m, 4H); 3.60 (m, 2H); 3.26 (m, 2H); 2.81 (m, 6H); 1.18 (s, 9H).
PREPARATION CLXXI
2-[4-[[[[2-[[(4-chloro-3-methylphenyl)sulphonyl]methylamino]-ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H -imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=59%).
M.Pt.=60° C.
PREPARATION CLXXII
2-[4-[[[[2-[[(2,4-difluorophenyl)sulphonyl]methylamino]ethoxy]-acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=64%).
1H NMR (250 MHz, DMSO) δ: 7.87 (m, 1H); 7.43 (m, 3H); 7.20 (m, 3H); 4.51 (s, 2H); 4.17 (d, 2H); 3.84 (m, 4H); 3.61 (m, 2H); 3.34 (m, 2H); 2.84 (m, 6H); 1.18 (s, 9H).
PREPARATION CLXXIII
2-[4-[[[[2-[[(3-chlorophenyl)sulphonyl]methylamino]ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=51%).
1H NMR (300 MHz, DMSO) δ: 7.78 (m, 3H); 7.66 (m, 1H); 7.45 (m, 2H); 7.23 (d, 2H); 4.51 (s, 2H); 4.19 (d, 2H); 3.82 (m, 4H); 3.52 (m, 2H); 3.37 (m, 2H); 2.78 (m, 6H); 1.18(s, 9H).
In operating analogously to Example 1, the following compounds are obtained:
EXAMPLE 48
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]ethoxy]-acetamide, trifluoroacetate
(fine white solid, yield=96%).
M.Pt.=60° C.
EXAMPLE 49
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]-N-methyl-acetamide, trifluoroacetate
(pasty solid, yield=99%).
1H NMR (250 MHz, DMSO) δ: 10.48 (broad s, 2H); 7.89 (d, 2H); 7.48 (d, 2H); 6.79 (s, 2H); 4.59 (s, 2H); 4.15 (d, 2H); 4.01 (s, 4H); 3.79 (s, 3H); 3.59 (m, 2H); 3.24 (m, 2H); 2.71 (m, 6H); 2.53 (s, 6H).
EXAMPLE 50
2-[2-[[(2,4-dichlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=99%).
M.Pt.=60° C.
EXAMPLE 51
2-[2-[[(2,4-dichloro-5-methylphenyl)sulphonyl]methylamino]-ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(pasty solid, yield=99%).
1H NMR (250 MHz, DMSO) δ: 10.5 (d, 2H); 7.87 (m, 4H); 7.50 (d, 2H); 4.60 (s, 2H); 4.10 (d, 2H); 4.01 (s, 4H); 3.62 (m, 2H); 3.45 (m, 2H); 2.85 (m, 6H); 2.38 (s, 3H).
EXAMPLE 52
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[(2-nitrophenyl)sulphonyl]amino]ethoxy]acetamide, trifluoroacetate
(yellow paste, yield=99%).
1H NMR (300 MHz, DMSO) δ: 10.49 (s, 2H); 7.89 (m, 6H); 7.49 (d, 2H); 4.61 (s, 2H); 4.22 (d, 2H); 4.01 (s, 4H); 3.66 (m, 2H); 3.41 (m, 2H); 2.90 (m, 6H).
EXAMPLE 53
2-[2-[[[2,6-dichloro-4-(trifluoromethyl)phenyl]sulphonyl]-methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=99%).
M.Pt.=60° C.
EXAMPLE 54
2-[2-[[(2-chloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=67%).
M.Pt.=63° C.
EXAMPLE 55
2-[2-[[(2-cyanophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=94%).
M.Pt.=60° C.
EXAMPLE 56
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[(2,3,4-trichlorophenyl)sulphonyl]amino]ethoxy]acetamide, trifluoroacetate
(white solid, yield=99%).
M.Pt.=70° C.
EXAMPLE 57
2-[2-[[(3-chloro-2-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(fine white solid, yield=74%).
M.Pt.=60° C.
EXAMPLE 58
2-[2-[[(2-chloro-4-cyanophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=97%).
M.Pt.=64° C.
EXAMPLE 59
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[2-nitro-4-(trifluoromethyl)phenyl]sulphonyl]amino]-ethoxy]acetamide, trifluoroacetate
(white solid, yield=85%).
1H NMR (250 MHz, DMSO) δ: 10.47 (s, 2H); 8.59 (s, 1H); 8.23 (m, 2H); 7.92 (m, 2H); 7.48 (d, 2H); 4.60 (s, 2H); 4.20 (d, 2H); 4.01 (s, 4H); 3.65 (m, 2H); 3.47 (m, 2H); 2.85 (m, 6H).
EXAMPLE 60
2-[2-[[(2,6-difluorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(foam, yield=99%).
1H NMR (250 MHz, DMSO) δ: 10.47 (s, 2H); 7.92 (m, 2H); 7.76 (m, 1H); 7.47 (d, 2H); 7.27 (t, 2H); 4.60 (s, 2H); 4.20 (d, 2H); 4.01 (s, 4H); 3.65 (m, 2H); 3.37 (m, 2H); 2.89 (m, 6H).
EXAMPLE 61
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[4-(trifluoromethoxy)phenyl]sulphonyl]amino]-ethoxy]acetamide, trifluoroacetate
(colourless oil, yield=67%).
1H NMR (250 MHz, DMSO) δ: 10.51 (s, 2H); 7.91 (t, 4H); 7.59 (d, 2H); 7.48 (d, 2H); 4.60 (s, 2H); 4.20 (d, 2H); 4.01 (s, 4H); 3.61 (m, 2H); 3.21 (m, 2H); 2.75 (m, 6H).
EXAMPLE 62
2-[2-[[(2,5-dichlorothien-3-yl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=99%).
M.Pt.=60° C.
EXAMPLE 63
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[(3-methylphenyl)sulphonyl]amino]ethoxy]acetamide, trifluoroacetate
(colourless oil, yield=68%).
1H NMR (250 MHz, DMSO) δ: 10.48 (s, 2H); 7.88 (m, 2H); 7.61 (m, 2H); 7.51 (m, 4H); 4.63 (s, 2H); 4.20 (d, 2H); 4.01 (s, 4H); 3.62 (m, 2H); 3.09 (m, 2H); 2.76 (m, 6H); 2.40 (s, 3H).
EXAMPLE 64
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl(1-naphthalenylsulphonyl)amino]ethoxy]acetamide, trifluoroacetate
(white solid, yield=99%).
M.Pt.=66° C.
EXAMPLE 65
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[3-(trifluoromethyl)phenyl]sulphonyl]amino]-ethoxy]acetamide, trifluoroacetate
(white solid, yield=99%).
M.Pt.=60° C.
EXAMPLE 66
2-[2-[[(4-chloro-3-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methylacetamide, trifluoroacetate
(white solid, yield=59%).
M.Pt.=60° C.
EXAMPLE 67
2-[2-[[(2,4-difluorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(colourless oil, yield=99%).
1H NMR (250 MHz, DMSO) δ: 10.51 (s, 2H); 7.88 (m, 3H); 7.53 (m, 3H); 7.29 (m, 1H); 4.60 (s, 2H); 4.20 (d, 2H); 4.01 (s, 4H); 3.60 (m, 2H); 3.26 (m, 2H); 2.85 (m, 6H).
EXAMPLE 68
2-[2-[[(3-chlorophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, trifluoroacetate
(white solid, yield=99%).
M.Pt.=60° C.
PREPARATION CLXXIV
5-bromo-N-[(4-cyanophenyl)methyl]-N-methylpentanamide
A solution of 30.14 g (0.206 M) of 4-[(methylamino)methyl]benzonitrile is prepared in 500 ml of dichloromethane and 22.9 g (0.227 M) of triethylamine are added. The mixture is cooled with the aid of an ice bath and a solution of 41.1 g (0.206 M) of 5-bromopentanoyl chloride in 200 ml of dichloromethane is added dropwise. The reaction mixture is kept under agitation at ambient temperature for 5 hours and then hydrolysed over 300 ml of cold 1N hydrochloric acid. The organic phase is separated, washed with water, and then with a solution of sodium bicarbonate, and then with water and dried over magnesium sulphate. After concentration under reduced pressure, the expected product is obtained as a yellow oil (yield=97%).
1H NMR (300 MHz, DMSO) δ: 7.80 (d, 2H); 7.39 (d, 2H); 4.62 (d, 2H); 3.50 (m, 2H); 2.81 and 2.50 (s, 3H); 2.41 (m, 2H); 1.80 (m, 2H); 1.64 (m, 2H).
PREPARATION CLXXV
N-[(4-cyanophenyl)methyl]-N-methyl-5-[methyl(phenylmethyl)-amino]pentanamide
A solution of 62.2 g (0.201 M) of the compound obtained according to preparation CLXXIV is prepared in 500 ml of acetonitrile and 24.4 g (0.201 M) of N-methyl-benzenemethanamine, and then 27.8 g (0.201 M) of potassium carbonate, are added at ambient temperature. The reaction mixture is agitated at 50° C. for 8 hours, and then for one night at ambient temperature. The solvent is then removed under reduced pressure and the residue of evaporation is taken up by 300 ml of dichloromethane. This organic phase is washed twice with water, and then dried over magnesium sulphate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel in eluting with the aid of a mixture of dichloromethane/methanol (95/5; v/v). 51.7 g of the expected compound are thus obtained as a yellow oil (yield=74%).
1H NMR (250 MHz, DMSO) δ: 7.78 (m, 2H); 7.35 (m, 2H); 7.26 (m, 5H); 4.60 (d, 2H); 3.40 (d, 2H); 2.75 (d, 3H); 2.32 (m, 4H); 2.05 (d, 3H); 1.50 (m, 4H).
PREPARATION CLXXVI
[5-[[(4-cyanophenyl)methyl]methylamino]-5-oxopentyl]methylcarbamic acid, phenylmethyl ester
51.67 g (0.148 M) of the compound obtained according to preparation CLXXV are dissolved in 400 ml of dichloromethane and a solution of 42 ml (0.296 M) of benzyl chloroformate in 200 ml of dichloromethane is added progressively. The reaction mixture is kept under agitation for 16 hours at ambient temperature, and then hydrolysed over 300 ml of cold 0.5 N hydrochloric acid. The organic phase is separated and then washed with water to neutrality, dried over magnesium sulphate and concentrated under reduced pressure. This crude product is purified by chromatography on silica gel in eluting with a mixture of toluene/isopropanol (95/5; v/v). 51.6 g of the desired product are thus obtained as a yellow oil (yield=89%).
1H NMR (250 MHz, DMSO) δ: 7.79 (m, 2H); 7.36 (m, 7H); 5.04 (d, 2H); 4.60 (d, 2H); 3.22 (m, 2H); 2.84 (m, 6H); 2.35 (m, 2H); 1.47 (m, 4H).
In operating analogously to Preparations II to IV, starting with the compound obtained according to Preparation CLXXVI, the following compounds are obtained:
PREPARATION CLXXVII
[5-[[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]methylamino]-5-oxopentyl]methylcarbamic acid, 1,1-dimethylethyl ester
(yellow oil, yield=94%).
1H NMR (250 MHz, DMSO) δ: 7.78 (m, 2H); 7.30 (m, 5H); 7.22 (d, 2H); 6.83 (broad s, 1H); 5.04 (d, 2H); 4.50 (d, 2H); 3.64 (m, 4H); 3.26 (m, 2H); 2.82 (m, 6H); 2.38 (m, 2H); 1.48 (m, 4H).
PREPARATION CLXXVIII
4,5-dihydro-2-[4-[[methyl[5-[methyl[(phenylmethoxy)carbonyl]-amino]-1-oxopentyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=95%).
PREPARATION CLXXIX
4,5-dihydro-2-[4-[[methyl[5-(methylamino)-1-oxopentyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(yellow oil, yield=90%).
1H NMR (250 MHz, DMSO) δ: 7.43 (m, 2H); 7.20 (m, 2H); 4.56 (d, 2H); 3.84 (m, 4H); 2.87 (d, 3H); 2.42 (m, 4H); 2.29 (d, 3H); 1.49 (m, 4H); 1.18 (s, 9H).
In operating analogously to Preparation V, the following compounds are obtained:
PREPARATION CLXXX
4,5-dihydro-2-[4-[[methyl[5-[methyl[[2-(trifluoromethyl)phenyl]-sulphonyl]amino]-1-oxopentyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=41%).
1H NMR (250 MHz, DMSO) δ: 7.91 (m, 4H); 7.43 (dd, 2H); 7.21 (dd, 2H); 4.56 (d, 2H); 3.85 (m, 4H); 3.21 (m, 2H); 2.84 (m, 6H); 2.36 (m, 2H); 1.55 (m, 4H); 1.14 (s, 9H).
PREPARATION CLXXXI
2-[4-[[[5-[[(2,4-dichloro-5-methylphenyl)sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white foam, yield=53%).
1H NMR (250 MHz, DMSO) δ: 7.92 (d, 1H); 7.83 (d, 1H); 7.43 (dd, 2H); 7.20 (dd, 2H); 4.54 (d, 2H); 3.85 (m, 4H); 3.17 (m, 2H); 2.85 (m, 6H); 2.39 (s, 3H); 2.35 (m, 2H); 1.52 (m, 4H); 1.17 (s, 9H).
PREPARATION CLXXXII
4,5-dihydro-2-[4-[[methyl[5-[methyl[(3-methylphenyl)sulphonyl]-amino]-1-oxopentyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=51%).
1H NMR (250 MHz, DMSO) δ: 7.52 (m, 3H); 7.42 (dd, 2H); 7.21 dd, 2H); 4.56 (d, 2H); 3.85 (m, 4H); 2.90 (m, 2H); 2.83 (d, 3H); 2.62 (d, 3H); 2.40 (s, 3H); 2.35 (m, 2H); 1.52 (m, 4H); 1.18 (s, 9H).
PREPARATION CLXXXIII
4,5-dihydro-2-[4-[[[5-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]-methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-1H -imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=20%).
1H NMR (250 MHz, DMSO) δ: 7.42 (m, 2H); 7.19 (m, 2H); 6.80 (m, 2H); 4.53 (d, 2H); 3.85 (m, 4H); 3.78 (s, 3H); 3.02 (m, 2H); 2.82 (d, 3H); 2.58 (m, 6H); 2.26 (m, 2H); 1.49 (m, 4H); 1.17 (s, 9H).
PREPARATION CLXXXIV
4,5-dihydro-2-[4-[[methyl[5-[methyl[(2.3.4-trichlorophenyl)sulphonyl]amino]-1-oxopentyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=62%)
M.Pt.=60° C.
PREPARATION CLXXXV
4,5-dihydro-2-[4-[[methyl[5-[methyl[(2-nitrophenyl)sulphonyl]-amino]-1-oxopentyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(white solid, yield=39%).
M.Pt.=60° C.
PREPARATION CLXXXVI
2-[4-[[[5-[[(2,4-dichlorophenyl)sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=46%).
1H NMR (250 MHz, DMSO) δ: 7.94 (m, 2H); 7.63 (m, 1H); 7.43 (dd, 2H); 7.20 (dd, 2H); 4.55 (d, 2H); 3.84 (m, 4H); 3.17 (m, 2H); 2.83 (m, 6H); 2.37 (m, 2H); 1.49 (m, 4H); 1.17 (s, 9H).
PREPARATION CLXXXVII
2-[4-[[[5-[[(2-chloro-3-methylphenyl)sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(colourless oil, yield=65%).
1H NMR (250 MHz, DMSO) δ: 7.82 (m, 1H); 7.64 (m, 1H); 7.43 (m, 3H); 7.20 (dd, 2H); 4.54 (d, 2H); 3.86 (m, 4H); 3.18 (m, 2H); 2.84 (m, 6H); 2.48 (s, 3H); 2.35 (m, 2H); 1.51 (m, 4H); 1.18 (s, 9H).
In operating analogously to Example 1, the following compounds are obtained:
EXAMPLE 69
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-5-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]pentanamide, trifluoroacetate
(amorphous solid, yield=99%).
1H NMR (300 MHz, DMSO) δ: 10.50 (d, 2H); 8.02 (m, 1H); 7.92 (m, 5H); 7.46 (d, 2H); 4.66 (d, 2H); 4.01 (s, 4H); 3.22 (, 2H); 2.90 (m, 6H); 2.40 (m, 2H); 1.55 (m, 4H).
EXAMPLE 70
5-[[(2,4-dichloro-5-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methylpentanamide, trifluoroacetate
(white solid, yield=99%).
M.Pt.=50° C.
EXAMPLE 71
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl-N-methyl-5-[methyl[(3-methylphenyl)sulphonyl]amino]pentanamide, trifluoroacetate
(white solid, yield=99%).
1H NMR (300 MHz, DMSO) δ: 10.48 (d, 2H); 7.90 (dd, 2H); 7.52 (m, 6H); 4.66 (d, 2H); 4.01 (s, 4H); 2.93 (m, 5H); 2.62 (d, 3H); 2.41 (m, 5H); 1.53 (m, 4H).
EXAMPLE 72
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-5-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-N-methyl-pentanamide, trifluoroacetate
(white solid, yield=66%).
M.Pt.=60° C.
EXAMPLE 73
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl-N-methyl-5-[methyl[(2,3,4-trichlorophenyl)sulphonyl]amino]pentanamide, trifluoroacetate
(white solid, yield=84%).
M.Pt.=70° C.
EXAMPLE 74
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl-N-methyl-5-[methyl[(2-nitrophenyl)sulphonyl]amino]pentanamide, trifluoroacetate
(white solid, yield=79%).
M.Pt.=60° C.
EXAMPLE 75
5-[[(2,4-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(white solid, yield=99%).
M.Pt.=60° C.
EXAMPLE 76
5-[[(2-chloro-3-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(white solid, yield=93%).
M.Pt.=72° C.
PREPARATION CLXXXVIII
N-[(4-cyanophenyl)methyl]-5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-methyl-pentanamide
In operating analogously to Preparation VIII, starting with 4-[(methylamino)methyl]benzonitrile, the expected compound is obtained as a colourless oil (yield=84%).
1H NMR (250 MHz, DMSO) δ: 7.83 (m, 3H); 7.65 (m, 1H); 7.39 (d, 2H); 4.60 (d, 2H); 3.22 (m, 2H); 2.85 (m, 6H); 2.50 (s, 3H); 2.38 (m, 2H); 1.53 (m, 4H).
EXAMPLE 77
N-[[4-[amino(hydroxyimino)methyl]phenyl]methyl]-5-[[(2,4-dichloro-3-methyl)phenyl]sulphonyl]methylamino]-N-methylpentanamide
A solution of 2.51 g (5.2 mM) of the compound obtained according to preparation CLXXXVIII is prepared in 56 ml of dimethylsulphoxide and 1.90 g (27 mM) of hydroxylamine hydrochloride and 7.5 ml (54 mM) of triethylamine are added progressively, at ambient temperature. The mixture is kept under agitation at ambient temperature for 30 hours and then poured onto 250 ml of iced water. The mixture is extracted with ethyl acetate (twice) and the combined organic phases are washed with water and then dried over magnesium sulphate and concentrated under reduced pressure. 2.47 g of the expected product are thus obtained as white crystals (yield=92%).
M.Pt.=74° C.
PREPARATION CLXXXIX
N-[[4-[[(acetyloxy)imino]aminomethyl]phenyl]methyl]-5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-methylpentanamide
A solution of 1 g (1.95 mM) of the compound obtained according to Example 77 is prepared in 50 ml of dichloromethane and 0.59 g (5.82 mM) of acetic anhydride are added. The reaction mixture is agitated at ambient temperature for 20 hours and then concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and the solution obtained is agitated for 15 min with a 5% aqueous solution of sodium carbonate. The aqueous phase is removed and the organic phase is washed with water, and then dried over magnesium sulphate and concentrated under reduced pressure. 1 g of the desired product is thus obtained as a colourless oil (yield=92%).
1H NMR (250 MHz, DMSO) δ: 7.82 (t, 1H); 7.65 (m, 3H); 7.26 (d, 2H); 6.76 (broad s, 2H); 4.56 (d, 2H); 3.20 (m, 2H); 2.80 (m, 6H); 2.50 (s, 3H); 2.36 (m, 2H); 2.12 (s, 3H); 1.52 (m, 4H).
EXAMPLE 78
N-[[4-(aminoiminomethyl)phenyl]methyl]-5-[[(2,4-dichloro-3-methylphenyl)sulphonyl]methylamino]-N-methyl-pentanamide, trifluoroacetate
1 g (1.79 mM) of the compound obtained according to preparation CLXXXIX is dissolved in 50 ml of methanol and 200 mg of 5% palladium on carbon are added. The mixture is agitated under a hydrogen atmosphere, at atmospheric pressure and at ambient temperature, for 6 hours. The mixture is then filtered and the filtrate is concentrated under reduced pressure. The crude product is taken up in the hot with 10 ml of dioxan. The product which crystallised by cooling of the solution is separated off by filtration and dried under vacuum. The compound obtained is then purified by chromatography on silica gel RP 18 in using a mixture of acetonitrile/water/trifluoroacetic acid (50/49/1; v/v/v) as mobile phase. The pure fractions are concentrated under reduced pressure, taken up with ethanol, concentrated once again under reduced pressure and then taken up in solution in water and lyophilised. The expected product is thus obtained with a yield of 20%.
1H NMR (300 MHz, DMSO) δ: 9.28 (m, 2H); 9.10 (m, 2H); 7.79 (m, 3H); 7.64 (m, 1H); 7.42 (d, 2H); 4.63 (d, 2H); 3.20 (m, 2H); 2.85 (m, 6H); 2.30 (m, 2H); 1.51 (m, 4H).
EXAMPLE 79
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]-N-methyl-acetamide, fumarate
A solution of 1 g of the compound obtained according to Example 49 is prepared in 20 ml of methanol and 2 g of basic IRA 400 resin are added. The mixture is agitated for 10 min and the resin is then separated off by filtration and the filtrate is concentrated under reduced pressure. 0.68 g of oil are thus obtained which is taken up in 2 ml of methanol. 157 mg of fumaric acid are then added and the mixture is agitated to dissolution. 20 ml of ethyl ether are then added. An oil is formed which is separated. This oil is taken up in 10 ml of water, the solution obtained is filtered and then lyophilised. 0.78 g of the expected compound are thus obtained as a fine white solid (yield=76%).
M.Pt.=88° C.
EXAMPLE 80
N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-4-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-(2E)-2-butenamide
In operating analogously to Preparation VIII, starting with the acid obtained according to Preparation XCIV and the amine obtained according to Preparation CXVI, the expected product is obtained as a colourless oil (yield=48%).
1H NMR (300 MHz, DMSO) δ: 8.04 (m, 2H); 7.90 (m, 2H); 7.52 (t, 2H); 7.23 (m, 2H); 6.60 (m, 2H); 4.66 and 4.59 (2s, 2H); 4.09 (d, 1H); 4.02 (m, 1H); 3.70 (t, 2H); 3.36 (t, 2H); 3.06 and 3.03 (2s, 3H); 2.99 and 2.72 (2s, 3H); 2.68 (s, 3H).
EXAMPLE 81
N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-4-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-(2E)-2-butenamide, fumarate
In operating analogously to Example 79, starting with the compound obtained according to Example 80, the expected product is obtained as a white solid
(yield=89%).
M.Pt.=76-78° C.
PREPARATION XCC
2-[4-[[[(2E)-4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]-3-fluorophenyl]-4,5-dihydro-1H -imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation VIII, starting with the acid obtained according to Preparation XXXVII and the amine obtained according to Preparation CXL, the expected product is obtained as a yellow oil (yield=47%).
1H NMR (300 MHz, DMSO) δ: 7.99 (m, 2H); 7.58 (m, 1H); 7.26 (m, 3H); 6.59 (m, 2H); 4.65 (d, 2H); 4.03 (m, 2H); 3.85 (m, 4H); 3.17 and 2.86 (2s, 3H); 3.00 (s, 3H); 1.20 (s, 9H).
EXAMPLE 82
4-[[(2,3-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)-2-fluorophenyl]methyl]-N-methyl-(2E)-2-butenamide, trifluoroacetate
In operating analogously to Example 1, starting with the compound obtained according to Preparation XCC, the expected product is obtained as a white ecru solid (yield=79%).
M.Pt.=80° C.
PREPARATION XCCl
2-[4-[[[(2E)-4-[[(2-chlorophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]-3-fluorophenyl]-4,5-dihydro-1H imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation XCC, starting with the acid obtained according to Preparation XXXIII, the expected product is obtained as a colourless oil (yield=69%).
1H NMR (250 MHz, DMSO) δ: 8.00 (m, 1H); 7.66 (m, 2H); 7.56 (m, 1H); 7.26 (m, 3H); 6.59 (m, 2H); 4.65 (d, 2H); 4.05 (d, 1H); 3.98 (d, 1H); 3.86 (m, 4H); 3.00 and 2.72 (2s, 3H); 2.83 (d, 3H); 1.20 (s, 9H).
EXAMPLE 83
4-[[(2-chlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)-2-fluorophenyl]methyl]-N-methyl-(2E)-2-butenamide, trifluoroacetate
In operating analogously to Example 1, starting with the compound obtained according to Preparation XCCl, the expected product is obtained as a white ecru solid (yield=62%).
M.Pt.=75° C.
PREPARATION XCCII
4-methoxy-N,2,6-trimethylbenzenesulphonamide
In operating analogously to Preparation V, starting with 4-methoxy-2,6-dimethylbenzenesulphonyl chloride, the expected compound is obtained as a white solid (yield=96%).
M.Pt.=131° C.
PREPARATION XCCIII
3-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-propanoic acid, ethyl ester
In operating analogously to Preparation VI, starting with the compound obtained according to Preparation XCCII and ethyl 3-bromopropanoate, the expected product is obtained as a yellow oil (yield=97%).
1H NMR (250 MHz, CDCl3) δ: 6.63 (s, 2H); 4.09 (q, 2H); 3.81 (s, 3H); 3.45 (t, 2H); 2.74 (s, 3H); 2.62 (m, 2H); 2.60 (s, 6H); 1.23 (t, 3H).
PREPARATION XCCIV
3-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-propanoic acid
In operating analogously to Preparation VII, starting with the compound obtained according to Preparation XCCIII, the expected acid is obtained as a white solid (yield=97%).
M.Pt.=103° C.
PREPARATION XCCV
4,5-dihydro-2-[4-[[[3-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-1-oxopropyl]methylamino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation VIII, starting with the acid obtained according to Preparation XCCIV and the amine obtained according to Preparation IV, the expected product is obtained as a colourless oil (yield=61%).
1H NMR (250 MHz, CDCl3) δ: 7.52 (m, 2H); 7.27 (m, 2H); 6.66 (d, 2H); 4.57 (d, 2H); 4.00 (m, 4H); 3.85 (d, 3H); 3.60 (m, 2H); 2.90 (d, 3H); 2.78 (d, 3H); 2.77 (m, 2H); 2.62 (d, 6H); 1.28 (d, 9H).
EXAMPLE 84
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-3-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-N-methyl-propanamide, trifluoroacetate
In operating analogously to Example 1, starting with the compound obtained according to Preparation XCCV, the expected product is obtained as a white solid (yield=99%).
M.Pt.=59° C.
In operating analogously to Preparations CXXXVI, I, II, III and IV, starting with 4-(bromomethyl)-3-chlorobenzonitrile, the following 5 compounds are obtained respectively:
PREPARATION XCCVI
4-cyano-2-chloro-N-methylbenzenemethanamine
(Colourless oil, yield=89%).
1H NMR (300 MHz, DMSO) δ: 7.99 (d, 1H); 7.83 (dd, 1H); 7.71 (d, 1H); 3.76 (s, 2H); 2.29 (s, 3H).
PREPARATION XCCVII
[(2-chloro-4-cyanophenyl)methyl]methylcarbamic acid, phenylmethyl ester
(Colourless oil, yield=99%).
1H NMR (250 MHz, DMSO) δ: 8.00 (s, 1H); 7.80 (m, 1H); 7.25 (m, 6H); 5.10 (d, 2H); 4.59 (s, 2H); 2.94 (s, 3H).
PREPARATION XCCVIII
[[2-chloro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]methylcarbamic acid, phenylmethyl ester
(Colourless oil, yield=99%).
PREPARATION ICC
2-[3-chloro-4-[[methyl[(phenylmethoxy)carbonyl]amino]-methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Yellow oil, yield=94%).
1H NMR (250 MHz, DMSO) δ: 7.51 (d, 1H); 7.41 (m, 7H); 5.10 (d, 2H); 4.57 (s, 2H); 3.85 (m, 4H); 2.89 (s, 3H); 1.14 (s, 9H).
PREPARATION CC
2-[3-chloro-4-[(methylamino)methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil, yield=11%).
1H NMR (250 MHz, DMSO) δ: 7.51 (d, 1H); 7.43 (d, 1H); 7.40 (dd, 1H); 3.85 (m, 4H); 3.74 (s, 2H); 2.31 (s, 3H); 1.19 (s, 9H).
In operating analogously to Preparations VI and VII, starting with the sulphonamide obtained according to Preparation XCCII and ethyl 5-bromopentanoate, the following compounds are obtained:
PREPARATION CCI
5-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-pentanoic acid, ethyl ester
(Colourless oil, yield=58%).
1H NMR (300 MHz, CDCl3) δ: 6.63 (s, 2H); 4.11 (q, 2H); 3.81 (s, 3H); 3.10 (t, 2H); 2.70 (s, 3H); 2.61 (s, 6H); 2.24 (t, 2H); 1.55 (m, 4H); 1.25 (t, 3H).
PREPARATION CCII
5-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-pentanoic acid
(White pasty solid, yield=99%).
M.Pt.=80-84° C.
PREPARATION CCIII
2-[3-chloro-4-[[[5-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]-methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation VIII, starting with the acid obtained according to Preparation CCII and the amine obtained according to Preparation CC, the expected product is obtained as an oil which is treated without further purification.
EXAMPLE 85
N-[[2-chloro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-5-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-N-methylpentanamide
234 mg (3.7 mM) of the compound obtained according to preparation CCIII are added to a mixture of 1.5 ml of trifluoroacetic acid in 2.5 ml of DCM. This reaction mixture is agitated for one hour at ambient temperature and this mixture is then concentrated under reduced pressure. The residue is then purified by chromatography on silica gel in eluting with the aid of a mixture of DC/methanol/aquous ammonia (120/10/0.02). 186 mg of the expected product are thus obtained as a colourless oil (yield: 94%).
1H NMR (300 MHz, DMSO) δ: 7.90 (d, 1H); 7.75 (dd, 1H); 7.18 (broad s, 1H); 7.15 (t, 1H); 6.79 (d, 2H); 4.60 (d, 2H); 3.79 (s, 3H); 3.61 (s, 4H); 3.01 (t, 2H); 2.94 and 2.82 (2s, 3H); 2.63 and 2.59 (2s, 3H); 2.51 (s, 6H); 2.37 and 2.17 (2t, 2H); 1.48 (m, 4H).
EXAMPLE 86
N-[[2-chloro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-5-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-N-methylpentanamide, fumarate
In operating analogously to Example 79, starting with the compound obtained according to Example 85, the expected salt is obtained as a white solid (yield=98%).
M.Pt.=60° C.
PREPARATION CCIV
2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-ethoxy]acetic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation VI, starting with the compound obtained according to Preparation LXXXIX and t-butyl (2-iodoethoxy)acetate, the expected product is obtained as a colourless oil (yield=72%).
1H NMR (250 MHz, DMSO) δ: 8.02 (m, 2H); 7.88 (m, 2H); 3.97 (s, 2H); 3.63 (t, 2H); 3.45 (t, 2H); 2.95 (s, 3H); 1.40 (s, 9H).
PREPARATION CCV
2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-ethoxy]acetic acid
In operating analogously to Preparation VII, starting with the compound obtained according to Preparation CCIV, the expected product is obtained as a colourless oil (yield=94%).
1H NMR (250 MHz, DMSO) δ: 8.03 (m, 2H); 7.86 (m, 2H); 4.01 (s, 2H); 3.65 (t, 2H); 3.45 (t, 2H); 2.95 (s, 3H).
EXAMPLE 87
N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-ethoxy]acetamide
In operating analogously to Preparation VIII, starting with the acid obtained according to Preparation CCV and the amine obtained according to Preparation CXVI, the expected product is obtained as a yellow oil (yield=62%).
1H NMR (300 MHz, DMSO) δ: 8.04 (m, 2H); 7.87 (m, 2H); 7.50 (m, 2H); 7.23 (d, 2H); 4.54 (s, 2H); 4.25 (d, 2H); 3.67 (m, 4H); 3.40 (m, 4H); 2.95 (d, 3H); 2.93 (d, 3H); 2.80 (s, 3H).
EXAMPLE 88
N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]-ethoxy]acetamide, fumarate
In operating analogously to Example 79, starting with the compound obtained according to Example 87, the expected product is obtained as a white solid
(yield=100%).
M.Pt.=62° C.
PREPARATION CCVI
2-[3-chloro-4-[[[[2-[[(2-chlorophenyl)sulphonyl]methylamino]-ethoxy]acetyl]methylamino]-methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation VIII, starting with the acid obtained according to Preparation CXXXI and the amine obtained according to Preparation CC, the expected product is obtained as a colourless oil (yield=41%).
1H NMR (250 MHz, DMSO) δ: 7.99 (m, 1H); 7.62 (m, 2H); 7.52 (m, 3H); 7.23 (m, 1H); 4.58 (s, 2H); 4.28 and 4.12 (2s, 2H); 3.85 (s, 4H); 3.58 (m, 2H); 3.42 (m, 2H); 2.91 and 2.86 (2s, 3H); 2.90 and 2.83 (2s, 3H); 1.20 (s, 9H).
EXAMPLE 89
N-[[2-chloro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(2-chlorophenyl)sulphonyl]methylamino]ethoxy]-N-methylacetamide, trifluoroacetate
In operating analogously to Example 1, starting with the product obtained according to Preparation CCVI, the expected product is obtained as a pink solid
(yield=99%).
1H NMR (250 MHz, DMSO) δ: 8.08 (m, 1H); 7.99 (m, 2H); 7.68 (m, 2H); 7.57 (m, 1H); 7.53 (d, 1H); 4.67 (d, 2H); 4.32 and 4.12 (2s, 2H); 4.02 (s, 4H); 3.67 and 3.54 (2t, 2H); 3.46 and 3.26 (2t, 2H); 2.98 (s, 3H); 2.90 (s, 3H).
PREPARATION CCVII
4-methoxy-2,6,N-trimethyl-N-(2-hydroxyethyl)benzenesulphonamide
In operating analogously to Preparation V, starting with 2,6-dimethyl-4-methoxybenzenesulphonyl chloride and 2-(N-methylamino)ethanol, the expected sulphonamide is obtained as a colourless oil (yield=95%).
1H NMR (300 MHz, DMSO) δ: 6.80 (s, 2H); 4.70 (t, 1H); 3.80 (s, 3H); 3.47 (t, 2H); 3.09 (t, 2H); 2.69 (s, 3H); 2.53 (s, 6H).
In operating analogously to Preparations CXXII and LXXVIII, starting with the compound obtained according to Preparation CCVII, the 2 following compounds are obtained:
PREPARATION CCVIII
[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]acetic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=94%)
1H NMR (250 MHz, DMSO) δ: 6.80 (s, 2H); 3.89 (s, 2H); 3.79 (s, 3H); 3.55 (t, 2H); 3.21 (t, 2H); 2.70 (s, 3H); 2.50 (s, 6H); 1.41 (s, 9H).
PREPARATION CCIX
[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-ethoxy]acetic acid
(White solid; yield=68%)
M.Pt.=85° C.
PREPARATION CCX
2-[3-chloro-4-[[[[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]-methylamino]ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation VIII, starting with the compounds obtained according to Preparations CCIX and CC, the expected product is obtained as a colourless oil (yield=57%).
1H NMR (300 MHz, DMSO) δ: 7.55 (d, 1H); 7.41 (dd, 1H); 7.21 (m, 1H); 6.80 (d, 2H); 4.57 (s, 2H); 4.22 and 4.08 (2s, 2H); 3.85 (m, 4H); 3.80 (d, 3H); 3.59 and 3.52 (2t, 2H); 3.27 and 3.16 (2t, 2H); 2.88 and 2.79 (2s, 3H); 2.71 and 2.66 (2s, 3H); 2.53 (s, 6H); 1.20 (s, 9H).
EXAMPLE 90
N-[[2-chloro-4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]-N-methyl-acetamide, trifluoroacetate
In operating analogously to Example 1, starting with the compound obtained according to preparation CCX, the expected product is obtained as a pink solid
(yield=94%).
M.Pt.=65° C.
PREPARATION CCXI
[(4-cyanophenyl)methyl][methyl]carbamic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation III, starting with [(4-cyanophenyl)methyl]methanamine, the expected product is obtained as a yellow oil (yield=92%).
1H NMR (300 MHz, DMSO) δ: 7.83 (d, 2H); 7.40 (d, 2H); 4.46 (s, 2H); 2.79 (s, 3H); 1.38 (m, 9H).
PREPARATION CCXII
[[4-[4,5-dihydro-1-(1-methylethyl)-1H-imidazol-2-yl]phenyl]methyl]-methylcarbamic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation II, starting with the compound obtained according to Preparation CCXI and N-(1-methylethyl)ethylenediamine, the expected product is obtained as a thick yellow oil (yield=99%).
1H NMR (300 MHz, DMSO) δ: 7.47 (d, 2H); 7.30 (d, 2H); 4.41 (s, 2H); 3.75 (m, 3H); 3.48 (t, 2H); 2.79 (s, 3H); 1.38 (s, 9H); 1.03 (d, 6H).
PREPARATION CCXIII
1-(1-methylethyl)-2-[4-(methylaminomethyl)phenyl]-4,5-dihydro-1H-imidazole
In operating analogously to Example 1, starting with the compound obtained according to Preparation CCXII, the expected product is obtained as a yellow paste (yield=99%).
1H NMR (250 MHz, DMSO) δ: 10.5 (s, 1H); 9.15 (broad s, 2H); 7.70 (s, 4H); 4.27 (t, 2H); 4.01 (m, 4H); 3.85 (m, 1H); 2.61 (t, 3H); 1.25 (d, 6H).
EXAMPLE 91
N-[[4-(4,5-dihydro-1-(1-methylethyl)-1H-imidazol-2-yl)phenyl]-methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]-N-methyl-acetamide
In operating analogously to Preparation VIII, starting with the acid obtained according to Preparation CCIX and the amine obtained according to Preparation CCXIII, the expected product is obtained as a colourless oil (yield=36%).
1H NMR (250 MHz, DMSO) δ: 7.40 (m, 2H); 7.24 (m, 2H); 6.80 (s, 2H); 4.51 (s, 2H); 4.18 and 4.12 (2s, 2H); 3.80 (s, 3H); 3.66 (m, 5H); 3.30 (m, 4H); 2.80 and 2.77 (2s, 3H); 2.70 and 2.66 (2s, 3H); 2.53 (s, 6H); 0.96 (d, 6H).
EXAMPLE 92
N-[[4-(4,5-dihydro-1-(1-methylethyl)-1H-imidazol-2-yl)phenyl]-methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]-methylamino]ethoxy]-N-methyl-acetamide, fumarate
In operating analogously to Example 79, starting with the compound obtained according to Example 91, the expected product is obtained as a cream solid
(yield=99%).
M.Pt.=106° C.
In operating analogously to Preparations CCXI to CCXIII, the following 3 compounds are obtained:
PREPARATION CCXIV
[(2-chloro-4-cyanophenyl)methyl]methylcarbamic acid, 1,1-dimethylethyl ester
(White solid; yield=72%).
M.Pt.=86-87° C.
PREPARATION CCXV
[[2-chloro-4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-methylcarbamic acid, 1,1-dimethylethyl ester
(Yellow oil; yield=66%).
1H NMR (300 MHz, DMSO) δ: 7.56 (s, 1H); 7.51 (d, 1H); 7.22 (d, 1H); 4.49 (s, 2H); 3.73 (t, 2H); 3.38 (t, 2H); 2.84 (s, 3H); 2.71 (s, 3H); 1.40 (d, 9H).
PREPARATION CCXVI
1-methyl-2-[3-chloro-4-(methylaminomethyl)phenyl]-4,5-dihydro-1H-imidazole
(Beige solid; yield=92%)
M.Pt.=94-98° C.
EXAMPLE 93
N-[[2-chloro-4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]-methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]-N-methyl-acetamide
In operating analogously to Preparation VIII, starting with the compounds obtained according to Preparations CCIX and CCXVI, the expected product is obtained as a white paste (yield=53%).
1H NMR (300 MHz, DMSO) δ: 7.60 (s, 1H); 7.50 (m, 1H); 7.25 (d, 1H); 6.80 (d, 2H); 4.57 (s, 2H); 4.27 and 4.08 (2s, 2H); 3.78 (s, 3H); 3.70 (t, 2H); 3.60 (t, 2H); 3.40 (t, 2H); 3.25 (t, 2H); 2.92 and 2.81 (2s, 3H); 2.74 (s, 3H); 2.71 and 2.64 (2s, 3H); 2.51 (d, 6H).
EXAMPLE 94
N-[[2-chloro-4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]-methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]ethoxy]-N-methyl-acetamide, fumarate
In operating analogously to Example 79, starting with the compound obtained according to Example 93, the expected product is obtained as a white solid
(yield=99%).
M.Pt.=65-68° C.
EXAMPLE 95
N-[[2-chloro-4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]-methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]-sulphonyl]amino]ethoxy]acetamide
In operating analogously to Preparation VIII, starting with the compounds obtained according to Preparations CCV and CCXVI, the expected product is obtained as a white oil (yield=41%).
1H NMR (300 MHz, DMSO) δ: 8.01 (m, 2H); 7.86 (m, 2H); 7.64 (s, 1H); 7.49 (m, 1H); 7.30 (m, 1H); 4.60 (s, 2H); 4.33 and 4.16 (2s, 2H); 3.70 (m, 4H); 3.49 (m, 4H); 2.97 and 2.89 (2s, 3H); 2.96 and 2.84 (2s, 3H); 2.79 and 2.76 (2s, 3H).
EXAMPLE 96
N-[[2-chloro-4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]-methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]-sulphonyl]amino]ethoxy]acetamide, fumarate
In operating analogously to Example 79, starting with the compound obtained according to Example 95, the expected product is obtained as a white solid
(yield=99%).
M.Pt.=55° C.
In operating analogously to Preparations CCVII to CCIX, the following 3 compounds are obtained:
PREPARATION CCXVII
2-cyano-N-methyl-N-(2-hydroxyethyl)benzenesulphonamide
(white oil, yield=90%).
1H NMR (300 MHz, DMSO) δ: 7.93 (d, 1H); 7.88 (d, 1H); 7.85 (m, 2H); 4.80 (s, 1H); 3.50 (q, 2H); 3.24 (t, 2H); 2.87 (s, 3H).
PREPARATION CCXVIII
[2-[[(2-cyanophenyl)sulphonyl]methylamino]ethoxy]acetic acid, 1,1-dimethylethyl ester
(Yellow oil; yield=87%)
1H NMR (300 MHz, DMSO) δ: 8.13 (d, 1H); 8.02 (d, 1H); 7.90 (m, 2H); 3.90 (s, 2H); 3.59 (t, 2H); 3.37 (t, 2H); 2.90 (s, 3H); 1.41 (s, 9H).
PREPARATION CCXIX
[2-[[(2-cyanophenyl)sulphonyl]methylamino]ethoxy]acetic acid
(White solid; yield=99%)
1H NMR (300 MHz, DMSO) δ: 8.13 (d, 1H); 8.02 (d, 1H); 7.80 (m, 2H); 3.93 (s, 2H); 3.60 (t, 2H); 3.77 (t, 2H); 2.90 (s, 3H).
EXAMPLE 97
2-[2-[[(2-cyanophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methylacetamide
In operating analogously to Preparation VIII, starting with the compounds obtained according to Preparations CXVI and CCXIX, the expected product is obtained as a yellow oil (yield=57%).
1H NMR (300 MHz, DMSO) δ: 8.11 (m, 2H); 7.88 (m, 2H); 7.50 (m, 2H); 7.28 (m, 2H); 4.51 (s, 2H); 4.20 and 4.13 (2s, 2H); 3.60 (m, 4H); 3.40 (m, 4H); 2.90 and 2.87 (2s, 3H); 2.85 and 2.78 (2s, 3H); 2.70 (s, 3H).
EXAMPLE 98
2-[2-[[(2-cyanophenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methylacetamide, fumarate
In operating analogously to Example 79, starting with the compound obtained according to Example 97, the expected product is obtained as a white solid
(yield=90%).
M.Pt.=59° C.
In operating analogously to Preparations CCVII to CCIX, the following 3 compounds are obtained:
PREPARATION CCXX
2-chloro-4-methoxy-N-methyl-N-(2-hydroxyethyl)benzenesulphonamide
(Colourless oil, yield=99%)
1H NMR (250 MHz, DMSO) δ: 7.90 (d, 1H); 7.24 (d, 1H); 7.06 (dd, 1H); 4.76 (t, 1H); 3.86 (s, 3H); 3.52 (q, 2H); 3.19 (t, 2H); 2.84 (s, 3H).
PREPARATION CCXXI
[2-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]-ethoxy]acetic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=96%)
1H NMR (300 MHz, DMSO) δ: 7.90 (d, 1H); 7.24 (d, 1H); 7.06 (dd, 1H); 4.03 (s, 2H); 3.86 (s, 3H); 3.58 (t, 2H); 3.34 (t, 2H); 2.85 (s, 3H); 1.42 (s, 9H).
PREPARATION CCXXII
[2-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]ethoxy]-acetic acid
(Colourless oil; yield=99%)
1H NMR (300 MHz, DMSO) δ: 7.91 (d, 1H); 7.24 (d, 1H); 7.07 (dd, 1H); 3.99 (s, 2H); 3.86 (s, 3H); 3.60 (t, 2H); 3.34 (t, 2H); 2.84 (s, 3H).
In operating analogously to Examples 97 and 98, starting with the acid obtained according to Preparation CCXXII, the 2 following compounds are obtained:
EXAMPLE 99
2-[2-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide
(Colourless oil; yield=27%)
1H NMR (300 MHz, DMSO) δ: 7.91 (d, 1H); 7.48 (m, 2H); 7.24 (m, 3H); 7.10 (dd, 1H); 4.52 (s, 2H); 4.23 and 4.18 (2s, 2H); 3.85 (s, 3H); 3.68 (m, 4H); 3.39 (m, 4H); 2.87 and 2.81 (2s, 3H); 2.84 and 2.80 (2s, 3H); 2.69 (s, 3H).
EXAMPLE 100
2-[2-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-acetamide, fumarate
(White solid; yield=87%)
M.Pt.=50° C.
PREPARATION CCXXIII
N-(2-cyanoethyl)-N-methyl-2-(trifluoromethyl)benzenesulphonamide
In operating analogously to Preparation V, starting with 2-(trifluoromethyl)benzenesulphonyl chloride and 3-(methylamino)propionitrile, the expected product is obtained as a yellow oil (yield=98%).
1H NMR (250 MHz, DMSO) δ: 8.02 (m, 2H); 7.90 (m, 2H); 3.55 (t, 2H); 2.29 (s, 3H); 2.86 (t, 2H).
PREPARATION CCXXIV
3-[methyl[[(2-(trifluoromethyl)phenyl]sulphonyl]amino]propanoic acid
140 mg (0.48 mM) of the compound obtained according to Preparation CCXIII is mixed with 3 ml of 10N hydrochloric acid and this mixture is agitated under smooth reflux for 3 hours. The reaction mixture is then cooled, diluted with water, partially neutralised to pH 2 with sodium hydroxide, and then extracted with 25 ml of ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The expected acid is thus obtained as a colourless oil (yield=64%).
1H NMR (250 MHz, DMSO) δ: 8.01 (m, 2H); 7.91 (m, 2H); 3.46 (t, 2H); 2.89 (s, 3H); 2.50 (t, 2H).
In operating analogously to Preparation VIII and Example 1, starting with the acid obtained according to Preparation CCXXIV, the 2 following compounds are obtained:
PREPARATION CCXXV
4,5-dihydro-2-[4-[[methyl[3-[methyl[[2-(trifluoromethyl)phenyl]-sulphonyl]amino]-1-oxopropyl]amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(White solid; yield=74%).
M.Pt.=50° C.
EXAMPLE 101
N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl-N-methyl-3-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]propanamide, trifluoroacetate
(White solid, yield=81%).
M.Pt.=56° C.
PREPARATION CCXXVI
N-[(4-cyanophenyl)methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]amino]ethoxy]acetamide
In operating analogously to Preparation VIII, starting with the acid obtained according to Preparation CCV and 4-(methylaminomethyl)benzonitrile, the expected product is obtained as a yellow oil (yield=62%).
1H NMR (250 MHz, DMSO) δ: 8.04 (m, 2H); 7.87 (m, 4H); 7.43 (d, 2H); 4.59 (s, 2H); 4.28 and 4.17 (2s, 2H); 3.67 (m, 2H); 3.46 and 3.40 (2t, 2H); 2.95 and 2.90 (2s, 3H); 2.89 and 2.78 (2s, 3H).
EXAMPLE 102
N-[[4-(1-ethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]sulphonyl]-amino]ethoxy]acetamide
In operating analogously to Preparation II, starting with the compound obtained according to Preparation CCXXVI and N-ethylethylenediamine, the expected product is obtained as a colourless oil (yield=19%).
1H NMR (250 MHz, DMSO) δ: 8.01 (m, 2H); 7.87 (m, 2H); 7.45 (m, 2H); 7.28 (d, 2H); 4.53 (s, 2H); 4.27 and 4.20 (2s, 2H); 3.70 (m, 4H); 3.40 (m, 4H); 3.01 (q, 2H); 2.98 and 2.95 (2s, 3H); 2.93 and 2.79 (2s, 3H); 0.99 (t, 3H).
EXAMPLE 103
N-[[4-[1-(1-methylethyl)-4,5-dihydro-1H-imidazol-2-yl]phenyl]-methyl]-N-methyl-2-[2-[methyl[[2-(trifluoromethyl)phenyl]-sulphonyl]amino]ethoxy]acetamide
In operating analogously to Example 102, starting with N-(1-methylethyl)ethylenediamine, the expected product is obtained as an oil (yield=54%).
1H NMR (250 MHz, DMSO) δ: 8.04 (m, 2H); 7.89 (m, 2H); 7.45 (m, 2H); 7.28 (d, 2H); 4.53 (s, 2H); 4.27 and 4.20 (2s, 2H); 3.67 (m, 5H); 3.48 (m, 2H); 3.30 (m, 2H); 2.95 and 2.93 (2s, 3H); 2.88 and 2.80 (2s, 3H); 0.99 (d, 6H).
PREPARATION CCXXVII
N-[(4-cyanophenyl)methyl]-N-methyl-2-[2-[methyl[(4-methoxy-2,6-dimethylphenyl)sulphonyl]amino]ethoxy]acetamide
In operating analogously to Preparation CCXXVI, starting with the acid obtained according to Preparation CCIX, the expected product is obtained as a colourless oil (yield=95%).
1H NMR (250 MHz, DMSO) δ: 7.81 (d, 2H); 7.37 (d, 2H); 6.80 (d, 2H); 4.57 (s, 2H); 4.20 and 4.10 (2s, 2H); 3.79 (s, 3H); 3.45 (m, 2H); 3.24 and 3.15 (2t, 2H); 2.85 and 2.76 (2s, 3H); 2.71 and 2.65 (2s, 3H); 2.53 (s, 6H).
PREPARATION CCXXVIII
N-[[4-(aminothioxomethyl)phenyl]methyl]-N-methyl-2-[2-[methyl-[(4-methoxy-2,6-dimethylphenyl)sulphonyl]amino]ethoxy]acetamide
A solution of 1.655 g (5 mM) of the compound obtained according to Preparation CCXXVII is prepared in 50 ml of pyridine and 2.09 ml (25 mM) of triethylamine are added. Gaseous hydrogen sulphide is then introduced into this solution and is bubbled in for 10 minutes. The solution which is yellow at the start takes a green colour. The reaction mixture is then agitated for 6 hours at ambient temperature and then diluted with 200 ml of ethyl acetate. The solution obtained is concentrated under reduced pressure. The residue is taken up in 200 ml of toluene and the solution is dried over magnesium sulphate and concentrated under reduced pressure. 1.5 g of the desired product are thus obtained as a yellow paste (yield=84%).
1H NMR (300 MHz, DMSO) δ: 9.82 (m large, 1H); 9.45 (m large, 1H); 7.87 (m, 2H); 7.20 (m, 2H); 6.79 (d, 2H); 4.51 (s, 2H); 4.18 and 4.12 (2s, 2H); 3.78 (s, 3H); 3.56 (m, 2H); 3.24 (m, 2H); 2.82 and 2.76 (2s, 3H); 2.71 and 2.68 (s, 3H); 2.53 (s, 6H).
PREPARATION CCXXIX
N-[[4-[imino(methylthio)methyl]phenyl]methyl]-N-methyl-2-[2-[methyl[(4-methoxy-2,6-dimethylphenyl)sulphonyl]-amino]ethoxy]acetamide
1.5 g (3.04 mM) of the compound obtained according to Preparation CCXXVIII are dissolved in 5 ml of acetone and 3 ml of methyl iodide are added. The mixture is heated under reflux for 1 hour and then concentrated under reduced pressure. The residue is taken up in 50 ml of DCM and the solution is washed with a solution of sodium bicarbonate. The organic phase is dried and then concentrated under reduced pressure. The expected product is thus obtained, and is used without other purification (yield=98%).
1H NMR (300 MHz, DMSO) δ: 10.25 (m, 1H); 7.78 (m, 2H); 7.27 (m, 2H); 6.79 (d, 2H); 4.53 (s, 2H); 4.18 and 4.12 (2s, 2H); 3.79 (s, 3H); 3.54 (m, 2H); 3.24 and 3.18 (2t, 2H); 2.85 and 2.77 (2s, 3H); 2.71 and 2.67 (2s, 3H) 2.58 (s, 6H); 2.40 (s, 3H).
EXAMPLE 104
N-[[4-(1H-2,4-triazol-5-yl)phenyl]methyl]-N-methyl-2-[2-[methyl-[(4-methoxy-2,6-dimethylphenyl)sulphonyl]amino]ethoxy]acetamide
A solution of 1.5 g (2.96 mM) of the compound obtained according to preparation CCXXIX is prepared in 16.5 ml of ethanol, and 324 mg (5.4 mM) of formylhydrazine, 279 mg (2.63 mM) of triethylamine and 35 μl of sulphuric acid then are added. The reaction mixture is heated under reflux for 2 hours and then concentrated under reduced pressure. The residue is taken up in solution in DCM, washed twice with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified first of all on a silica column in eluting with the aid of a mixture of toluene/isopropanol (9/1; v/v), and then secondly by reverse phase chromatography on RP18 grafted silica, in eluting with a mixture of acetonitrile/water (4/6; v/v). The pure product is obtained by lyophilisation of the pure fractions. 340 mg of the desired product are thus obtained as a green flaky solid (yield=23%).
M.Pt.=60° C.
PREPARATION CCXXX
N-methyl-2,4-dinitrobenzenesulphonamide
In operating analogously to Preparation V, starting with 2,4-dinitrobenzenesulphonyl chloride, the expected product is obtained as a yellow solid
(yield=76%).
M.Pt.=155° C.
PREPARATION CCXXXI
4-[[(2,4-dinitrophenyl)sulphonyl]methylamino]-2-butenoic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation VI, starting with the compound obtained according to Preparation CCXXX and the t-butyl ester of 4-bromo-2-butenoic acid, the expected product is obtained as a yellow solid (yield=82%).
1H NMR (300 MHz, CDCl3) δ: 8.50 (dd, 1H); 8.48 (m, 1H); 8.25 (d, 1H); 6.69 (dt, 1H); 5.92 (dt, 1H); 4.04 (dd, 2H); 2.93 (s, 3H); 1.48 (s, 9H),
PREPARATION CCXXXII
4-[[(2,4-dinitrophenyl)sulphonyl]methylamino]-2-butenoic acid
In operating analogously to Preparation LXXVIII, starting with the ester obtained according to Preparation CCXXXI, the expected product is obtained as a pale yellow solid (yield=99%).
M.Pt.=174° C.
PREPARATION CCXXXIII
2-[4-[[[(2E)-4-[[(2,4-dinitrophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
In operating analogously to Preparation VIII, starting with the acid obtained according to Preparation CCXXXII and the amine obtained according to Preparation IV, the expected product is obtained as a yellow solid (yield=88%).
M.Pt.=78° C.
PREPARATION CCXXXIV
4,5-dihydro-2-[4-[[methyl[(2E)-4-(methylamino)-1-oxo-2-butenyl]-amino]methyl]phenyl]-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
1 g (1.62 mM) of the compound obtained according to Preparation CCXXXIII are dissolved in 18 ml of DCM and 672 mg (4.9 mM) of potassium carbonate and 167 μl (1.62 mM) of thiophenol are added. The mixture is agitated for 1.5 hours at ambient temperature, and diluted with 25 ml of DCM. This organic phase is washed 3 times with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel in eluting with the aid of a mixture of DCM/methanol (9/1; v/v). 560 mg of the desired product are thus obtained as a yellow oil (yield=89%).
1H NMR (250 MHz, CDCl3) δ: 7.49 (dd, 2H); 7.22 (dd, 2H); 6.96 (m, 1H); 6.47 (dd, 1H); 4.65 (d, 2H); 3.97 (m, 4H); 3.40 (m, 2H); 2.98 and 2.96 (2s, 3H); 2.49 and 2.42 (2s, 3H); 1.29 and 1.25 (2s, 9H).
In operating analogously to Preparation V, starting with the amine obtained according to Preparation CCXCCIV and various benzenesulphonyl chlorides, the following compounds are obtained:
PREPARATION CCXXXV
2-[4-[[[(2E)-4-[[(2-chloro-4-fluorophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil, yield=59%)
1H NMR (250 MHz, CDCl3) δ: 8.13 (m, 1H); 7.50 (m, 2H); 7.25 (m, 4H); 6.79 (m, 1H); 6.51 (dd, 1H); 4.66 and 4.59 (2s, 2H); 4.10 and 4.01 (2d, 2H); 4.00 (m, 4H); 2.99 and 2.95 (2s, 3H); 2.86 and 2.75 (2s, 3H); 1.30 (d, 9H).
PREPARATION CCXXXVI
2-[4-[[[(2E)-4-[[[2,6-dichloro-4-(trifluoromethyl)phenyl]sulphonyl]-methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=73%).
1H NMR (250 MHz, CDCl3) δ: 7.70 (d, 2H); 7.50 (m, 2H); 7.24 (m, 2H); 6.84 (m, 1H); 6.55 (dd, 1H); 4.66 and 4.59 (2s, 2H); 4.18 and 4.07 (2d, 2H); 4.00 (m, 4H); 3.00 and 2.96 (2s, 3H); 2.97 and 2.84 (2s, 3H); 1.27 (d, 9H).
PREPARATION CCXXXVII
2-[4-[[[(2E)-4-[[(2,6-difluorophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=61%).
1H NMR (250 MHz, CDCl3) δ: 7.52 (m, 3H); 7.27 (m, 2H); 7.02 (m, 2H); 6.85 (m, 1H); 6.53 (dd, 1H); 4.66 and 4.59 (2s, 2H); 4.09 and 4.01 (2d, 2H); 3.98 (m, 4H); 2.99 and 2.94 (2s, 3H); 2.95 and 2.82 (2s, 3H); 1.27 (d, 9H).
PREPARATION CCXXXVIII
2-[4-[[[(2E)-4-[[(2-nitrophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
PREPARATION CCXXXIX
2-[4-[[[(2E)-4-[[(2,4,6-trimethylphenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(White paste; yield=69%).
1H NMR (300 MHz, CDCl3) δ: 7.49 (dd, 2H); 7.25 (dd, 2H); 6.93 (d, 2H); 6.77 (m, 1H); 6.53 (dd, 1H); 4.65 and 4.57 (2s, 2H); 4.06 and 3.85 (2d, 2H); 3.94 (m, 4H); 2.98 and 2.94 (2s, 3H); 2.71 and 2.57 (2s, 3H); 2.61 (s, 6H) 2.29 and 2.28 (2s, 3H); 1.25 (d, 9H).
PREPARATION CCXL
2-[4-[[[(2E)-4-[[(2,5-dichlorophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=63%).
1H NMR (300 MHz, CDCl3) δ: 8.05 (m, 1H); 7.46 (m, 4H); 7.27 (d, 1H); 7.17 (d, 1H); 6.81 (m, 1H); 6.50 (dd, 1H); 4.66 and 4.59 (2s, 2H); 4.12 and 4.04 (2d, 2H); 4.01 (m, 4H); 2.99 and 2.95 (2s, 3H); 2.89 and 2.78 (2s, 3H); 1.27 (d, 9H).
PREPARATION CCXLI
2-[4-[[[(2E)-4-[[(2,4-dichlorophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=48%).
1H NMR (250 MHz, CDCl3) δ: 8.05 (t, 1H); 7.54 (m, 3H); 7.37 (m, 1H); 7.27 (d, 1H); 7.20 (d, 1H); 6.83 (m, 1H); 6.50 (dd, 1H); 4.66 and 4.56 (2s, 2H); 4.10 and 3.99 (2d, 2H); 3.96 (m, 4H); 2.99 and 2.95 (2s, 3H); 2.86 and 2.75 (2s, 3H); 1.27 (d, 9H).
PREPARATION CCXLII
2-[4-[[[(2E)-4-[[(3-chloro-2-methylphenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=69%).
1H NMR (250 MHz, CDCl3) δ: 7.84 (t, 1H); 7.50 (m, 3H); 7.26 (m, 3H); 6.82 (m, 1H); 6.54 (dd, 1H); 4.66 and 4.58 (2s, 2H); 3.97 (m, 6H); 3.01 and 2.94 (2s, 3H); 2.82 and 2.70 (2s, 3H); 2.67 and 2.63 (2s, 3H); 1.27 (d, 9H).
PREPARATION CCXLIII
2-[4-[[[(2E)-4-[[(2-cyanophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Yellow solid; yield=67%).
M.Pt.=64° C.
PREPARATION CCXLIV
2-[4-[[[(2E)-4-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Yellow solid; yield=78%).
M.Pt.=58° C.
PREPARATION CCXLV
2-[4-[[[(2E)-4-[[(2,4-dichloro-5-methylphenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(White ecru solid; yield=75%).
M.Pt.=70° C.
PREPARATION CCXLVI
2-[4-[[[(2E)-4-[[(2,3,4-trichlorophenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(White ecru solid; yield=78%).
M.Pt.=66° C.
PREPARATION CCXLVII
2-[4-[[[(2E)-4-[[(2-chloro-4-(trifluoromethoxy)phenyl]sulphonyl]-methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(White solid; yield=81%).
M.Pt.=50° C.
PREPARATION CCXLVIII
2-[4-[[[(2E)-4-[[[4-methoxy-2-(trifluoromethyl)phenyl]sulphonyl]-methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic, 1,1-dimethylethyl ester
(White solid; yield=62%).
M.Pt.=50° C.
PREPARATION CCIL
2-[4-[[[(2E)-4-[[(2,6-dimethyl-4-methoxyphenyl)sulphonyl]methylamino]-1-oxo-2-butenyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(White solid; yield=75%).
M.Pt.=50° C.
In operating analogously to Example 1, starting with the compounds obtained according to Preparations CCXXXV to CCIL, the following products are obtained:
EXAMPLE 105
(2E)-4-[[(2-chloro-4-fluorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(Pink paste; yield=99%)
1H NMR (250 MHz, DMSO) δ: 10.48 (s, 2H); 8.09 (m, 1H); 7.91 (m, 2H); 7.78 (m, 1H); 7.49 (m, 3H); 6.61 (m, 2H); 4.76 and 4.66 (2s, 2H); 4.05 (m, 2H); 4.01 (s, 4H); 3.09 and 3.03 (2s, 3H); 2.96 and 2.90 (2s, 3H).
EXAMPLE 106
(2E)-4-[[[2,6-dichloro-4-(trifluoromethyl)phenyl]sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(white solid; yield=99%)
M.Pt.=62° C.
EXAMPLE 107
(2E)-4-[[(2,6-difluorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(Pink paste; yield=99%)
1H NMR (250 MHz, DMSO) δ: 10.49 (s, 2H); 7.90 (m, 2H); 7.80 (m, 1H); 7.47 (d, 2H); 7.32 (m, 2H); 6.60 (m, 2H); 4.76 and 4.66 (2s, 2H); 4.04 and 3.94 (2d, 2H); 4.01 (s, 4H); 3.03 and 2.90 (2s, 3H); 2.86 and 2.71 (2s, 3H).
EXAMPLE 108
(2E)-4-[[(2-nitrophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(Pink paste; yield=94%)
1H NMR (250 MHz, DMSO) δ: 10.54 (s, 2H); 7.94 (m, 6H); 7.48 (m, 2H); 6.60 (m, 2H); 4.74 and 4.65 (2s, 2H); 4.08 and 3.99 (2d, 2H); 4.01 (s, 4H) 3.01 and 2.89 (2s, 3H); 2.87 and 2.72 (2s, 3H).
EXAMPLE 109
(2E)-4-[[(2,4,6-trimethylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=78%)
M.Pt.=64° C.
EXAMPLE 110
(2E)-4-[[(2,5-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=99%)
M.Pt.=65° C.
EXAMPLE 111
(2E)-4-[[(2,4-dichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=99%)
M.Pt.=65° C.
EXAMPLE 112
(2E)-4-[[(3-chloro-2-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=99%)
M.Pt.=64° C.
EXAMPLE 113
(2E)-4-[[(2-cyanophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=99%)
M.Pt.=60° C.
EXAMPLE 114
(2E)-4-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=90%)
M.Pt.=68° C.
EXAMPLE 115
(2E)-4-[[(2,4-dichloro-5-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=99%)
M.Pt.=79° C.
EXAMPLE 116
(2E)-4-[[(2,3,4-trichlorophenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=90%)
M.Pt.=87° C.
EXAMPLE 117
(2E)-4-[[[2-chloro-4-(trifluoromethoxy)phenyl]sulphonyl]-methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=99%)
M.Pt.=68° C.
EXAMPLE 118
(2E)-4-[[[4-methoxy-2-(trifluoromethyl)phenyl]sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=99%)
M.Pt.=50° C.
EXAMPLE 119
(2E)-4-[[(4-methoxy-2,6-dimethylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-2-butenamide, trifluoroacetate
(White solid; yield=99%)
M.Pt.=50° C.
In operating analogously to Preparation V, starting with the amine obtained according to Preparation CL)(XIX and various benzenesulphonyl chlorides, the following compounds are obtained:
PREPARATION CCL
2-[4-[[[5-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(White solid; yield=32%)
M.Pt.=60° C.
PREPARATION CCLI
2-[4-[[[5-[[(4-methoxy-2-methylphenyl)sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=24%)
1H NMR (250 MHz, DMSO) δ: 7.73 (t, 1H); 7.42 (m, 2H); 7.20 (m, 2H); 6.93 (m, 2H); 4.56 (d, 2H); 3.86 (s, 4H); 3.81 (s, 3H); 3.04 (m, 2H); 2.88 and 2.80 (2s, 3H); 2.68 and 2.65 (2s, 3H); 2.48 (m, 2H); 1.50 (m, 4H); 1.17 (s, 9H).
PREPARATION CCLII
2-[4-[[[5-[[[2-methyl-4-(trifluoromethoxy)phenyl]sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=30%)
1H NMR (300 MHz, DMSO) δ: 7.88 (t, 1H); 7.44 (m, 4H); 7.20 (m, 2H); 4.59 and 4.52 (2s, 2H); 3.83 (m, 4H); 3.14 (m, 2H); 2.89 and 2.81 (2s, 3H); 2.76 and 2.74 (2s, 3H); 2.55 and 2.51 (2s, 3H); 2.50 (m, 2H); 1.52 (m, 4H); 1.17 (s, 9H).
PREPARATION CCLIII
2-[4-[[[5-[[[4-methoxy-2-(trifluoromethyl)phenyl]sulphonyl]methylamino]-1-oxopentyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=35%)
1H NMR (300 MHz, DMSO) δ: 7.95 (t, 1H); 7.41 (m, 4H); 7.22 (m, 2H); 4.59 and 4.52 (2s, 2H); 3.91 (s, 3H); 3.83 (m, 4H); 3.16 (m, 2H); 2.89 and 2.81 (2s, 3H); 2.78 and 2.76 (2s, 3H); 2.36 (m, 2H); 1.48 (m, 4H); 1.17 (s, 9H).
In operating analogously to Example 1, starting with the compounds obtained according to Preparations CCL to CCLIII, the following products are obtained:
EXAMPLE 120
5-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(Yellow oil; yield=97%)
1H NMR (300 MHz, DMSO) δ: 10.50 (d, 2H); 7.90 (m, 3H); 7.45 (d, 2H); 7.26 (s, 1H); 7.11 (m, 1H); 4.69 and 4.60 (2s, 2H); 4.00 (s, 4H); 3.86 (s, 3H); 3.14 (m, 2H); 2.95 and 2.82 (2s, 3H); 2.75 and 2.72 (2s, 3H); 2.49 and 2.30 (2m, 2H); 1.52 (m, 4H).
EXAMPLE 121
5-[[(4-methoxy-2-methylphenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methyl-pentanamide, trifluoroacetate
(Colourless oil; yield=94%)
1H NMR (300 MHz, DMSO) δ: 10.52 (d, 2H); 7.90 (m, 2H); 7.70 (m, 1H); 7.47 (m, 2H); 6.90 (m, 2H); 4.68 and 4.60 (2s, 2H); 4.01 (s, 4H); 3.81 (s, 3H); 3.07 (m, 2H); 2.94 and 2.82 (2s, 3H); 2.68 and 2.64 (2s, 3H); 2.50 (s, 3H); 2.49 and 2.39 (2t, 2H); 1.52 (m, 4H).
EXAMPLE 122
5-[[[2-methyl-4-(trifluoromethoxy)phenyl]sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methylpentanamide, trifluoroacetate
(Red paste; yield=99%)
1H NMR (250 MHz, DMSO) δ: 10.49 (d, 2H); 7.89 (m, 3H); 7.44 (m, 4H); 4.69 and 4.60 (2s, 2H); 4.00 (s, 4H); 3.14 (m, 2H); 2.95 and 2.82 (2s, 3H); 2.76 and 2.73 (2s, 3H); 2.57 and 2.55 (2s, 3H); 2.44 and 2.38 (2m, 2H); 1.50 (m, 4H).
EXAMPLE 123
5-[[[4-methoxy-2-(trifluoromethyl)phenyl)sulphonyl]methylamino]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methylpentanamide, trifluoroacetate
(Pink paste; yield=99%)
1H NMR (250 MHz, DMSO) δ: 10.50 (d, 2H); 7.90 (m, 3H); 7.40 (m, 4H); 4.69 and 4.60 (2s, 2H); 4.00 (s, 4H); 3.92 (s, 3H); 3.19 (m, 2H); 2.96 and 2.83 (2s, 3H); 2.78 and 2.75 (2s, 3H); 2.49 and 2.45 (2m, 2H); 1.53 (m, 4H).
In operating analogously to Preparation V, starting with the amine obtained according to Preparation CLII and various benzenesulphonyl chlorides, the following compounds are obtained:
PREPARATION CCLIV
2-[4-[[[[2-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]-ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=64%)
1H NMR (300 MHz, DMSO) δ: 7.89 (m, 1H); 7.42 (m, 2H); 7.22 (m, 3H); 7.05 (dd, 1H); 4.52 (s, 2H); 4.22 and 4.18 (2s, 2H); 3.82 (m, 4H); 3.79 (s, 3H); 3.60 (m, 2H); 3.39 (m, 2H); 2.85 and 2.76 (2s, 3H); 2.84 and 2.82 (2s, 3H); 1.18 (s, 9H).
PREPARATION CCLV
2-[4-[[[[2-[[(4-methoxy-2-methylphenyl)sulphonyl]methylamino]-ethoxy]acetyl]methylamino]methyl]phenyl]-4,5-dihydro-1H-imidazole-1-carboxylic acid, 1,1-dimethylethyl ester
(Colourless oil; yield=53%)
1H NMR (300 MHz, DMSO) δ: 7.74 (m, 1H); 7.44 (m, 2H); 7.23 (d, 2H); 6.92 (m, 2H); 4.51 (s, 2H); 4.20 and 4.17 (2s, 2H); 3.84 (m, 4H); 3.81 (s, 3H); 3.59 (m, 2H); 3.26 (m, 2H); 2.83 and 2.77 (2s, 3H); 2.78 and 2.75 (2s, 3H) 2.50 (s, 3H); 1.17 (s, 9H).
In operating analogously to Example 1, starting with the preceding compounds, the following compounds are obtained:
EXAMPLE 124
2-[2-[[(2-chloro-4-methoxyphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methylacetamide, trifluoroacetate
(White solid, yield=96%).
M.Pt.=60° C.
EXAMPLE 125
2-[2-[[(4-methoxy-2-methylphenyl)sulphonyl]methylamino]ethoxy]-N-[[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl]-N-methylacetamide, trifluoroacetate
(White paste; yield=94%).
1H NMR (300 MHz, DMSO) δ: 10.50 (d, 2H); 7.90 (m, 2H); 7.73 (m, 1H); 7.49 (d, 2H); 6.97 (m, 1H); 6.90 (m, 1H); 4.60 (s, 2H); 4.25 and 4.16 (2s, 2H); 4.00 (s, 4H); 3.81 (s, 3H); 3.56 (m, 2H); 3.30 and 3.20 (2t, 2H); 2.89 and 2.72 (2s, 3H); 2.78 (s, 3H); 2.50 (s, 3H).
TABLE I
Ex.*
R1
R2
Y
R3
R4
R5
R6
1
CH3
—(CH2)4—
—(CH2)2—
H
H
2
CH3
—(CH2)3—
—(CH2)2—
H
H
3
CH3
—(CH2)2—
—(CH2)2—
H
H
4
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
5
CH3
—(CH2)4—
—(CH2)2—
H
H
6
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
7
CH3
—(CH2)2—
—(CH2)2—
H
H
8
CH3
—(CH2)3—
—(CH2)2—
H
H
9
CH3
—(CH2)4—
—(CH2)2—
H
H
10
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
11
CH3
—(CH2)4—
—(CH2)2—
H
H
12
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
13
CH3
—(CH2)4—
—(CH2)2—
H
H
14
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
15
cPr
—(CH2)4—
—(CH2)2—
H
H
16
cPr
—(CH2)4—
—(CH2)2—
H
H
17
cPr
—(CH2)4—
—(CH2)2—
H
H
18
CH(CH3)2
—(CH2)4—
—(CH2)2—
H
H
19
CH2CONH2
—(CH2)4—
—(CH2)2—
H
H
20
(CH2)2CONH2
—(CH2)4—
—(CH2)2—
H
H
21
CH(CH3)2
—(CH2)2—
—(CH2)2—
H
H
22
CH(CH3)2
—(CH2)2—
—(CH2)2—
H
H
23
cPr
—(CH2)2—O—CH2—
—(CH2)2—
H
H
24
cPr
—(CH2)2—O—CH2—
—(CH2)2—
H
H
25
cPr
—(CH2)2—O—CH2—
—(CH2)2—
H
H
26
(CH2)2—Ph
—(CH2)2—O—CH2—
—(CH2)2—
H
H
27
CH3
—(CH2)2—
—(CH2)2—
H
H
28
cPr
—(CH2)2—
—(CH2)2—
H
H
29
cPr
—(CH2)2—
—(CH2)2—
H
H
30
CH2—CF3
—(CH2)2—
—(CH2)2—
H
H
31
CH2—CF3
—(CH2)2—
—(CH2)2—
H
H
32
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
33
H
—CH2—CH═CH—
—(CH2)2—
H
H
34bas
CH3
—(CH2)4—
—CH2—C(CH3)2—
H
H
35
CH3
—(CH2)4—
—CH2—C(CH3)2—
H
H
36bas
CH3
—(CH2)2—O—CH2—
—(CH2)3—
H
H
37bas
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
H
38bas
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
H
39
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
40
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
41
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
42
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
43
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
2-F
44chl
CH3
—(CH2)2—
H
H
45
CH3
—(CH2)2—O—CH2—
—(CH2)3—
H
H
46chl
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
H
47chl
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
H
48
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
49
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
50
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
51
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
52
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
53
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
54
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
55
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
56
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
57
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
58
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
59
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
60
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
61
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
62
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
63
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
64
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
65
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
66
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
67
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
68
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
69
CH3
—(CH2)4—
—(CH2)2—
H
H
70
CH3
—(CH2)4—
—(CH2)2—
H
H
71
CH3
—(CH2)4—
—(CH2)2—
H
H
72
CH3
—(CH2)4—
—(CH2)2—
H
H
73
CH3
—(CH2)4—
—(CH2)2—
H
H
74
CH3
—(CH2)4—
—(CH2)2—
H
H
75
CH3
—(CH2)4—
—(CH2)2—
H
H
76
CH3
—(CH2)4—
—(CH2)2—
H
H
77
CH3
—(CH2)4—
OH
H
H
H
78
CH3
—(CH2)4—
H
H
H
H
79fum
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
80base
CH3
—CH2—CH═CH—
—(CH2)2—
CH3
H
81fum
CH3
—CH2—CH═CH—
—(CH2)2—
CH3
H
82
CH3
—CH2—CH═CH—
—(CH2)2—
H
2-F
83
CH3
—CH2—CH═CH—
—(CH2)2—
H
2-F
84
CH3
—(CH2)2—
—(CH2)2—
H
H
85base
CH3
—(CH2)4—
—(CH2)2—
H
2-Cl
86fum
CH3
—(CH2)4—
—(CH2)2—
H
2-Cl
87base
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
H
88fum
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
H
89
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
2-Cl
90
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
2-Cl
91base
CH3
—(CH2)2—O—CH2—
—(CH2)2—
iPr
H
92fum
CH3
—(CH2)2—O—CH2—
—(CH2)2—
iPr
H
93base
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
2-Cl
94fum
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
2-Cl
95base
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
2-Cl
96fum
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
2-Cl
97base
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
H
98fum
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
H
99base
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
H
100fum
CH3
—(CH2)2—O—CH2—
—(CH2)2—
CH3
H
101
CH3
—(CH2)2—
—(CH2)2—
H
H
102base
CH3
—(CH2)2—O—CH2—
—(CH2)2—
Et
H
103base
CH3
—(CH2)2—O—CH2—
—(CH2)2—
iPr
H
104base
CH3
—(CH2)2—O—CH2—
—N═CH—
H
H
105
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
106
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
107
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
108
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
109
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
110
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
111
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
112
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
113
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
114
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
115
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
116
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
117
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
118
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
119
CH3
—CH2—CH═CH—
—(CH2)2—
H
H
120
CH3
—(CH2)4—
—(CH2)2—
H
H
121
CH3
—(CH2)4—
—(CH2)2—
H
H
122
CH3
—(CH2)4—
—(CH2)2—
H
H
123
CH3
—(CH2)4—
—(CH2)2—
H
H
124
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
125
CH3
—(CH2)2—O—CH2—
—(CH2)2—
H
H
Et denotes Ethyl
cPr denotes Cyclopropyl
iPr denotes isopropyl (1-methylethyl)
Ph denotes Phenyl
*All the compounds described in the table are in salt form with trifluoroacetic acid, with the exception of the compounds marked:
(chl) salt with hydrochloric acid
(bas) non salified
(fum) salt with fumaric acid
Biological Activity
The compounds of the present invention were evaluated for their analgesic properties in the formalin-induced pain response test in mice (Shibata, M., Ohkubo, T., Takahashi, H. & R. Inoki. Modified formalin test: characteristic biphasic pain response. Pain, 38, 347-352). To summarize, formalin (0.92% in saline solution) is injected into the hind paw and the paw licking time, which reflects pain intensity, is recorded from 0 to 5 min (1st phase) and from 15 to 30 min (2nd phase) after injection. The percentage inhibition of the second formalin-induced licking phase for some compounds of the invention is given in the following table:
% inhibition of the
Administration
2nd paw licking
Example
Dose (mg/kg)
route
phase
16
100
p.o.
80
9
100
p.o.
60
19
10
i.p.
42
49
1
i.v.
40
p.o.: oral route
i.p.: intraperitoneal route
i.v.: intravenous route
These results demonstrate very substantial lowering of pain after administration of the compounds.
Further to the results of the preceding test, the compounds of the invention were subjected to a test intended to display their mode of action and involving the B1 receptor of bradykinin.
This test uses the human umbilical vein and is conducted in acoordance with the following protocol:
Human umbilical cords 15-25 cm long are recovered just after delivery and immediately placed in a flask containing a Krebs solution of composition (in mM): 119 NaCl, 4.7 KCl, 1.18 KH2PO4, 1.17 MgSO4, 25 NaHCO3, 2.5 CaCl2, 5.5 Glucose, 0.026 EDTA then stored at 4° C.
The cord is dissected in the Krebs solution to release the umbilical vein. The vein is cleansed of all adhering tissue and cut into small rings 3-4 mm in width. The endothelium is carefully removed by inserting a fine no 1 catheter, made slightly abrasive, into the vessel lumen.
To induce the expression of the B1 receptor of bradykinin, the vein segments are left to incubate at 37° C. in a 25 ml chamber for 16 hours in EMEM culture medium oxygenated by a 95% O2+5% CO2 mixture to which antibiotics are added: penicillin 10 000 IU/ml and streptomycin 10 000 IU/ml. The following day, the vein segments are mounted on a stainless steel support connected to an isometric sensor and placed in a 8 ml organ bath thermostatted at 37° C., containing Krebs solution oxygenated with a 95% O2+5% CO2 mixture.
After a rest period of one hour during which the ring segments are rinsed 5 to 6 times with the Krebs solution (maintained at 37° C. throughout all handling procedures and oxygenated with the 95% O2+5% CO2 mixture), the vein is gradually subjected to a 1 g load. When the load is stable, after approximately 45 minutes, the Krebs solution is replaced by a high potassium solution (KPSS: at a temperature of 37° C.) of the same composition, but containing 125 mM KCl and not NaCl.
After a series of rinsings, rest periods and load readjustments, the maximum contraction of each segment is determined by further depolarisation with the KPSS solution.
After a new rest period during which the 1 g load is constantly readjusted, the following compounds are added to the isolated organ bath: Mepyramine (1 μM), Atropine (1 μM), Indometacine (3 μM), LNA (30 μM), Captopril (10 μM), DL-Thiorphan (1 μM) and Nifedipine (0.1 μM).
After 20 minutes, the molecule to be tested or the solvent of the molecule is added to the isolated organ bath. The molecules are examined at 10 μM; if a molecule shows sufficient level of activity, it is examined at lower concentrations (e.g.: 1-0.1-0.01 μM).
After 15 minutes incubation, the vein segments are contracted through the addition of increasing concentrations of des-Arg10-Kallidin (0.1 nM to 30 000 nM) to the chamber.
The EC50 values (effective concentrations of agonists required to produce 50% of the maximum response obtained with the KPSS) are calculated using the least square method.
The pKB=[−log KB] is obtained from the equation:
KB=[A]/(concentration ratio−1)
where [A] is the concentration of antagonist and the (concentration ratio) represents the ratio between EC50 in the presence of antagonists, and EC50 in the absence of antagonists.
According to this test, the compounds of the invention cited in the description show a pKB value of between 7 and 10, which tends to show that the mode of action of these compounds involves antagonism to the B1 receptor of bradykinin.
The compounds of the present invention are of use in the treatment of various forms of pain such as inflammatory hyperalgesia, allodynia, neuropathic pain associated for example with diabetes, with neuropathies (constriction of sciatica nerve, lumbago) with any form of trauma, surgery (tooth extraction, tonsil removal), interstitial cystitis, inflammatory colon disease and with cancer.
The compounds of the present invention may also be used to treat any pathology associated with neutrophil migration, such as acute respiratory distress syndrome, psoriasis, chronic lung obstructions, inflammatory diseases of the colon, rheumatoid polyarthritis.
The activity of the compounds of the invention, evidenced throughout the biological tests, is indicative of analgesic properties and permits the consideration of their therapeutic use.
According to the invention, the use is advocated of the compounds defined by formula 1, and of their salts with non-toxic acids, preferably their pharmaceutically suitable salts, as active ingredients of medicinal products intended for mammals, man in particular, to treat pain or some diseases generally characterized by massive migration of neutrophils.
Among the diseases which can be treated by administering a therapeutically efficient quantity of at least one of the formula I compounds, mention may be made of inflammatory hyperalgesia, neuropathic pain, pain associated with trauma or cancer, inflammatory diseases of the colon, rheumatoid polyarthritis, psoriasis, chronic lung obstructions or acute respiratory distress syndrome.
The compounds of the invention, on account of their mode of action, also find use in the treatment or prevention of any pathological condition in which the B1 receptors of bradykinin are involved and in particular are over-expressed. In addition to the various forms of pain and inflammatory diseases already cited, the compounds of the invention may be used to treat:
certain respiratory problemes such as asthma, bronchitis, pleuresy or rhinitis of allergic or viral origin,
certain forms of diabetes,
certain skin diseases such as dermatitis, eczema, psoriasis,
eye diseases such as glaucoma, retinitis,
Alzheimer's disease,
septic shock,
traumas, especially involving the skull,
some cancers, in particular by slowing or inhibiting the proliferation of cancer cells and more particularly cancer of the prostate.
The invention also concerns a method for treating pain or the aforesaid diseases which consists of administering a therapeutically effective quantity of the formula I compound to patients in need thereof.
The dose of the active ingredient is dependent upon the mode of administration and type of pathology: it is generally between 0.05 and 10 mg/kg of the treated patient. In relation to the intended treatment, the formula I compounds or their salts may be associated with other active ingredients, and are to be formulated with routinely used excipients.
With a view to obtaining swift action, in particular when treating acute pain, the administration mode of the medicinal product is preferably by injection, for example via intramuscular or subcutaneous routes. In cases of chronic pain, the administering of the medicinal product may be made using common galenic formulations, for example by oral route in capsule or tablet form, in which a compound of the invention is associated with excipients known to persons skilled in the art, or in adhesive patch form in which a compound of the invention is formulated with excipients known to persons skilled in the art to promote the transdermal passage of the active ingredient.
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10517909
|
laboratoires fournier sa
|
USA
|
B2
|
Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
|
Open
|
514/604
|
|
Mar 31st, 2022 02:21PM
|
Mar 31st, 2022 02:21PM
|
AbbVie
|
Health Care
|
Pharmaceuticals & Biotechnology
|