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nasdaq:vtrs
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Viatris
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Jan 18th, 2005 12:00AM
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Jul 30th, 2002 12:00AM
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https://www.uspto.gov?id=US06844449-20050118
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Modifications of the trometamol salt of R-thioctic acid as well as a process for their production
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The invention relates to new modifications of the trometamol salt of R-thioctic acid of the formula I,
processes for their production, pharmaceutical preparations containing these modifications, and their medical application.
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6844449
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1. A process for the production of a modification A of compound I
characterized by the X-ray diffraction pattern in which reflections not coinciding with the reflections of the other modifications are observed inter alia at 14.87°2θ20(5.96 Å), 19.99°2θ(4.44 Å), 20.88°2θ(4.25 Å), 22.78°2θ(3.90 Å), 24.53°2θ(3.63 Å), 25.66°2θ(3.47 Å), 30.05°2θ(2.97 Å) and at 37.29°2θ(2.41 Å), and modification B of the compound I characterized by the X-ray diffraction pattern in which reflections not coinciding with the reflections of the other modifications are observed inter alia at 13.80°2θ(6.41 Å), 15.22°2θ(5.82 Å), 17.50°2θ(5.06 Å) and at 23.48°2θ(3.79 Å) as well as of A/B mixtures of arbitrary composition by reacting R-thioctic acid with trometamol, wherein trometamol is metered into a solution of R-thioctic acid in a polar solvent, the suspension is heated until the trometamol has dissolved, and is then crystallized by cooling.
2. Process for the production of the modifications A and B as well as of A/B mixtures of arbitrary composition according to claim 1, wherein straight-chain or branched alcohols with 1 to 6 C atoms as well as mixtures thereof with water are used as polar solvents.
3. Process for the production of the modification A according to claim 1, wherein an R-thioctic acid prepared by racemate resolution is employed in the reaction.
4. Process for the production of modification A according to claim 1, wherein an R-thioctic acid produced by incorporation of sulfur in the end stage of the synthesis and highly purified by recrystallisation and/or dissolution and crystallisation, is employed in the reaction.
5. Process for the production of modification B according to claim 1, wherein an R-thioctic acid produced by incorporation of sulfur in the end stage of the synthesis is employed in the reaction.
6. Process for the production of a modification mixture A/B of arbitrary composition according to claim 1, wherein an R-thioctic acid produced by incorporation of sulfur in the end stage of the synthesis and only partially purified by recrystallisation and/or dissolution and crystallisation, is employed in the reaction.
7. Process for the production of modification B according to claim 1, wherein an R-thioctic acid produced by racemate resolution is used in the reaction with the addition of nucleophilic compounds.
8. Process for the production of modification A, wherein modification B or A/B mixtures are recrystallised from straight-chain or branched alcohols with 1 to 6 C atoms.
9. Process for the production of modification A, wherein modification B or A/B mixtures are dissolved in straight-chain or branched alcohols with 1 to 6 C atoms, optionally under the addition of water, and the solvent is removed by distillation in vacuo.
10. Process for the production of modification A, wherein the modification B or A/B mixtures, suspended in straight-chain or branched alcohols with 1 to 6 C atoms, optionally under the addition of water, are stirred as a suspension at temperatures of about 0° to 60° C., and have reaction times of in general 1 to 24 hours.
11. Process for the production of modification A, wherein non-polar solvents are added to the modification B dissolved in straight-chain or branched alcohols with 1 to 6 C atoms, optionally under the addition of water, and the mixture is then cooled.
12. Process for the production of modification B, wherein modification A or A/B mixtures are recrystallised from straight-chain or branched alcohols with 1 to 6 C atoms, optionally under the addition of water.
13. Process for the production of modification B, wherein modification A is dissolved in straight-chain or branched alcohols with 1 to 6 C atoms and the solvent is removed by distillation.
14. Process for the production of modification B, wherein a melt of the modification A is maintained for about 10 to 40 minutes at about 115°-130° C., and is crystallised by cooling.
15. Process for the production of modification B, wherein modification A is recrystallised under the addition of nucleophilic compounds from straight-chain or branched alcohols with 1 to 6 C atoms, optionally under the addition of water.
16. Process for the production of modification mixtures A/B, wherein a solution of modification A in straight-chain or branched alcohols with 1 to 6 C atoms is heated in general for ca. 2 to 12 hours, and is then crystallised by cooling.
17. Process for the production of modification mixtures A/B, wherein the modification A is dissolved in straight-chain or branched alcohols with 1 to 6 C atoms under the addition of water and the solvent is removed by distillation.
18. Process for the production of modification mixtures A/B, wherein modification A is briefly melted and the melt is then rapidly cooled.
19. Process for the production of modification mixtures A/B, wherein modification A is dissolved in water or dimethylformamide and the modification mixture A/B is precipitated by addition of acetone.
20. Process for the production of modification mixtures A/B, wherein modification A is recrystallised under the addition of nucleophilic compounds from straight-chain or branched alcohols with 1 to 6 C atoms, optionally under the addition of water.
21. Process for the production of modification mixtures A/B, wherein modification A is recrystallised from dipolar-aprotic solvents.
22. Process for the production of modification mixtures A/B, wherein modification B is recrystallised from straight-chain or branched alcohols with 1 to 6 C atoms, optionally under the addition of water.
23. A method for the production of pharmaceutical preparations comprising using modifications A and B as well as modification mixtures A/B of arbitrary composition of the compound.
24. A pharmaceutical composition containing the modifications A or B or modification mixtures A/B of arbitrary composition of the compound I and optionally carriers and/or auxiliary substances.
25. The process of claim 1, wherein the crystallization by cooling occurs after concentration by evaporation.
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The present invention relates to new modifications of the trometamol salt of R-thioctic acid of the formula I,
processes for their production, pharmaceutical preparations containing these modifications, and their medical application.
This compound is effective for example as an anti-inflammatory and cytoprotective agent (EP 427247) and is used to treat diabetes mellitus and insulin resistance (DE 4.343.593) as well as in glucose metabolic disorders of the central nervous system (DE 4.343.592) and as an appetite suppressant (DE 19.818.563), and may therefore be employed in pharmaceutical preparations (EP 702953). The requirements that an active constituent must meet as regards the relevant physicochemical properties for galenical processibility and bioavailability are determined both by the nature and also by the production technology of the respective pharmaceutical preparation. Particularly in the case of high dosage active constituents, among which is included the trometamol salt of R-thioctic acid, the physicochemical properties significantly influence the galenical processibility and bioavailability.
It is therefore advantageous with such an active constituent to have available, for various pharmaceutical preparations and production technologies, various modifications and mixtures thereof that exhibit different physicochemical properties.
Modifications of the compound I have not been known up to now.
The object of the present invention is accordingly to provide the compound I in various modifications as well as mixtures thereof, corresponding to the pharmaceutical requirements.
The two modifications, termed A and B, have different physicochemical properties. The in each case characteristic X-ray powder diffraction patterns are used to identify these two modifications of the compound of the formula I. The modifications differ furthermore in their DSC (differential scanning calorimetry) curves, by the in each case typical crystal forms, the different solubilities and/or dissolution rates, as well as by the different flow properties.
The X-ray diffraction patterns shown in FIGS. 1-6 were recorded with a powder diffractometer using CuKαradiation.
The modification A is characterised by:
The X-ray diffraction pattern (see FIGS. 1-3 and FIG. 6), in which connection there are observed reflections inter alia at
14.87°2θ(5.96 Å), 19.99°2θ(4.44 Å), 20.88 °2θ(4.25 Å), 22.78°2θ(3.90 Å), 24.53°2θ(3.63 Å), 25.66°2θ(3.47 Å), 30.05°2θ(2.97 Å) and at 37.29°2θ(2.41 Å)
that do not coincide with the reflections of the other modification.
The melting point in the range from about 117.1° to 118.4° C.
The modification A occurs predominantly in the form of small platelets.
The modification B is characterised by:
The X-ray diffraction pattern (see FIGS. 1, 2 and 4 as well as FIG. 6), in which connection there are observed reflections inter alia at
13.80°2θ(6.41 Å), 15.22°2θ(5.82 Å), 17.50°2θ(5.06 Å), and at 23.48°2θ(3.79 Å)
that do not coincide with the reflections of the other modification.
The melting point in the range from about 115.20 to 116.8° C.
The modification B occurs predominantly in the form of aggregates.
The X-ray diffraction patterns of the modification mixtures A/B are characterised by overlapping of the reflections from A and B (mixture A/B=ca. 1:1, see FIGS. 1, 2 and 5, 6).
The solubility and/or dissolution rate of the modification A in water and organic solvents, such as for example lower alcohols, octanol and acetone, as well as their mixtures with water, is raised compared to modification B.
The angle of repose α of the modifications as a measure of the flowability and pourability is likewise different:
Angle of Repose α1)
Modification A
46°
Modification B
32°
Modification mixture A/B = 1:1
34°
1)Determined according to R. Voigt, Lehrbuch der pharmazeutischen Technologie, 3rd Edition 1979, p. 165
It is generally known that R-thioctic acid readily polymerises and has a tendency to undergo such reactions, particularly in polar media.
It is therefore surprising that in the reaction of R-thioctic acid with trometamol, polymer-free products may be obtained if the trometamol is metered into the solution of R-thioctic acid in polar solvents, such as for example lower alcohols, optionally under the addition of water, and the suspension obtained is warmed in order to effect dissolution.
The term “lower alcohols” is understood in this connection to denote straight-chain or branched alcohols with 1 to 6 C atoms.
The crystallisation then takes place under cooling. Further product is obtained from the mother liquor by concentrating the solution by evaporation under gentle conditions and cooling.
Surprisingly the modifications A and B of the compound I as well as their mixtures of arbitrary composition can be produced by salt formation of R-thioctic acid with trometamol in suitable polar solvents such as for example lower alcohols, as well as by modification transformation under special reaction conditions.
Accordingly, either pure modifications of the compound I or alternatively mixtures thereof of varying composition may be prepared for the production of various pharmaceutical preparations.
The preparation of the modifications A and B and their mixtures by salt formation of R-thioctic acid with trometamol depends on the purity of the R-thioctic acid that is used (content of trace impurities resulting from the synthesis).
Thus, the modification A is obtained with R-thioctic acid that has been obtained by racemate resolution according to DE 4.137.773 (hereinafter denoted as synthesis pathway a). On the other hand with R-thioctic acid in the preparation of which sulfur is introduced at the end of the synthesis (hereinafter denoted as synthesis pathway b; for example DE 4.037.440, DE 19.533.881, DE 19.533.882, DE 19.709.069), the modification B is obtained as main product, together with a minor amount of A. By means of one or more additional purification steps carried out on the R-thioctic acid obtained by synthesis pathway b (e.g. recrystallisation from inert solvents such as cyclohexane, cyclohexane/ethyl acetate (in particular 19:1), n-heptane/toluene, n-hexane/toluene, optionally under the addition of water and/or dilute mineral acid as well as dissolution and crystallisation from dilute alkali solution/dilute mineral acid under simultaneous extraction, for example with cyclohexane/ethyl acetate, trace impurities resulting from the synthesis can be successively removed so that in the salt formation either a modification A/B or the modification A are formed as main products. On the other hand by adding nucleophilic compounds, such as for example sodium sulfite or 6,8-dimercaptooctanoic acid, in the salt formation with R-thioctic acid prepared by the synthesis pathway a the modification B is obtained as the main product.
The modifications may also be prepared by modification transformation, in which a complete or partial transformation of A after B as well as of B after A may take place.
In this connection it is possible to use the pure modifications A and B as well as their mixtures. When using mixtures the transformation preferably proceeds in the direction of the formation of a pure modification.
The following methods may be employed:
Recrystallisation from lower alcohols, optionally under the addition of water
Prolonged heating in lower alcohols, optionally under the addition of water, at temperatures up to the boiling point, followed by cooling crystallisation
Concentration by evaporation of solutions in lower alcohols, optionally under the addition of water, by distilling off the solvent under normal pressure or in vacuo.
Reprecipitation from solvent mixtures.
Conversion of the salt I suspended in solvents.
Thermal phase conversion below the melting point or by melting.
Preparation of Modification A
Recrystallisation of modification B or A/B mixtures from lower alcohols.
Distilling off the solvent in vacuo from solutions of the modification B or A/B mixtures in lower alcohols.
Suspension of modification B or of A/B mixtures in lower alcohols, optionally under the addition of water, at temperatures of about 0° to 60° C., preferably at about 20° to 40° C., and stirring times of in general 1 to 24 hours, in particular about 2 to 15 hours.
Reprecipitation by addition of hydrocarbons to the solution of the modification A in lower alcohols.
Preparation of Modification B
Recrystallisation of modification A or A/B mixtures from lower alcohols, optionally under the addition of water.
Distilling off the solvent from solutions of the modification A in lower alcohols.
Heating a melt of the modification A preferably for about 10 to 40 minutes at ca. 115°-130° C., in particular for 15 to 25 minutes at about 115°-120° C., and crystallisation by cooling.
Recrystallisation of modification A from lower alcohols, optionally under the addition of water, with the addition of nucleophilic compounds such as for example sodium sulfite or 6,8-dimercaptooctanoic acid.
Preparation of Mixtures of Modifications A/B
Heating a solution of the modification A in lower alcohols at the reflux temperature generally for ca. 2 to 12 hours, preferably for about 4 to 8 hours, followed by cooling crystallisation.
Distilling off the solvent from solutions of the modification A in lower alcohols, optionally under the addition of water.
Brief melting of the modification A and crystallisation under cooling.
Reprecipitation by addition of acetone to the solution of the modification A in water or dimethylformamide.
Recrystallisation of modification A from lower alcohols, optionally under the addition of water, as well as addition of nucleophilic compounds such as for example sodium sulfite or 6,8-dimercaptooctanoic acid.
Recrystallisation of modification A from dipolar-aprotic solvents such as for example N,N-dimethylacetamide, ethylene glycol dimethyl ether, 1,2-dichloroethane, methyl ethyl ketone, and dimethyl carbonate.
Recrystallisation of modification A or B from lower alcohols, optionally under the addition of water.
The modifications A and B as well as their mixtures may be processed in a conventional way with suitable carriers and/or auxiliary substances into pharmaceutical preparations. Preferred application forms are tablets and capsules.
The modifications are for example valuable agents for treating insulin resistance, diabetes mellitus, and glucose metabolic disturbances of the central nervous system. The production processes for the modifications A and B as well as their mixtures will be described in more detail hereinafter with the aid of examples.
EXAMPLES
The modifications of the compound I were, after suction filtration, washed with the relevant cooled solvent and dried for 2 hours at 50° C. unless otherwise stated.
Formation of Modifications in the Preparation of the Trometamol salt of R-Thioctic Acid
Example 1
12.1 g (0.1 mole) of trometamol were added to a solution of 41.2 g (0.2 mole) of R-thioctic acid (produced according to process a) in 220 ml of ethanol (96%) and heated while stirring to 55° C.
1 g of Diacel (filter aid) was added to the solution, heated for 20 minutes at 55°-57° C., suction filtered until clear, slowly cooled and stirred at −5° C. to −10° C. for 2 hours.
Yield: 58.0 g (88.6% of theory) of I, modification A.
A further 1.7 g (2.6% of theory) of I, modification A, were obtained by concentrating by evaporation the mother liquor to ca. ⅕of its original volume.
Example 2
41.2 g (0.2 mole) of R-thioctic acid (produced according to process a) were dissolved in 600 ml of ethanol (anhydrous). 24.2 g (0.2 mole) of trometamol were added while stirring, and the mixture was heated to 50°-55° C. to dissolve the trometamol and after addition of 2 g of Diacel was stirred for ca. 10 minutes at 50°-55° C. and suction filtered until clear. The solution was then slowly cooled (over 3-4 hours) at a roughly uniform cooling rate to −5° C. and stirred for a further 4-5 hours at −5° to −10° C.
Yield: 55.5 g (84.9% of theory) of I, modification A.
A further 4.1 g (6.3% of theory) of I, modification A, were obtained by concentrating by evaporation the mother liquor to ca. 20%.
Example 3
41.2 g (0.2 mole) of R-thioctic acid (produced according to process a) were dissolved in 230 ml of ethanol (anhydrous). 24.2 g (0.2 mole) of trometamol were added and the mixture was stirred at 55°-60° C. until all the trometamol had dissolved. After suction filtration the resultant clear solution was slowly cooled to 0° to 5° C., stirred for 2 to 4 hours in this temperature range, suction filtered, washed with cold ethanol and dried.
Yield: 61.0 g (93.1% of theory) of I, modification A.
A further 2.4 g (3.7% of theory) of I, modification A, were obtained by concentrating by evaporation the mother liquor in vacuo to ca. 20%.
Example 4
41.2 g (0.2 mole) of R-thioctic acid (produced according to process b followed by recrystallisation from cyclohexane/ethyl acetate/water corresponding to Example 31) were dissolved in 600 ml of ethanol (anhydrous). 24.2 g (0.2 mole) of trometamol were then added and the solution was heated to 50°-55° C. while stirring. 2 g of Diacel were added to the solution, which was stirred for 20 minutes, suction filtered until clear, and slowly cooled. The solution was seeded at 30° C., and stirred for 4 hours in the range from −5° to −10° C.
Yield: 56.1 g (85.7% of theory) of I, modification A.
A further 6.7 g (10.2% of theory) of I, modification A, were obtained by concentrating by evaporation the mother liquor to ca. ⅕of the original volume.
Example 5
54.9 g (83.9% of theory) of I, modification mixture A/B (ca. 1:1) were obtained, similarly to Example 4, as a first crystallisate from R-thioctic acid (produced according to process b followed by recrystallisation once from cyclohexane). 6.8 g (10.4% of theory) of I, modification A, were then obtained by concentration by evaporation of the mother liquor.
Example 6
25.8 g (0.125 mole) of R-thioctic acid (produced according to process b) were dissolved in 375 ml of ethanol (anhydrous). 15.13 g (0.125 mole) of trometamol were then added and the mixture was heated at 50°-55° C. while stirring until the trometamol had dissolved. After addition of 1.25 g of Diacel and suction filtration of the solution until clear, the latter was slowly cooled, seeded at 30° C., and cooled for a further 4 hours at −5° to +12° C.
Yield: 28.1 g (68.6% of theory) of I, modification B.
9.3 g (22.6% of theory) of I, modification A, were obtained by concentration by evaporation of the mother liquor to 70 ml and cooling.
Example 7
41.2 g (0.2 mole) of R-thioctic acid (produced according to process b) were dissolved in 250 ml of ethanol (anhydrous). 24.2 g (0.2 mole) of trometamol were then added and the solution was heated at 55°-57° C. while stirring until the trometamol had dissolved.
After addition of 1.25 g of Diacel and suction filtration of the solution until clear, the latter was slowly cooled (ca. 1-2 hours) and stirred at −5° to −10° C. for 2 hours.
Yield: 55.0 g (84.1% of theory) of I, modification B.
5.7 g (8.7% of theory) of I, modification A, were obtained by concentration by evaporation of the mother liquor to 70 ml and cooling.
Example 8
41.2 g (0.2 mole) of R-thioctic acid (produced according to process b) were dissolved in 220 ml of ethanol (anhydrous). 24.2 g (0.2 mole) of trometamol were then added and the solution was heated to 57° C.
2 g of Diacel were added to the solution, which became clear after 10 minutes, and the latter was stirred for 20 minutes at 55°-57° C., suction filtered until clear, and slowly cooled. The solution was stirred for 2 hours at −5° to −10° C.
Yield: 57.8 g (88.4% of theory) of I, modification B.
3.7 g (5.7% of theory) of I, modification A, were obtained by concentration by evaporation of the mother liquor to ca. 20% followed by cooling.
Example 9
20.6 g (0.1 mole) of R-thioctic acid (produced according to process a) were dissolved in 300 ml of ethanol (anhydrous). Following the addition of 12.1 g (0.1 mole) of trometamol and 0.5 g of 6,8-dimercaptooctanoic acid the mixture was heated at 55° C. until the trometamol had dissolved. After addition of 1 g of Diacel the solution was stirred for 20 minutes at 53°-55° C., suction filtered until clear, and then slowly cooled. The solution was then stirred for 2 hours at −8° to −12° C.
1.9 g (5.8% of theory) were recovered from the flask wall (modification mixture B>A).
20.2 g (61.8% of theory) of I, modification B, were obtained by concentrating by evaporation the mother liquor to half the original volume and cooling overnight at −5° to −10° C.
1.9 g (5.8% of theory) of I, modification A, were obtained by further concentration by evaporation to ca. half the original volume followed by cooling.
Example 10
20.6 g (0.1 mole) of R-thioctic acid (produced according to process a) were dissolved in 110 ml of ethanol (96%).
12.1 g (0.1 mole) of trometamol as well as 2 g of sodium sulfite were then added and the whole was heated to 55° C. After addition of 1 g of Diacel the solution was stirred for 20 minutes at 53°-55° C., suction filtered until clear, and slowly cooled. The solution was then stirred for 2 hours at −5° to −10° C.
8.1 g (yield 24.8% of theory) of I, modification A, were obtained.
The mother liquor was concentrated by evaporation to about half the original volume and cooled overnight at −5° to −10° C.
19.1 g (yield 58.4% of theory) of I, modification B, were obtained.
Production of Modifications by Transformation
Example 11
10 g of I, modification B, were dissolved in 85 ml of ethanol (anhydrous) at 50°-55° C. The solution was slowly cooled to −5° to −10° C. while stirring, and was then seeded with I, modification A, at 30° C.
After stirring (2 hours) at −5° to −10° C. and standing overnight in a deep-freeze cabinet, 5.4 g (54% of theory) of I, modification B, were recovered.
4.0 g (40% of theory) of I, modification A, were obtained by concentration by evaporation of the mother liquor to ⅕of the original volume and cooling in a deep-freeze cabinet overnight.
Example 12
1 g of I, modification B, was dissolved in 10 ml of ethanol (anhydrous) at 55° C., the solvent was evaporated at room temperature, and the residue was investigated after drying (2 hours, 50° C.): I, modification A.
Example 13
30 ml of n-heptane are added at 57° C. to a solution of 3 g of I, modification B, in 25 ml of anhydrous ethanol and then cooled to −5° to −10° C.
The crystallisate is dried (2 hours, 50° C.).
Yield: 2.5 g (75% of theory) of I, modification A.
Example 14
2 g of a mixture consisting of 80% of modification A and 20% of modification B were suspended in 3 ml of ethanol (96%) and stirred for 11 hours at 35° C., the pure modification A thereby being obtained.
Example 15
20 g of I, consisting of ca. 50% of each of the modifications A and B, were dissolved in 170 ml of ethanol (anhydrous) at 50°-55° C., and after addition of 0.5 g of Diacel the solution was suction filtered until clear. The filtrate was rapidly cooled to −5° to −10° C. while stirring, and stirred for a further 2 hours at this temperature.
Yield: 16.8 g (84% of theory) of I, modification A.
Example 16
20 g of I, modification A, were dissolved in 170 ml of ethanol (anhydrous) at 50°-55° C. The filtrate was slowly cooled to −5° to −10° C., and was then seeded at 31° C. The mixture was stirred for 2 hours at −5° to −10° C.
16.9 g (84.5% of theory) of I, modification A, were recovered.
2.0 g (10% of theory) of I, modification B with traces of A, were obtained by concentration by evaporation of the mother liquor to ⅕of the original volume followed by cooling.
The same result was also obtained without seeding.
Example 17
40 g of I, mixture A>B, were dissolved at 50°-55° C. in 120 ml of ethanol (96%), rapidly cooled to −5° to −10° C., and stirred for 2 hours in the same temperature range.
Yield: 34 g (85% of theory) of I, modification B.
Example 18
10 g of I, modification A, were heated for 6 hours under reflux in 85 ml of ethanol (anhydrous), and the solution was then cooled and stirred for one hour at −5°to −10° C.
Yield: 8.3 g (83% of theory) of I, mixture of the modifications A and B (ca. 1:1).
The mother liquor was concentrated to 20% by evaporation: 0.91 g (9.1% of theory) of I, modification B.
Example 19
8.6 g of I (yield 86% of theory) in the form of a modification mixture (B>A) were obtained as first crystallisate by heating under reflux (6 hours) 10 g of I, modification A, in 30 ml of ethanol (96%), followed by cooling and stirring (1 hour at −5° to −10° C.).
Example 20
15 g of I, modification B, were dissolved in 70 ml of ethanol (96%) at 55° C. The solution was cooled and stirred for 2 hours at −5°to −8° C.
Yield: 12.8 g (84.8% of theory) of I, modification mixture A/B (ca. 1:1).
0.6 g (3.9% of theory) of I, modification A, was obtained by concentration by evaporation of the mother liquor to ca. 20% followed by cooling.
Example 21
5 g of I, modification A, were dissolved at 50°-55° C. in 200 ml of isopropanol. The solution was rapidly cooled and then stirred for 1 hour at −5° to −10° C.
4.2 g (84% of theory) of I, modification mixture A/B, were obtained.
A further 0.4 g (8% of theory) of I, modification mixture A/B, was obtained by concentration by evaporation of the mother liquor to 20% followed by cooling.
Example 22
3 g of I, modification A, were dissolved in 3 ml of N,N-dimethylacetamide at 50°-55° C. The solution was cooled and stirred at −5°to −10° C. for 1 hour.
Yield: 1.6 g (53.3% of theory) of I, modification mixture (A>B).
Example 23
10 g of I, modification A, were dissolved at 55° C. in 90 ml of ethanol (anhydrous). The majority of the solvent was distilled off under normal pressure, and the remainder under a vacuum. The oil obtained crystallised on cooling: I, modification B, quantitative yield.
Example 24
10 g of I, modification A, were dissolved at 55° C. in 30 ml of ethanol (96%). The solution was then concentrated by evaporation on a rotary evaporator up to a maximum bath temperature of 100° C., and was finally evaporated in vacuo. The oil crystallised on cooling: mixture (ca. 1:1) of the modifications A and B, quantitative yield.
Example 25
2 g of I, modification A, were melted at a bath temperature of 115°-120° C. and maintained for 20 minutes at this temperature. The crystallisate obtained on cooling consisted mainly of modification B with traces of A in addition to polymer.
Example 26
2 g of I, modification A, were briefly melted at a bath temperature of ca. 140° C. and then rapidly cooled. The crystallisate consisted of an A/B modification mixture together with polymer.
Example 27
400 ml of acetone were added to a solution of 3 g of I, modification A, in 8 ml of water and the whole was cooled at −5° to −8° C. (2 hours)
Yield: 1.8 g (60% of theory) of I, modification mixture (B>A).
Example 28
80 ml of acetone were added to a solution of 3 g of I, modification A, in 12 ml of dimethylformamide. The solution was cooled to −5° and stirred for 90 minutes at this temperature.
Yield: 2.75 g (91.3% of theory) of I, modification B together with traces of A.
Example 29
20 g of I, modification A, and 2 g of sodium sulfite were dissolved or suspended at 50°-55° C. in 50 ml of ethanol (96%). After the addition of 1 g of Diacel the solution was suction filtered until clear, slowly cooled to −6° to −8° C. and stirred for 2 hours at this temperature.
Yield: 15.9 g (79.5% of theory) of I, modification mixture (B>A).
Example 30
10 g of I, modification A, and 0.25 g of 6,8-dimercaptooctanoic acid were dissolved at 50°-55° C. in 85 ml of ethanol (anhydrous). After the addition of 1 g of Diacel the solution was suction filtered until clear, slowly cooled to −8° to −12° C., and stirred for 2 hours in this temperature range.
Yield: 1.9 g (19% of theory) of I, modification mixture (B>A).
6.1 g (61% of theory) of modification B were obtained by concentration by evaporation of the mother liquor to ca. 50% followed by cooling.
Example 31
100 g of R-thioctic acid (produced according to process b) were dissolved in a mixture consisting of 760 ml of cyclohexane and 40 ml of water-saturated ethyl acetate (water content: 3.2%) at 40°-42° C. After addition of 5 g of Diacel the solution was suction filtered until clear, slowly cooled to −5°, stirred for 1 hour at this temperature, suction filtered, washed with cyclohexane and dried at 30° C.
Yield: 87.5 g (87.5% of theory) of pure R-thioctic acid.
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10207201
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viatris gmbh & co. kg
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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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549/39
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Apr 1st, 2022 05:10PM
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Apr 1st, 2022 05:10PM
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Viatris
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nasdaq:vtrs
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Viatris
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Nov 14th, 2006 12:00AM
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Jul 20th, 2001 12:00AM
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https://www.uspto.gov?id=US07135328-20061114
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Process for the enantioselective reduction of 8-chloro-6-oxo-octanoic acid alkyl esters
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The invention relates to a process for the production of (R)- or (S)-8-chloro-6-hydroxyoctanoic acid alkyl esters of the general formula (R)-II or (S)-II,
in which R means C1-4 alkyl, from 8-chloro-6-oxo-octanoic acid alkyl esters of the general formula I,
in which R has the above meaning.
The desired enantiomers are produced biocatalytically in an enantioselective reduction, wherein as desired the strains Mucor racemosus are used for (S)-II compounds and Geotrichum candidum for (R)-II compounds.
The resultant esters may, in known manner, be converted stereospecifically into (R)-α-lipoic acid.
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7135328
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1. A process for the production of (R)-8-chloro-6-hydroxyoctanoic acid alkyl esters of the formula (R)-ll from 8-chloro-6-oxo-octanoic acid alkyl esters of the formula I,
in which P. in each case means C alkyl, wherein the reaction is performed by means of a biocatalyst, wherein the biocatalyst is Geotrichum candidum of the strain DSM 13776; and wherein the (R)-8-chloro-6-hydroxyoctanoic acid alkyl esters of the formula (R)-ll are isolated and recovered.
2. A process according to claim 1, wherein 8-chloro-6-oxo-octanoic acid methyl ester is used as the prochiral starting compound.
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2
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AREA OF USE OF THE IVENTION
The present invention relates to a novel biocatalytic process for the enantiose-lective reduction of prochiral 8-chloro-6-oxo-octanoic acid alkyl esters of the formula I as desired with the assistance of the strains Mucor racemosus or Geotrichum candidum to yield respectively the corresponding (S)- or (R)-enantiomer of the reaction products. Once the chiral centre has been formed, the further stereospecific conversion into R-α-lipoic acid may proceed in known manner (DE 195 33 881). As a racemate, α-lipoic acid is primarily used for treating diabetic neuropathy and acute and chronic liver disease. Since it is only the natural (R)-(+)-enantiomer which exhibits biological activity, asymmetric synthesis of this pure natural substance is of great importance.
CHARACTERISTICS OF THE KNOWN PRIOR ART
The compounds I are known and serve as intermediates for the large scale industrial production of racemic thioctic acid (M. W. Bullock et al., J. Am. Chem. Soc. 1954, 76, 1828).
The literature describes not only chemical synthesis processes but also processes comprising biocatalytic sub-stages for the production of enantiomerically pure (R)-α-lipoic acid (review article: J. S. Yadav et al., J. Sci. Ind. Res. 1990, 49, 400). Chemical, asymmetric synthesis processes generally require costly and complicated starting compounds since, for example, the possibility of using enantioselective chemocatalysis is associated with specific electronic and steric structural features.
Production processes with biocatalytic sub-stages use, on the one hand, en-zyme preparations of lipases and oxidoreductases and, on the other, yeast.
Known lipase-catalysed process stages (Y. R. Santosh Laxmi and D. S. Iyengar, Synthesis, 1996, 594; N. W, Fadnavis and K. Koteshwar, Tetrahedron: Asymmetry 1997, 8, 337; N. W. Fadnavis et al., Tetrahedron: Asymmetry 1998, 9, 4019; S. Lee and Y. Ahn, J. Korean Chem. Soc. 1999, 43, 128) are based on enantioselective ester cleavage in order to achieve elevated enantiomeric purity. These processes start from racemic mixtures. The biocatalytic reaction is only capable of utilising at most 50% of the racemic mixture to obtain the enantiomerically pure compound. The remaining unwanted enantiomer must either be discarded or be converted back into a racemic mixture by means of complex reaction stages. Processes with monooxygenases (B. Adger et al., Bioorg. Biomed. Chem. 1997, 5, 253) require costly cofactors, such as NADH or NADPH, or costly cofactor recycling systems.
It is known that yeast (Saccharomyces cerevisiae) and fungi of the genera Mucor and Geotrichum are capable of the biocatalytic conversion of intermediates.
Yeast has already long been used as a biocatalyst in reduction reactions of β-keto esters, ester cleavage and other syntheses (review article: S. Servi, Synthesis 1990, 93, 1).
Enantioselective ester cleavage reactions have in particular been described for Mucor species (for example Mucor miehei and Muco javanicus). While Mucor racemosus is only mentioned in relation to the reduction of tetramethylcyclo-hexanedione (J. d'Angelo et al. J. Org. Chem. 1986, 51, 40), the biocatalytic reduction of β-keto esters has been described for Geotrichum candidum (B. Wipf et al. Helv. Chim. Acta 1983, 66, 485).
No hitherto known processes with yeast (A. S. Gopalan and H. K. Hollie, Tetrahe-dron Lett. 1989, 30, 5705; L. Dasaradhi et al., J. Chem. Soc., 1990, 729; M. Bezbarua et al., Synthesis, 1996, 1289; DE 40 37 440) or Geotrichum candidum (B. Wipf et al. Helv. Chim. Acta 1983, 66, 485) are capable of enantioselectively converting intermediates with oxygen-free, small ligands in β-position relative to the reaction centre into the corresponding S- or R-enantiomers. Instead, large, oxygen-containing ligands are introduced by means of complicated intermediate stages into the β position relative to the keto group, which ligands then enable an enantioselective conversion.
In the solution described herein, in comparison with known syntheses, the starting compounds used are those which only bear very small ligands in α- or β-position to the keto group but are nevertheless converted with elevated enantioselectivity.
The solution presented here was particularly surprising relative to the known prior art since K. Nakamura et al. Tetrahedron Letters 29, 2453-4, 1988 describe that dehydrogenases recognise only ester functions and not chlorine atoms in the adjacent position to the reaction centre and give rise to enantiose-lective conversions.
DESCRIPTION OF THE ESSENCE OF THE INVENTION
The object underlying the invention was accordingly to provide, while making use of known synthesis building blocks, a simpler and more economic, biocatalytically-based process for asymmetric induction within the (R)-α-lipoic acid synthesis sequence.
According to the invention, said object was achieved by finding novel processes which permit enantioselective reduction of the prochiral 8-chloro-6-oxo-octanoic acid alkyl esters of the formula I, in which R denotes C1-4 alkyl, as desired with the assistance of the strains Mucor racemosus or Geotrichum candidum to yield respectively the corresponding (S)- or (R)-enantiomer. 8-Chloro-6-oxo-octanoic acid methyl ester has proved particularly suitable.
Enantioselective reduction of prochiral compounds to yield the (R)-enantiomer of the formula (R)-II proceeds with the assistance of Geotrichum candidum. Conversion of the prochiral precursors into the (S)-enantiomer of the formula (S)-II may be achieved by means of Mucor racemosus.
The elevated enantioselectivity of the reduction of 8-chloro-6-oxo-octanoic acid alkyl esters of the formula I was not to have been anticipated as elevated asymmetric induction has only been described in the literature for compounds in which sterically and/or electronically highly different groups promote selectivity on both sides in α- or β-position relative to the keto group. It was furthermore surprising that two strains could also be found which catalyse the conversion into opposite enantiomers at elevated yield and enantioselectivity.
The process according to the invention is distinguished from the prior art in that the 8-chloro-6-hydroxyoctanoic acid alkyl esters of the formula (R)-II are obtained by culturing Geotrichum candidum (DSM 13776; deposited Oct. 13, 2000 with the DSMZ-Deutsche Sammlung Von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1b, D-38124, Braunschweig, Germany) on a conventional fungal nutrient agar, preferably Sabouraud's glucose agar. The strain is precultured using a complex medium, preferably with 1% yeast extract, 2% peptone and 2% glucose. Further multiplication of biomass is achieved in a completely synthetic medium with glucose as carbon source, ammonium sulfate as nitrogen source together with further nutrient salts, preferably in the composition 20 g/l glucose, 3 g/l (NH4)2SO4, 4 g/l KH2PO4, 0.5 g/l MgSO4, 0.2 g/l NaCl, 0.2 g/l yeast extract, 3 mg/l FeCl3×6 H2O, 3 mg/l CaCl2×2 H2O, 0.4 mg/l MnSO4×H2O, 0.5 mg/l ZnSO4×7H2O and 0.05 mg CuSO4×5 H2O. Both the preculture and the main culture are cultured at 19 to 28° C., preferably 24° C., over a period of 1 to 5 days, preferably 3 days, with shaking on an orbital shaker at 100 to 300 rpm, preferably 190 rpm.
The actual biocatalytic conversion is performed in a buffered aqueous solution with addition of glucose as energy source. The concentration of the biocatalyst is 0.1 to 100 g of biomass solids per litre, preferably 5 g of biomass solids per litre. The substrate is added to the biotransformation batch in a concentration of 5 g/l. Biotransformation is performed with shaking at 24° C. over 1 to 3 days.
Once the biotransformation is complete, the biomass is centrifuged off and the supernatant extracted twice with an organic solvent, preferably ethyl acetate. The extract obtained is evaporated to dryness. The crude product contains proportions of (R)-8-chloro-6-hydroxyoctanoic acid of the formula (R)-II (R=H), which are converted in known manner into the particular alkyl ester by subsequent esterification (DE 195 33 881).
Mucor racemosus (DSM 13775) is cultured and the conversions performed therewith in a similar manner to that described for Geotrichum candidum.
The crude product contains proportions of (S)-8-chloro-6-hydroxyoctanoic acid of the formula (S)-II (R=H), which are converted in known manner into the particular alkyl ester by subsequent esterification (DE 195 33 881).
The compounds (R)-II and (S)-II produced using the process according to the invention generally exhibit an elevated enantiomeric excess, corresponding to an optical yield of 70–95%. Enantiomer ratios are measured directly by chiral gas chromatography on optically active columns.
PRACTICAL EXAMPLES
Example 1
The strain Mucor racemosus (DSM 13775) is cultured on Sabouraud's agar at 24° C. 100 ml of YPD nutrient solution (1% yeast extract, 2% peptone and 2% glucose) is inoculated with an inoculating loop and incubated for 3 days at 24° C. on an orbital shaker (190 rpm). 10% of this preculture are transferred into 100 ml of SMG medium (20 g/l glucose, 3 g/l (NH4)2SO4, 4 g/l KH2PO4, 0.5 g/l MgSO4, 0.2 g/l NaCl, 0.2 g/l yeast extract, 3 mg/l FeCl3×6 H2O, 3 mg/l CaCl2×2 H2O, 0.4 mg/l MnSO4×H2O, 0.5 mg/l ZnSO4×7 H2O and 0.05 mg CuSO4×5 H2O) and cultured for a further 3 days at 24° C.
The resultant biomass is centrifuged off and transferred into 100 ml of buffered aqueous solution (50 mmol Na phosphate buffer, pH 6.5) comprising 5 g/l of glucose. 0.5 g of 8-chloro-6-oxo-octanoic acid methyl ester are dissolved in 2 ml of ethanol and added to the biotransformation batch. After 24 hours, the biomass is removed and the medium extracted twice with 50 ml portions of ethyl acetate. The extracts are combined and the solvent stripped out in a rotary evaporator. The residue is redissolved with 10 ml of methanol and, after addition of 0.04 ml of conc. HCl, refluxed for 1 hour. The solvent is then removed by distillation. Once the residue has been purified by column chromatography (silica gel, ethyl acetate:hexane=3:1), 0.33 g (66%) of (S)-8-chloro-6-hydroxyoctanoic acid methyl ester are obtained with an enantiomeric excess of 92% (chiral GC).
Example 2
The strain Geotrichum candidum (DSM 13776) is cultured on Sabouraud's agar at 24° C. 100 ml of YPD nutrient solution (1% yeast extract, 2% peptone and 2% glucose) is inoculated with an inoculating loop and incubated for 3 days at 24° C. on an orbital shaker (190 rpm). 10% of this preculture are transferred into 100 ml of SMG medium (20 g/l glucose, 3 g/l (NH4)2SO4, 4 g/l KH2PO4, 0.5 g/l MgSO4, 0.2 g/l NaCl, 0.2 g/l yeast extract, 3 mg/l FeCl3×6 H2O, 3 mg/l CaCl2×2 H2O, 0.4 mg/l MnSO4×H2O, 0.5 mg/l ZnSO4×7 H2O and 0.05 mg CuSO4×5 H2O) and cultured for a further 3 days at 24° C.
The resultant biomass is centrifuged off and transferred into 100 ml of buffered aqueous solution (50 mmol Na phosphate buffer, pH 6.5) comprising 5 g/l of glucose. 0.5 g of 8-chloro-6-oxo-octanoic acid methyl ester are dissolved in 2 ml of ethanol and added to the biotransformation batch. After 24 hours, the biomass is removed and the medium extracted twice with 50 ml portions of ethyl acetate. The extracts are combined and the solvent stripped out in a rotary evaporator. The residue is redissolved with 10 ml of methanol and, after addition of 0.04 ml of conc. HCl, refluxed for 1 hour. The solvent is then removed by distillation. Once the residue has been purified by column chromatography (silica gel, ethyl acetate:hexane=3:1), 0.31 g (62%) of (R)-8-chloro-6-hydroxyoctanoic acid methyl ester are obtained with an enantiomeric excess of 88% (chiral GC).
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10343029
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viatris gmbh & co. kg
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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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435/280
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Apr 1st, 2022 05:10PM
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Apr 1st, 2022 05:10PM
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Viatris
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nasdaq:vtrs
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Viatris
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Jan 2nd, 2007 12:00AM
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Oct 14th, 2002 12:00AM
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https://www.uspto.gov?id=US07157253-20070102
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Method for the production of (r)- and (S)-8-chloro-6-hydroxyoctanic acid alkyl esters by enzymatic reduction
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The invention relates to a method for the production of (R)- or (S)-8-chloro-6-hydroxyoctanoic acid alkyl esters of the general formula (R)-II or (S)-II
in which R has the meaning C1-4-alkyl, from 8-chloro-6-oxooctanoic acid alkyl esters of the general formula I
in which R has the above meaning, by enzymatic reduction using alcohol dehydrogenases, such as Lactobacillus brevis or Thermoanaerobium brokii, in the presence of cofactor regeneration systems.
The resulting (R)- and (S)-8-chloro-6-hydroxyoctanoic acid esters can be converted in a known manner into (R)-α-lipoic acid and (S)-α-lipoic acid, respectively.
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7157253
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1. A method for the production of (R)-S-chloro-6-hydroxyoctanoic acid alkyl esters of the formula (R)-II,
in which R has in each case the meaning C1-4-alkyl, characterized in that 8-chloro-6 -oxooctanoic acid alkyl esters of the formula I are reduced enzymatically using alcohol dehydrogenases or carbonyl reductases in the presence of NAD(H) or NADP(H) as cofactor.
2. A method for the production of (S)-8-chloro-6-hydroxyoctanoic acid alkyl esters of the formula (S)-II,
in which R has in each case the meaning C1-4-alkyl, characterized in that 8-chloro-6-oxooctanoic acid alkyl esters of the formula I are reduced enzymatically using alcohol dehydrogenases or carbonyl reductases in the presence of NAD(H) NADP(H) as cofactor.
3. The method as claimed in claim 1, characterized in that an alcohol dehydrogenase from Thermoanaerobium brokii is employed.
4. The method as claimed in claim 2, characterized in that an alcohol dehydrogenase from Lactobacillus brevis is employed.
5. The method as claimed in according to one of claims 1–4, characterized in that a cofactor regeneration system which shifts the reduction equilibrium is included in the enzymatic reduction.
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5
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The invention relates to a method for the production of (R)- and (S)-8-chloro-6-hydroxyoctanoic acid alkyl esters of the formula I by enzymatic reduction of a suitable prochiral keto compound.
The synthesis of α-lipoic acid on the industrial scale starts from 8-chloro-6-oxooctanoic acid alkyl esters, which are converted by NaBH4 reduction into 8-chloro-6-hydroxyoctanoic acid alkyl esters (reference: Kleemann and Engel, Pharmaceutical Substances, 3rd Ed., Thieme, 1999, p. 1860). A subsequent three-stage synthetic sequence results in the racemic α-lipoic acid in a high overall yield. Besides the synthesis of racemic α-lipoic acid, also of great importance is the synthesis of the pure enantiomers for specific pharmaceutical use (concerning this, see, for example EP 04 27 247). It is appropriate to carry out the synthesis of the pure enantiomers in analogy to the established economic method for synthesizing the racemic active ingredient. Accordingly, various methods have been developed to prepare the enantiopure intermediates, see, inter alia, DE-A-19533882. Enantio-selective reductions of prochiral ketone compounds to chiral secondary alcohols, which lead as intermediates in alternative synthetic routes to enantiopure α-lipoic acids, are to be found in DE-A-197 09 069. All the methods involve multistage synthetic sequences, some of which are associated with complicated purification operations or else are based on racemate resolution (DE 4137773), leading to the maximum yield of an enantiomer being 50%—without recycling by racemization or inversion. The low overall yield of these methods make them appear economically unrewarding. None of the described methods is based on a direct, one-stage preparation of an enantiopure intermediate of the established economic method for synthesizing racemic α-lipoic acid.
The object of the invention was thus to indicate a method for the production of certain intermediates for producing (R)- and (S)-α-lipoic acid and of (R)- and (s)-α-lipoic acid itself, which makes it possible to produce these compounds and the intermediates with high yield and high enantiopurity.
This object is achieved by enzymatic reduction of 8-chloro-6-oxooctanoic acid alkyl esters using alcohol dehydrogenases or carbonyl reductases. This conversion results in either the (R) or (S)-8-chloro-6-hydroxyoctanoic acid alkyl ester of the formula (R)-II or (S)-II indicated in the claim.
The invention derives from the realization that the employed initial ester can be reduced in a simple manner and very effectively using known alcohol dehydrogenases or carbonyl reductases.
There are certain indications in the literature that dehydrogenases might be suitable for synthesizing chiral compounds (see, inter alia, Kragl and Kula, in. Stereoselective Biotransformations, editor R. Patel, Marcel Dekker, 2000, pages 839–866). However, the general statements in this and similar references cannot be applied to complex starting compounds. The worry for the skilled worker in this connection is ordinarily side reactions and reduced enantio-selectivity. Thus, only one example of the biocatalytic reduction of the chloroethyl ketone could be found in the literature (Mele at al., J. Org. Chem. 1991, 56, 6019). In this case, a chloroethyl aryl ketone is reduced to the chiral secondary alcohol by whole-cell biotransformation (Saccharomyces cerevisiae). The reduction proceeds with neither high chemoselectivity nor high enantioselectivity. In the reduction of chloroethyl ketones with biocatalysts which, as in the case of compounds of the formula I, have a second bulky substituent, it is not possible to predict, owing to the large spatial demands of the substituents, whether a particular biocatalyst will accept such a compound as substrate.
J. Org. Chem. 66, 8682–84 (2001) reveals that an 8-chloro-3-hydroxyoxtanoic acid alkyl ester can be obtained by reduction from the corresponding ketone with purified carbonyl reductase and whole cells. EP 0 939 132 A1 discloses an enzymatic reduction of 4-halo-3-ketobutyric acid esters. J. Org. Chem. 63, 1102–08 (1998) describes the reduction of 3-chloro-4-ketooctanoic acid ethyl esters. EP 0 487 986 A2 discloses obtaining (3S)-3-hydroxyoctanedioic acid diesters for preparing lipoic acid by reduction with baker's yeast.
Surprisingly, various alcohol dehydrogenases and carbonyl reductases show high acceptance of compounds of the formula I as substrate (analytical assay), and it has been possible to confirm this in preparative conversions.
The invention is indicated more precisely in claim 1 and further dependent claims. In the conversion of the invention, generally known cofactors are employed, such as, for example, NAD(H), NADP(H), FADH2. NAD(H) or NADP(H) is preferably used.
The configuration of the resulting 8-chloro-6-hydroxyoctanoic acid alkyl esters is determined by the enzyme employed. Thus, reduction of 8-chloro-6-oxooctanoic acid alkyl esters using alcohol dehydrogenase from Thermoanaeorubium brokii results in enantiopure (R)-8-chloro-6-hydroxyoctanoic acid alkyl esters. In the case of reduction using Lactobacillus brevis alcohol dehydrogenase, there is enantioselective formation of (S)-8-chloro-6-hydroxyoctanoic acid alkyl esters (ee>65%). Enzymes which show an activity with the compounds of the formula I as substrate are listed in the table below.
The enzymes are commercially available.
The starting compounds for preparing the intermediates, the prochiral 8-chloro-6-oxooctanoic acid alkyl esters, can be obtained in a known way (L. J. Reed et al., J. Am. Chem. Soc. 1955, 774, 416).
Y-ADH yeast alcohol dehydrogenase
HL-ADH horse liver ADH
READH Rhodococcus erythropolis ADH
CPCR Candida parapsilosis carbonyl reductase
CBADH Candida boidinii ADH
LKADH Lactobacillus kefir ADH
LEADH Lactobacillus brevis ADH
TEADH Thermoanaerobium brokii ADH
TEA triethanolamine
Tris trishydroxymethylaminomethane
Kpi mixture of monopotassium phosphate and dipotassium phosphate
DTT dithiothreitol
Cosubstrate/
Activity/
Enzyme
Cofactor
Buffer
Coenzyme
(conversion)
Standard
Y-ADH
NAD(H)
100 mM TEA,
20%
2-butanone
pH 7.0
HL-ADH
NAD(H)
100 mM TEA,
<1%
methyl
1 mM MgCl2
aceto-
pH 7.0
acetate
READH
NAD(H)
100 mM
2%
methyl
glycyl-
aceto-
glycine, pH
acetate
6.5
CBADH
NAD(H)
50 mM Kpi,
(30° C.)
60%
acetone
pH 6.5
CPCR
NAD(H)
100 mM TEA,
(HCO2Na,
60%
methyl
pH 7.8
FDH)
aceto-
acetate
LKADH
NADP(H)
50 mM Kpi,
iso-propanol
10%
aceto-
0.1 mM MgCl2,
200 mM
(36%)
phenone
pH 7.0
LBADH
NADP(H)
50 mM Kpi,
iso-propanol
6%
methyl
1 mM MgCl2,
200 mM
(>25%)
aceto-
pH 6.5
acetate
TBADH
NADP(H)
50 mM Tris,
HCO2Na,
6%
2-butanone
1 mM DTT,
FDH
(>85%)
pH 7.8
(37° C.)
For preparative conversions it proves advantageous to include a cofactor regeneration system in the enzymatic biotransformation. Cofactor regeneration systems which prove to be particularly advantageous are those which shift the equilibrium of the main reaction. Thus, for example in the case of reductions with Lactobacillus brevis alcohol dehydrogenase, a substrate-coupled co-factor regeneration in the presence of an excess of a secondary alcohol (e.g. 2-propanol) is possible and advantageous. Alternatively, enzyme-coupled cofactor regeneration systems (e.g. formate dehydrogenase (FDH)/formate) can be employed, and can be utilized for the reduction of NAD(P) to NAD(P)H. The CO2 resulting from the oxidation of the cosubstrate sodium formate escapes as gas and is thus removed from the equilibrium. Both NAD- and NADP-dependent formate dehydrogenases are described in the literature and commercially available.
The absolute configuration of the optical isomers of 8-chloro-6-hydroxyoctanoic acid alkyl esters of the formula I was determined by comparison with the signs of the specific optical rotations with literature data (Gewald et al., DE 195 33 881). In addition, the relative contents of the optical isomers of the 8-chloro-6-hydroxyoctanoic acid alkyl esters of the formula I was found by GC on columns with chiral phase with a limit of detection of <0.5%.
The present invention makes it possible to obtain the (R)- and (S)-8-chloro-6-hydroxyoctanoic acid alkyl esters of the formula I in a simple and economic manner in high chemical and optical yield (theoretically 100% chemical and optical yield) in a one-stage method.
The invention also relates to the use of the enantiopure octanoic acid alkyl esters obtained in the method of the invention for producing (R)- or (S)-α-lipoic acid in a manner know per se. In the known methods, the chlorohydroxyoctanoic acid alkyl esters are normally converted into the corresponding dichlorooctanoic acid alkyl esters. The known lipoic acid structure is then obtained in a further reaction step by introducing sulfur.
As an example of the enantioselective production of an 8-chloro-6-hydroxyoctanoic acid alkyl ester in accordance with the present invention, the following scheme shows the production of enantiopure (R)-8-chloro-6-hydroxyoctanoic acid methyl ester.
(S)-8-Chloro-6-hydroxyoctanoic acid alkyl esters are obtainable in an analogous manner by employing as biocatalyst for example Lactobacillus brevis alcohol dehydrogenase. The synthesis of (+)- and (−)-α-lipoic acids starting from (+)- and (−)-8-chloro-6-hydroxyoctanoic acid alkyl esters can be carried out in accordance with known methods. The invention is illustrated in detail by the following example.
EXAMPLE 1
100 mg (0.5 mmol) of 8-chloro-6-oxooctanoic acid methyl ester (substrate), dissolved in 50 ml of 50 mM TRIS buffer pH 7, containing 0.1 mM DTT and 0.5 mM NADP, are mixed with in each case 2 U/mg (substrate) TBADH and FDH (NADP-dependent) and stirred at 37° C. Workup by standard methods affords enantiopure (ee>99.5%) (R)-8-chloro-6-hydroxyoctanoic acid methyl ester (product).
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10493630
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viatris gmbh & co. kg
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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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435/130
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Apr 1st, 2022 05:10PM
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Apr 1st, 2022 05:10PM
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Viatris
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nasdaq:vtrs
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Viatris
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Nov 15th, 2005 12:00AM
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Jul 17th, 2001 12:00AM
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https://www.uspto.gov?id=US06965029-20051115
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Method for producing enantiomer-free 6,8 dihydroxy octanoic acid esters by means of asymmetric, catalytic hydrogenation
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The invention relates to a process for the preparation of compounds of the general formula I
in which R1 represents a C1-C20-alkyl group, a C3-C12-cycloalkyl group, a C7-C12-aralkyl group or a mono- or bi-nuclear aryl group, in which a ketone of formula II
wherein R1 is as defined above, is subjected to asymmetric hydrogenation.
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6965029
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1. Process for the preparation of compounds of the general formula I
in which R1 represents a C1-C20-alkyl group, a C3-C12-cycloalkyl group, a C7-C12-aralkyl group or a mono- or bi-nuclear aryl group, wherein a ketone of formula II
in which R1 is as defined above, is subjected to asymmetric hydrogenation.
2. Process according to claim 1, wherein the asymmetric hydrogenation is carried out in the presence of a ruthenium-diphosphine complex of formulae VI to XII:
[RuHal2D]n (L)x
VI
[RuHalAD]+Y−
VII
RuDnOOCR2OOCR3
VIII
[RuHxDn]m+Ym−
IX
[RuHal (PR42R5)D]2+Hal2−
X
[RuHHalD2]
XI
[DRu (acac)2]
XII
wherein:
acac represents acetyl acetonate,
D represents a diphosphine of the general formula XIII,
Hal represents halogen,
R2 and R3 are the same or different and represent alkyl having up to 9 carbon atoms, which is optionally substituted by halogen, or represent phenyl which is optionally substituted by alkyl having from 1 to 4 carbon atoms, or represent an α-aminoalkyl acid having up to 4 carbon atoms, or together form an alkylidene group having up to 4 carbon atoms,
R4 and R5 are the same or different and represent optionally substituted phenyl,
Y represents Cl, Br, I, ClO4, BE4 or PF6,
A represents an unsubstituted or substituted benzene ring,
L represents a neutral ligand
n and m each represent 1 or 2,
x represents 0 or 1,
wherein in formula IX n represents 1 and m represents 2 when x=0, and n represents 2 and m represents 1 when x=1
and as the optically active diphosphine ligands D are compounds of the general formula XIII
wherein:
Q represents a group bridging the two P atoms and having from 2 to 24 carbon atoms and optionally from 1 to 4 hetero atoms, the bridging being formed by at least 2 of the carbon atoms and optionally from 1 to 4 of the hetero atoms,
R6-R9 are the same or different and represent alkyl groups having from 1 to 18 carbon atoms, cycloalkyl groups having from 5 to 7 carbon atoms or aryl groups having from 6 to 12 carbon atoms.
3. Process according to claim 1, wherein the asymmetric hydrogenation is carried out at temperatures of from approximately 10° C. to approximately 140° C. and under a pressure of approximately from 1 to 100 bar.
4. Process according to claim 1, wherein the asymmetric hydrogenation is carried out with reaction times of from 2 to 48 hours with a molar ratio between ruthenium in complexes VI to XII and the compounds II to be hydrogenated are approximately 0.001 to approximately 5 mol %.
5. 8-Hydroxy-6-oxo-octanoic acid esters of the general formula II
in which R1 represents a C1-C20-alkyl group, a C3-C12-cycloalkyl group, a C7-C12-aralkyl group or mono- or bi-nuclear aryl group.
6. 7,8-Epoxy-6-oxo-octanoic acid esters of the general formula III
in which R1 represents a C1-C20-alkyl group, a C3-C12-cycloalky group, a C7-C12-aralkyl group or a mono- or bi-nuclear aryl group.
7. Process for the preparation of (R)-(+)-α-lipoic acid of formula (R)-(+)-IV
wherein the compounds II according to claim 1 are subjected to asymmetric hydrogenation to form the compounds (S)-I, and said compounds,
a) are converted, in organic solution, with a sulfonic acid chloride and a tertiary nitrogen base, into the bissulfonic acid ester of (S)-I,
b) the compound obtained in step a) is reacted, in a polar solvent, with sulfur and an alkali metal sulfide to form the (R)-(+)-α-lipoic acid ester, and
c) that ester is, optionally, converted into (R)-(+)-α-lipoic acid.
8. Process for the preparation of (S)-(−)-α-lipoic acid of formula (S)-(−)-IV
wherein the compounds II according to claim 1 are subjected to asymmetric hydrogenation to form the compounds (R)-I, and said compounds,
a) are converted, in organic solution, with a sulfonic acid chloride and a tertiary nitrogen base, into the bissulfonic acid ester of (R)-I,
b) the compound obtained in step a) is reacted, in a polar solvent, with sulfur and an alkali metal sulfide to form the (S)-(−)-α-lipoic acid ester, and
c) that ester is, optionally, converted into (S)-(−)-α-lipoic acid.
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TECHNICAL FIELD
The present invention relates to a novel process for the preparation of enantiomerically pure 6,8-dihydroxyoctanoic acid esters of the general formula I, wherein R1 represents a C1-C20-alkyl group, a C3-C12-cycloalkyl group, a C7-C12-aralkyl group or a mono- or bi-nuclear aryl group.
The invention relates also to novel compounds of formulae II and III, which are used as starting compounds or intermediates in the synthesis of the compounds (R)-I and (S)-I.
PRIOR ART
The compounds (R)-I and (S)-I are known. They are both used predominantly as intermediates for the synthesis of enantiomerically pure α-lipoic acid of formula IV and its derivatives. α-Lipoic acid is 1,2-dithiolane-3-pentanoic acid (thioctic acid).
The (R)-enantiomer of α-lipoic acid (R)-(+)-IV is a natural substance which occurs in small concentrations in virtually all animal and vegetable cells. α-Lipoic acid is of crucial importance as a coenzyme in the oxidative decarboxylation of α-ketocarboxylic acids (e.g. pyruvic acid). α-Lipoic acid is pharmacologically active and has antiphlogistic and antinociceptive (analgesic) properties, as well as cytoprotective properties. An important medicinal indication of racemic α-lipoic acid is the treatment of diabetic polyneuropathy. According to more recent results (A. Baur et al., Klin. Wochenschr. 1991, 69, 722; J. P. Merin et al., FEBS Lett. 1996, 394, 9) α-lipoic acid may possibly gain importance in the control of diseases caused by HIV-1 and HTLV IIIB viruses.
In the case of the pure optical isomers of α-lipoic acid (R- and S-form, i.e (R)-α-lipoic acid and (S)-α-lipoic acid), in contrast to the racemate, the (R)-enantiomer, has predominantly antiphlogistic activity and the (S)-enantiomer has predominantly antinociceptive activity (EP 0427247, 08.11.90). The two enantiomers have also been found to have different pharmacokinetic properties (R. Hermann et al., Eur. J. Pharmaceut. Sci. 1996, 4, 167; G. Raddatz and H. Bisswanger, J. Biotechnol. 1997, 58, 89; T. M. Hagen et al., FASEB J. 1999, 13, 411). The synthesis of the pure enantiomers is therefore of great importance.
Known processes for preparing enantiomerically pure (α-lipoic acids include racemate cleavage of α-lipoic acid or its precursors, asymmetric syntheses using chiral auxiliaries, chiral pool syntheses using naturally occurring optically active starting compounds, and also microbial syntheses (overview article: J. S. Yadav et al., J. Sci. Ind. Res. 1990, 49, 400; and also: E. Walton et al., J. Am. Chem. Soc. 1955, 77, 5144; D. S. Acker and W. J. Wayne, J. Am. Chem. Soc. 1957, 79, 6483; L. G. Chebotareva and A. M. Yurkevich, Khim.-Farm. Zh. 1980, 14, 92; A. S. Gopalan et al., Tetrahedron Lett. 1989, 5705; A. G. Tolstikov et al., Bioorg. Khim. 1990, 16, 1670; L. Dasaradhi et al., J. Chem. Soc., Chem. Commun. 1990, 729; A. S. Gopalan et al., J. Chem. Perkin Trans. 1 1990, 1897; EP 0487986 A2, 14.11.91; R. Bloch et al., Tetrahedron 1992, 48, 453; B. Adger et al., J. Chem. Soc., Chem. Commun. 1995, 1563; DE-OS 19533881.1, 13.09.95; DE-OS 19533882.1, 13.09.95; Y. R. Santosh Laxmi and D. S. Iyengar, Synthesis, 1996, 594; M. Bezbarua et al., 1996, 1289; N. W. Fadnavis et al., Tetrahedron: Asymmetry 1997, 8, 337; N. W. Fadnavis et al., Tetrahedron: Asymmetry 1998, 9, 4109; S. Lee and Y. Ahn, J. Korean Chem. Soc. 1999, 43, 128).
Of those processes, racemate cleavage via the formation of diastereoisomeric salts of α-lipoic acid with optically active α-methylbenzylamine (DE-OS 4137773.7, 16.11.91 and DE-OS 4427079.8, 30.07.94) represents the most economical variant hitherto. However, because the racemate separation does not take place until the last stage of the synthesis sequence, high yields cannot be achieved.
The known chemocatalytic asymmetric processes for the preparation of enantiomerically pure α-lipoic acid (DE-OS 3629116.1, 27.08.86; DE-OS 19709069.1, 6.03.97); R. Zimmer et al., Tetrahedron: Asymmetry 2000, 11, 879) are uneconomical because of the high costs of the starting compounds.
The object of the invention is, therefore, to make available, as desired, the 6,8-dihydroxyoctanoic acid esters (R)-I and (S)-I leading to the two enantiomers of α-lipoic acid, in a high chemical and optical space-time yield using inexpensive starting materials.
DESCRIPTION OF THE INVENTION
According to the invention, that is achieved by asymmetric chemocatalytic hydrogenation of 8-hydroxy-6-oxo-octanoic acid esters of formula II, in which R1 represents a C1-C20-alkyl group, a C3-C12-cycloalkyl group, a C7-C12-aralkyl group or a mono- or bi-nuclear aryl group, in the presence of complexes consisting of ruthenium and optically active phosphines.
The compounds II are novel and can be obtained by selective hydrogenation of the 7,8-epoxy-6-oxo-octanoic acid esters III, preferably in the presence of platinum, palladium or nickel catalysts.
The preparation of the 7,8-epoxy-6-oxo-octanoic acid esters III, which are also novel, is possible in high yields by epoxidation of 6-oxo-7-octenoic acid esters of formula V, preferably by means of sodium percarbonate in methanol. The compounds V are known and are obtainable by elimination of hydrogen chloride from 8-chloro-6-oxo-octanoic acid esters, which are used as inexpensive starting compounds for the commercial synthesis of racemic α-lipoic acid (M. W. Bullock et al., J. Am. Chem. Soc. 1954, 76, 1828).
Alternatively, racemic 6,8-dihydroxyoctanoic acid esters of formula I can be converted into compounds of formula II by regioselective oxidation of the secondary hydroxy group, preferably by means of sodium hypochlorite in acetic acid. The preparation of racemic 6,8-dihydroxyoctanoic acid esters of formula I is known and can be carried out, inter alia, starting from butadiene and acetic acid (J. Tsuji et al., J. Org. Chem. 1978, 43, 3606).
Ruthenium-diphosphine complexes are of particular interest as catalysts for the asymmetric hydrogenation of the compounds II. As typical but non-limiting examples there may be mentioned the ruthenium complexes of the following formulae VI to XII:
[RuHa12D]n(L)x
VI
[RuHa1AD]+Y−
VII
RuDnOOCR2OOCR3
VIII
[RuHxDn]m+Ym−
IX
[RuHa1 (PR42R5)D]2+Hal2−
X
[RuHHalD2]
XI
[DRu (acac)2]
XII
wherein:
acac represents acetyl acetonate,
D represents a diphosphine of the general formula XIII,
Hal represents halogen, especially iodine, chlorine or bromine,
R2 and R3 are the same or different and represent alkyl having up to 9 carbon atoms, preferably up to 4 carbon atoms, which is optionally substituted by halogen, especially fluorine, chlorine or bromine, or represent phenyl which is optionally substituted by alkyl having from 1 to 4 carbon atoms, or represent an α-aminoalkyl acid having preferably up to 4 carbon atoms, or together form an alkylidene group having up to 4 carbon atoms,
R4 and R5 are the same or different and represent optionally substituted phenyl, preferably substituted by alkyl having from 1 to 4 carbon atoms or by halogen,
Y represents Cl, Br, I, ClO4, BF4 or PF6,
A represents an unsubstituted or substituted benzene ring, such as p-cymene,
L represents a neutral ligand such as acetone, a tertiary amine or dimethylformamide,
n and m each represent 1 or 2,
x represents 0 or 1,
wherein in formula IX n represents 1 and m represents 2 when x=0, and n represents 2 and m represents 1 when x=1.
The complexes of formulae VI to XII can be prepared by methods known per se (VI and XI: EP 174057 and J. P. Genet et al., Tetrahedron Asymmetry 1994, 5, 675; VII: EP 366390; VII: EP 245959 and EP 272787; IX: EP 256634; X: EP 470756; XII: P. Stahly et al., Organometallics 1993, 1467).
As optically active diphosphine ligands there are used compounds of the general formula XIII:
wherein:
Q represents a group bridging the two P atoms and having from 2 to 24 carbon atoms and optionally from 1 to 4 hetero atoms, preferably O, S, N and Si, the bridging being formed by at least 2 of the carbon atoms and optionally from 1 to 4 of the hetero atoms,
R6-R9 are the same or different and represent alkyl groups having from 1 to 18 carbon atoms, cycloalkyl groups having from 5 to 7 carbon atoms or aryl groups having from 6 to 12 carbon atoms.
The following ligands may be mentioned as examples of particularly preferred chiral diphosphines used in enantiomerically pure form:
BINAP: R1 = Phenyl
Tolyl-BINAP: R1 p-Tolyl
BIMOP: R1 = Ph, R2 = R4 = Me, R3 = OMe
FUPMOP: R1 = Ph, R2 = R4 = CF3, R3 = OMe
BIFUP: R1 = Ph, R2 = R4 CF3, R3 = H
BIPHEMP: R1 = Ph, R2 = R3 = H, R4 = Me
MeO-BIPHEP: R1 = Ph, R2 = R3 = H, R4 = OMe
BICHEP: R1 = c-C6H11, R2 = R3 = H, R4 = Me
Me-DuPHOS: R1 = Me
Et-DuPHOS: R1 = Et
BIBFUP
Me-BPE: R1 = Me
iPr-BPE: R1 = iPr
XIV
CHIRAPHOS
The ligands listed above as racemic structures for the sake of simplicity are compounds that are known in their enantiomerically pure forms (BINAP: R. Noyori et al., J. Am. Chem. Soc. 1980, 102, 7932; BIMOP, FUPMOP, BIFUP: M. Murata et al., Synlett 1991, 827; BIBHEMP: R. Schmid et al., Helv. Chim. Acta 1988, 71, 697; MeO-BIPHEP: R. Schmid et al., Helv. Chim. Acta 1991, 74, 370; BICHEP: A. Miyashita et al., Chem. Lett. 1989, 1849; DuPHOS: M. Burk et al., Organometallics 1990, 9, 2653; BPE: M. Burk et al., J. Am. Chem. Soc. 1995, 117, 4423; BIBFUP: EP 643065; CHIRAPHOS: B. Bosnich et al., J. Am. Chem. Soc. 1977, 99, 6262; XIV: WO 96/01831).
The asymmetric hydrogenation of the compounds of formula II in the presence of the above-described optically active ruthenium-diphosphine complexes of formulae VI to XII can be carried out in suitable organic solvents that are inert under the reaction conditions. Special mention may be made as such solvents of alcohols, such as methanol or ethanol, chlorinated hydrocarbons, such as methylene chloride or dichloroethane, cyclic ethers, such as tetrahydrofuran or dioxane, esters, such as, for example, ethyl acetate, aromatic hydrocarbons, such as benzene or toluene, or also mixtures thereof and the like. In order to suppress possible ketal formation when working in alcohols as solvent, up to 10 vol. % water can be added. The substrate concentrations are preferably from 5 to 50 vol. %, especially from 20 to 40 vol. %.
The reactions can preferably be carried out at temperatures of approximately from 10° C. to 140° C., especially approximately from 20° C. to 70° C., and under a hydrogen pressure of approximately from 1 to 100 bar, especially from 4 to 50 bar. The reaction times are generally from 2 to 48 hours, mostly from 6 to 24 hours. The molar ratio between ruthenium in the complexes VI to XII and the compounds II to be hydrogenated is advantageously from approximately 0.001 to approximately 5 mol %, preferably from approximately 0.005 to approximately 0.2 mol %.
In the reaction, the desired enantiomer of formula I can be obtained by choosing the optically active diphosphine ligand of formula XIII having the appropriate configuration. Accordingly, the use of (R)-(+)-BINAP, for example, yields products of formula (R)-I, and the use of (S)-(−)-BINAP yields products of formula (S)-I.
The compounds (S)-I and (R)-I are used to prepare the enantiomerically pure α-lipoic acids of formula IV by, in known manner (J. D. Gopalan et al., Tetrahedron Lett. 1985, 2535):
a) converting those compounds, in organic solution, with a sulfonic acid chloride and a tertiary nitrogen base, into the bissulfonic acid ester of I,
b) reacting that compound, in a polar solvent, with sulfur and an alkali metal sulfide to form the α-lipoic acid ester, and
c) if desired, converting that ester into the respective pure enantiomer of α-lipoic acid. In that process, the compounds (R)-I yield (S)-(−)-α-lipoic acid and the compounds (S)-I yield (R)-(+)-α-lipoic acid.
The compounds (R)-I and (S)-I and (R)-(+)-IV and (S)-(−)-IV prepared by the process according to the invention generally have a high enantiomeric excess, corresponding to an optical yield of from 90 to 99%.
The enantiomeric ratios are measured directly by chiral HPLC or GC on optically active columns.
By means of the present invention it is possible to make available, in an economical manner and in high chemical and optical yields, the enantiomerically pure 6,8-dihydroxy-octanoic acid esters of the general formula I (R1=C1-C20-alkyl, C3-C12-cycloalkyl, C7-C12-aralkyl or mono- or bi-nuclear aryl) as intermediates for the preparation of the enantiomerically pure α-lipoic acids of formula IV.
The Examples which follow illustrate but do not limit the invention.
EXAMPLE 1
43.5 mg (0.087 mmol) of [RuCl2(C6H6)]2, 113.7 mg (0.183 mmol) of (R)-BINAP and 3 ml of dimethylformamide were placed into a 20 ml Schlenk flask under Argon. The reddish-brown suspension was heated for 10 minutes at 100° C. The solution, which was then clear, was cooled and concentrated in vacuo (1 to 0.1 mmHg) at 50° C. with vigorous stirring over a period of 1 hour. The orange-brown solid that remained was taken up in 1 ml of tetrahydrofuran and was used in that form as a Ru-(R)-BINAP catalyst in the asymmetric hydrogenations.
EXAMPLE 2
43.5 mg (0.087 mmol) of [RuCl2(C6H6)]2, 113.7 mg (0.183 mmol) of (S)-BINAP and 3 ml of dimethylformamide were placed into a 20 ml Schlenk flask under Argon. The reddish-brown suspension was heated for 10 minutes at 100° C. The solution, which was then clear, was cooled and concentrated in vacuo (1 to 0.1 mmHg) at 50° C. with vigorous stirring over a period of 1 hour. The orange-brown solid that remained was taken up in 1 ml of tetrahydrofuran and was used in that form as a Ru-(S)-BINAP catalyst in the asymmetric hydrogenations.
EXAMPLE 3
A 100 ml autoclave was charged under argon with 3.8 g (20 mmol) of 8-hydroxy-6-oxo-octanoic acid methyl ester, with the Ru-(R)-BINAP catalyst solution prepared under Example 1, and with 20 ml of oxygen-free methanol. The hydrogenation was carried out for 20 hours at 60° C., at a constant pressure of 40 bar pure H2 and with intensive stirring. When the reaction was complete, the solvent was distilled off using a rotary evaporator. Purification of the residue by column chromatography (silica gel, ethyl acetate/n-hexane) yielded 3.2 g (85%) of (R)-6,8-dihydroxyoctanoic acid methyl ester having an enantiomeric excess of 96% (chiral GC).
EXAMPLE 4
A 100 ml autoclave was charged under argon with 3.8 g (20 mmol) of 8-hydroxy-6-oxo-octanoic acid methyl ester, with the Ru-(S)-BINAP catalyst solution prepared under Example 2, and with 20 ml of oxygen-free methanol. The hydrogenation was carried out for 20 hours at 60° C., at a constant pressure of 40 bar pure H2 and with intensive stirring. When the reaction was complete, the solvent was distilled off using a rotary evaporator. Purification of the residue by column chromatography (silica gel, ethyl acetate/n-hexane) yielded 3.1 g (82%) of (S)-6,8-dihydroxyoctanoic acid methyl ester having an enantiomeric excess of 96% (chiral GC).
EXAMPLE 5
100 ml of aqueous sodium hypochlorite solution (10-13% active chlorine) were added dropwise at room temperature, over a period of 45 minutes, to 16.6 g (87 mmol) of 6,8-dihydroxyoctanoic acid methyl ester in 200 ml of glacial acetic acid. After stirring for a further 3 hours at room temperature, 180 ml of isopropanol were added in order to destroy excess sodium hypochlorite, and stirring was carried out for 10 minutes. The reaction mixture was then added to 1200 ml of water and extracted several times with methylene chloride. The combined organic phases were washed with cold-saturated sodium hydrogen carbonate solution. After drying over sodium sulfate, the solvent was distilled off using a rotary evaporator. 13.0 g (80%) of 8-hydroxy-6-oxo-octanoic acid methyl ester were obtained.
13C NMR (CDCl3): δ=23.4, 25.3, 34.0, 42.8, 45.2, 51.7, 57.9, 174.1, 211.0
EXAMPLE 6
A 100 ml autoclave was charged under argon with 9.4 g (50 mmol) of 7,8-epoxy-6-oxo-octanoic acid methyl ester, with 0.4 g of platinum(IV) oxide catalyst, and with 50 ml of ethyl acetate. The hydrogenation was carried out for 16 hours at 20° C., at a constant pressure of 50 bar pure H2 and with intensive stirring. When the reaction was complete, the catalyst was filtered off and the solvent was distilled off using a rotary evaporator. Purification of the residue by column chromatography (silica gel, ethyl acetate/n-hexane) yielded 6.3 g (67%) of 8-hydroxy-6-oxo-octanoic acid methyl ester.
EXAMPLE 7
39.1 g (250 mmol) of sodium percarbonate were added in four portions at room temperature, over a period of 2 hours, with stirring, to 13.9 g (82 mmol) of 6-oxo-7-octenoic acid methyl ester in 210 ml of methanol. After stirring for a further one hour at room temperature, the reaction mixture was added to 1000 ml of water and extracted several times with methylene chloride. The combined organic phases were washed with water. After drying over sodium sulfate, the solvent was distilled off using a rotary evaporator. 13.5 g (88%) of 7,8-epoxy-6-oxo-octanoic acid methyl ester were obtained.
13C NMR (CDCl3): δ=21.8, 23.2, 32.4, 41.5, 50.1, 57.4, 66.5, 172.5, 207.4
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10333812
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viatris gmbh & co. kg
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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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546/39
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Apr 1st, 2022 05:10PM
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Apr 1st, 2022 05:10PM
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Viatris
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nasdaq:vtrs
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Viatris
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Apr 18th, 2006 12:00AM
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Jun 18th, 2004 12:00AM
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https://www.uspto.gov?id=US07030251-20060418
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Modifications of the trometamol salt of R-thioctic acid as well as a process for their production
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The invention relates to new modifications of the trometamol salt of R-thioctic acid of the formula I,
processes for their production, pharmaceutical preparations containing these modifications, and their medical application.
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7030251
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1. Modification A of the compound I
characterised by the X-ray diffraction pattern in which reflections not coinciding with the reflections of the other modifications are observed inter alia at 14.87°2θ20(5.96 Å), 19.99°2θ(4.44 Å), 20.88°2θ(4.25 Å), 22.78°2θ(3.90 Å), 24.53°2θ(3.63 Å), 25.66°2θ(3.47 Å), 30.05°2θ(2.97 Å) and at 37.29°2θ(2.41 Å).
2. Modification B of the compound I characterised by the X-ray diffraction pattern in which reflections not coinciding with the reflections of the other modification are observed inter alia at 13.80°2θ(6.41 Å), 15.22°2θ(5.82 Å), 17.50°2θ6(5.06 Å) and at 23.48°2θ(3.79 Å).
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CROSS-REFERENCE TO RELATED APPLICATION
This application is a divisional of application Ser. No. 10/207,201, filed Jul. 30, 2002, now U.S. Pat. No. 6,844,449.
The present invention relates to new modifications of the trometamol salt of R-thioctic acid of the formula I,
processes for their production, pharmaceutical preparations containing these modifications, and their medical application.
This compound is effective for example as an anti-inflammatory and cytoprotective agent (EP 427247) and is used to treat diabetes mellitus and insulin resistance (DE 4.343.593) as well as in glucose metabolic disorders of the central nervous system (DE 4.343.592) and as an appetite suppressant (DE 19.818.563), and may therefore be employed in pharmaceutical preparations (EP 702953).
The requirements that an active constituent must meet as regards the relevant physicochemical properties for galenical processibility and bioavailability are determined both by the nature and also by the production technology of the respective pharmaceutical preparation.
Particularly in the case of high dosage active constituents, among which is included the trometamol salt of R-thioctic acid, the physicochemical properties significantly influence the galenical processibility and bioavailability.
It is therefore advantageous with such an active constituent to have available, for various pharmaceutical preparations and production technologies, various modifications and mixtures thereof that exhibit different physicochemical properties.
Modifications of the compound I have not been known up to now.
The object of the present invention is accordingly to provide the compound I in various modifications as well as mixtures thereof, corresponding to the pharmaceutical requirements.
The two modifications, termed A and B, have different physicochemical properties. The in each case characteristic X-ray powder diffraction patterns are used to identify these two modifications of the compound of the formula I. The modifications differ furthermore in their DSC (differential scanning calorimetry) curves, by the in each case typical crystal forms, the different solubilities and/or dissolution rates, as well as by the different flow properties.
The X-ray diffraction patterns shown in FIGS. 1–6 were recorded with a powder diffractometer using CuKα radiation.
The modification A is characterised by:
The X-ray diffraction pattern (see FIGS. 1–3 and FIG. 6), in which connection there are observed reflections inter alia at
14.87°2θ(5.96 Å), 19.99°2θ(4.44 Å), 20.88°2θ(4.25 Å), 22.78°2θ(3.90 Å), 24.53°2θ(3.63 Å), 25.66°2θ(3.47 Å), 30.05°2θ(2.97 Å) and at 37.29°2θ(2.41 Å)
that do not coincide with the reflections of the other modification.
The melting point in the range from about 117.1° to 118.4° C.
The modification A occurs predominantly in the form of small platelets.
The modification B is characterised by:
The X-ray diffraction pattern (see FIGS. 1, 2 and 4 as well as FIG. 6), in which connection there are observed reflections inter alia at
13.80°2θ(6.41 Å), 15.22°2θ(5.82 Å), 17.50°2θ(5.06 Å), and at 23.48°2θ(3.79 Å)
that do not coincide with the reflections of the other modification.
The melting point in the range from about 115.2° to 116.8° C.
The modification B occurs predominantly in the form of aggregates.
The X-ray diffraction patterns of the modification mixtures A/B are characterised by overlapping of the reflections from A and B (mixture A/B=ca. 1:1, see FIGS. 1, 2 and 5, 6).
The solubility and/or dissolution rate of the modification A in water and organic solvents, such as for example lower alcohols, octanol and acetone, as well as their mixtures with water, is raised compared to modification B.
The angle of repose α of the modifications as a measure of the flowability and pourability is likewise different:
Angle of Repose α1)
Modification A
46°
Modification B
32°
Modification mixture A/B = 1:1
34°
1)Determined according to R. Voigt, Lehrbuch der pharmazeutischen Technologie, 3rd Edition 1979, p. 165
It is generally known that R-thioctic acid readily polymerises and has a tendency to undergo such reactions, particularly in polar media.
It is therefore surprising that in the reaction of R-thioctic acid with trometamol, polymer-free products may be obtained if the trometamol is metered into the solution of R-thioctic acid in polar solvents, such as for example lower alcohols, optionally under the addition of water, and the suspension obtained is warmed in order to effect dissolution.
The term “lower alcohols” is understood in this connection to denote straight-chain or branched alcohols with 1 to 6 C. atoms.
The crystallisation then takes place under cooling. Further product is obtained from the mother liquor by concentrating the solution by evaporation under gentle conditions and cooling.
Surprisingly the modifications A and B of the compound I as well as their mixtures of arbitrary composition can be produced by salt formation of R-thioctic acid with trometamol in suitable polar solvents such as for example lower alcohols, as well as by modification transformation under special reaction conditions.
Accordingly, either pure modifications of the compound I or alternatively mixtures thereof of varying composition may be prepared for the production of various pharmaceutical preparations.
The preparation of the modifications A and B and their mixtures by salt formation of R-thioctic acid with trometamol depends on the purity of the R-thioctic acid that is used (content of trace impurities resulting from the synthesis).
Thus, the modification A is obtained with R-thioctic acid that has been obtained by racemate resolution according to DE 4.137.773 (hereinafter denoted as synthesis pathway a). On the other hand with R-thioctic acid in the preparation of which sulfur is introduced at the end of the synthesis (hereinafter denoted as synthesis pathway b; for example DE 4.037.440, DE 19.533.881, DE 19.533.882, DE 19.709.069), the modification B is obtained as main product, together with a minor amount of A. By means of one or more additional purification steps carried out on the R-thioctic acid obtained by synthesis pathway b (e.g. recrystallisation from inert solvents such as cyclohexane, cyclohexane/ethyl acetate (in particular 19:1), n-heptane/toluene, n-hexane/toluene, optionally under the addition of water and/or dilute mineral acid as well as dissolution and crystallisation from dilute alkali solution/dilute mineral acid under simultaneous extraction, for example with cyclohexane/ethyl acetate, trace impurities resulting from the synthesis can be successively removed so that in the salt formation either a modification A/B or the modification A are formed as main products. On the other hand by adding nucleophilic compounds, such as for example sodium sulfite or 6,8-dimercaptooctanoic acid, in the salt formation with R-thioctic acid prepared by the synthesis pathway a the modification B is obtained as the main product.
The modifications may also be prepared by modification transformation, in which a complete or partial transformation of A after B as well as of B after A may take place.
In this connection it is possible to use the pure modifications A and B as well as their mixtures. When using mixtures the transformation preferably proceeds in the direction of the formation of a pure modification.
The following methods may be employed:
Recrystallisation from lower alcohols, optionally under the addition of water
Prolonged heating in lower alcohols, optionally under the addition of water, at temperatures up to the boiling point, followed by cooling crystallisation
Concentration by evaporation of solutions in lower alcohols, optionally under the addition of water, by distilling off the solvent under normal pressure or in vacuo.
Reprecipitation from solvent mixtures.
Conversion of the salt I suspended in solvents.
Thermal phase conversion below the melting point or by melting.
Preparation of Modification A
Recrystallisation of modification B or A/B mixtures from lower alcohols.
Distilling off the solvent in vacuo from solutions of the modification B or A/B mixtures in lower alcohols.
Suspension of modification B or of A/B mixtures in lower alcohols, optionally under the addition of water, at temperatures of about 0° to 60° C., preferably at about 20° to 40° C., and stirring times of in general 1 to 24 hours, in particular about 2 to 15 hours.
Reprecipitation by addition of hydrocarbons to the solution of the modification A in lower alcohols.
Preparation of Modification B
Recrystallisation of modification A or A/B mixtures from lower alcohols, optionally under the addition of water.
Distilling off the solvent from solutions of the modification A in lower alcohols.
Heating a melt of the modification A preferably for about 10 to 40 minutes at ca. 115°–130° C., in particular for 15 to 25 minutes at about 115°–120° C., and crystallisation by cooling.
Recrystallisation of modification A from lower alcohols, optionally under the addition of water, with the addition of nucleophilic compounds such as for example sodium sulfite or 6,8-dimercaptooctanoic acid.
Preparation of Mixtures of Modifications A/B
Heating a solution of the modification A in lower alcohols at the reflux temperature generally for ca. 2 to 12 hours, preferably for about 4 to 8 hours, followed by cooling crystallisation.
Distilling off the solvent from solutions of the modification A in lower alcohols, optionally under the addition of water.
Brief melting of the modification A and crystallisation under cooling.
Reprecipitation by addition of acetone to the solution of the modification A in water or dimethylformamide.
Recrystallisation of modification A from lower alcohols, optionally under the addition of water, as well as addition of nucleophilic compounds such as for example sodium sulfite or 6,8-dimercaptooctanoic acid.
Recrystallisation of modification A from dipolar-aprotic solvents such as for example N,N-dimethylacetamide, ethylene glycol dimethyl ether, 1,2-dichloroethane, methyl ethyl ketone, and dimethyl carbonate.
Recrystallisation of modification A or B from lower alcohols, optionally under the addition of water.
The modifications A and B as well as their mixtures may be processed in a conventional way with suitable carriers and/or auxiliary substances into pharmaceutical preparations. Preferred application forms are tablets and capsules.
The modifications are for example valuable agents for treating insulin resistance, diabetes mellitus, and glucose metabolic disturbances of the central nervous system. The production processes for the modifications A and B as well as their mixtures will be described in more detail hereinafter with the aid of examples.
EXAMPLES
The modifications of the compound I were, after suction filtration, washed with the relevant cooled solvent and dried for 2 hours at 50° C. unless otherwise stated.
Formation of Modifications in the Preparation of the Trometamol Salt of R-Thioctic Acid
Example 1
12.1 g (0.1 mole) of trometamol were added to a solution of 41.2 g (0.2 mole) of R-thioctic acid (produced according to process a) in 220 ml of ethanol (96%) and heated while stirring to 55° C.
1 g of Diacel (filter aid) was added to the solution, heated for 20 minutes at 55°–57° C., suction filtered until clear, slowly cooled and stirred at −5° C. to −10° C. for 2 hours.
Yield: 58.0 g (88.6% of theory) of I, modification A.
A further 1.7 g (2.6% of theory) of I, modification A, were obtained by concentrating by evaporation the mother liquor to ca. ⅕ of its original volume.
Example 2
41.2 g (0.2 mole) of R-thioctic acid (produced according to process a) were dissolved in 600 ml of ethanol (anhydrous). 24.2 g (0.2 mole) of trometamol were added while stirring, and the mixture was heated to 50°–55° C. to dissolve the trometamol and after addition of 2 g of Diacel was stirred for ca. 10 minutes at 50°–55° C. and suction filtered until clear. The solution was then slowly cooled (over 3–4 hours) at a roughly uniform cooling rate to −5° C. and stirred for a further 4-5 hours at −5° to −10° C.
Yield: 55.5 g (84.9% of theory) of I, modification A.
A further 4.1 g (6.3% of theory) of I, modification A, were obtained by concentrating by evaporation the mother liquor to ca. 20%.
Example 3
41.2 g (0.2 mole) of R-thioctic acid (produced according to process a) were dissolved in 230 ml of ethanol (anhydrous). 24.2 g (0.2 mole) of trometamol were added and the mixture was stirred at 55°–60° C. until all the trometamol had dissolved. After suction filtration the resultant clear solution was slowly cooled to 0° to 5° C., stirred for 2 to 4 hours in this temperature range, suction filtered, washed with cold ethanol and dried.
Yield: 61.0 g (93.1% of theory) of I, modification A.
A further 2.4 g (3.7% of theory) of I, modification A, were obtained by concentrating by evaporation the mother liquor in vacuo to ca. 20%.
Example 4
41.2 g (0.2 mole) of R-thioctic acid (produced according to process b followed by recrystallisation from cyclohexane/ethyl acetate/water corresponding to Example 31) were dissolved in 600 ml of ethanol (anhydrous). 24.2 g (0.2 mole) of trometamol were then added and the solution was heated to 50°-55° C. while stirring. 2 g of Diacel were added to the solution, which was stirred for 20 minutes, suction filtered until clear, and slowly cooled. The solution was seeded at 30° C., and stirred for 4 hours in the range from −5° to −10° C.
Yield: 56.1 g (85.7% of theory) of I, modification A.
A further 6.7 g (10.2% of theory) of I, modification A, were obtained by concentrating by evaporation the mother liquor to ca. ⅕ of the original volume.
Example 5
54.9 g (83.9% of theory) of I, modification mixture A/B (ca. 1:1) were obtained, similarly to Example 4, as a first crystallisate from R-thioctic acid (produced according to process b followed by recrystallisation once from cyclohexane). 6.8 g (10.4% of theory) of I, modification A, were then obtained by concentration by evaporation of the mother liquor.
Example 6
25.8 g (0.125 mole) of R-thioctic acid (produced according to process b) were dissolved in 375 ml of ethanol (anhydrous). 15.13 g (0.125 mole) of trometamol were then added and the mixture was heated at 50°–55° C. while stirring until the trometamol had dissolved. After addition of 1.25 g of Diacel and suction filtration of the solution until clear, the latter was slowly cooled, seeded at 30° C., and cooled for a further 4 hours at −5° to −12° C.
Yield: 28.1 g (68.6% of theory) of I, modification B.
9.3 g (22.6% of theory) of I, modification A, were obtained by concentration by evaporation of the mother liquor to 70 ml and cooling.
Example 7
41.2 g (0.2 mole) of R-thioctic acid (produced according to process b) were dissolved in 250 ml of ethanol (anhydrous). 24.2 g (0.2 mole) of trometamol were then added and the solution was heated at 55°–57° C. while stirring until the trometamol had dissolved.
After addition of 1.25 g of Diacel and suction filtration of the solution until clear, the latter was slowly cooled (ca. 1–2 hours) and stirred at −5° to −10° C. for 2 hours.
Yield: 55.0 g (84.1% of theory) of I, modification B.
5.7 g (8.7% of theory) of I, modification A, were obtained by concentration by evaporation of the mother liquor to 70 ml and cooling.
Example 8
41.2 g (0.2 mole) of R-thioctic acid (produced according to process b) were dissolved in 220 ml of ethanol (anhydrous). 24.2 g (0.2 mole) of trometamol were then added and the solution was heated to 57° C.
2 g of Diacel were added to the solution, which became clear after 10 minutes, and the latter was stirred for 20 minutes at 55°–57° C., suction filtered until clear, and slowly cooled. The solution was stirred for 2 hours at −5° to −10° C.
Yield: 57.8 g (88.4% of theory) of I, modification B.
3.7 g (5.7% of theory) of I, modification A, were obtained by concentration by evaporation of the mother liquor to ca. 20% followed by cooling.
Example 9
20.6 g (0.1 mole) of R-thioctic acid (produced according to process a) were dissolved in 300 ml of ethanol (anhydrous). Following the addition of 12.1 g (0.1 mole) of trometamol and 0.5 g of 6,8-dimercaptooctanoic acid the mixture was heated at 55° C. until the trometamol had dissolved. After addition of 1 g of Diacel the solution was stirred for 20 minutes at 53°–55° C., suction filtered until clear, and then slowly cooled. The solution was then stirred for 2 hours at −8° to −12° C.
1.9 g (5.8% of theory) were recovered from the flask wall (modification mixture B>A).
20.2 g (61.8% of theory) of I, modification B, were obtained by concentrating by evaporation the mother liquor to half the original volume and cooling overnight at −5° to −10° C.
1.9 g (5.8% of theory) of I, modification A, were obtained by further concentration by evaporation to ca. half the original volume followed by cooling.
Example 10
20.6 g (0.1 mole) of R-thioctic acid (produced according to process a) were dissolved in 110 ml of ethanol (96%). 12.1 g (0.1 mole) of trometamol as well as 2 g of sodium sulfite were then added and the whole was heated to 55° C. After addition of 1 g of Diacel the solution was stirred for 20 minutes at 53°–55° C., suction filtered until clear, and slowly cooled. The solution was then stirred for 2 hours at −5° to −10° C.
8.1 g (yield 24.8% of theory) of I, modification A, were obtained.
The mother liquor was concentrated by evaporation to about half the original volume and cooled overnight at −5° to −10° C.
19.1 g (yield 58.4% of theory) of I, modification B, were obtained.
Production of Modifications by Transformation
Example 11
10 g of I, modification B, were dissolved in 85 ml of ethanol (anhydrous) at 50°–55° C. The solution was slowly cooled to −5° to −10° C. while stirring, and was then seeded with I, modification A, at 30° C.
After stirring (2 hours) at −5° to −10° C. and standing overnight in a deep-freeze cabinet, 5.4 g (54% of theory) of I, modification B, were recovered.
4.0 g (40% of theory) of I, modification A, were obtained by concentration by evaporation of the mother liquor to ⅕ of the original volume and cooling in a deep-freeze cabinet overnight.
Example 12
1 g of I, modification B, was dissolved in 10 ml of ethanol (anhydrous) at 55° C., the solvent was evaporated at room temperature, and the residue was investigated after drying (2 hours, 50° C.): I, modification A.
Example 13
30 ml of n-heptane are added at 57° C. to a solution of 3 g of I, modification B, in 25 ml of anhydrous ethanol and then cooled to −5° to −10° C.
The crystallisate is dried (2 hours, 50° C.).
Yield: 2.5 g (75% of theory) of I, modification A.
Example 14
2 g of a mixture consisting of 80% of modification A and 20% of modification B were suspended in 3 ml of ethanol (96%) and stirred for 11 hours at 35° C., the pure modification A thereby being obtained.
Example 15
20 g of I, consisting of ca. 50% of each of the modifications A and B, were dissolved in 170 ml of ethanol (anhydrous) at 50°–55° C., and after addition of 0.5 g of Diacel the solution was suction filtered until clear. The filtrate was rapidly cooled to −5° to −10° C. while stirring, and stirred for a further 2 hours at this temperature.
Yield: 16.8 g (84% of theory) of I, modification A.
Example 16
20 g of I, modification A, were dissolved in 170 ml of ethanol (anhydrous) at 50°–55° C. The filtrate was slowly cooled to −5° to −10° C., and was then seeded at 31° C. The mixture was stirred for 2 hours at −5° to −10° C.
16.9 g (84.5% of theory) of I, modification A, were recovered.
2.0 g (10% of theory) of I, modification B with traces of A, were obtained by concentration by evaporation of the mother liquor to ⅕ of the original volume followed by cooling.
The same result was also obtained without seeding.
Example 17
40 g of I, mixture A>B, were dissolved at 50°–55° C. in 120 ml of ethanol (96%), rapidly cooled to −5° to −10° C., and stirred for 2 hours in the same temperature range.
Yield: 34 g (85% of theory) of I, modification B.
Example 18
10 g of I, modification A, were heated for 6 hours under reflux in 85 ml of ethanol (anhydrous), and the solution was then cooled and stirred for one hour at −5° to −10° C.
Yield: 8.3 g (83% of theory) of I, mixture of the modifications A and B (ca. 1:1).
The mother liquor was concentrated to 20% by evaporation: 0.91 g (9.1% of theory) of I, modification B.
Example 19
8.6 g of I (yield 86% of theory) in the form of a modification mixture (B>A) were obtained as first crystallisate by heating under reflux (6 hours) 10 g of I, modification A, in 30 ml of ethanol (96%), followed by cooling and stirring (1 hour at −5° to −10° C.).
Example 20
15 g of I, modification B, were dissolved in 70 ml of ethanol (96%) at 55° C. The solution was cooled and stirred for 2 hours at −5° to −8° C.
Yield: 12.8 g (84.8% of theory) of I, modification mixture A/B (ca. 1:1).
0.6 g (3.9% of theory) of I, modification A, was obtained by concentration by evaporation of the mother liquor to ca. 20% followed by cooling.
Example 21
5 g of I, modification A, were dissolved at 50°–55° C. in 200 ml of isopropanol. The solution was rapidly cooled and then stirred for 1 hour at −5° to −10° C.
4.2 g (84% of theory) of I, modification mixture A/B, were obtained.
A further 0.4 g (8% of theory) of I, modification mixture A/B, was obtained by concentration by evaporation of the mother liquor to 20% followed by cooling.
Example 22
3 g of I, modification A, were dissolved in 3 ml of N,N-dimethylacetamide at 50°–55° C. The solution was cooled and stirred at −5° to −10° C. for 1 hour.
Yield: 1.6 g (53.3% of theory) of I, modification mixture (A>B).
Example 23
10 g of I, modification A, were dissolved at 55° C. in 90 ml of ethanol (anhydrous). The majority of the solvent was distilled off under normal pressure, and the remainder under a vacuum. The oil obtained crystallised on cooling: I, modification B, quantitative yield.
Example 24
10 g of I, modification A, were dissolved at 55° C. in 30 ml of ethanol (96%). The solution was then concentrated by evaporation on a rotary evaporator up to a maximum bath temperature of 100° C., and was finally evaporated in vacuo. The oil crystallised on cooling: mixture (ca. 1:1) of the modifications A and B, quantitative yield.
Example 25
2 g of I, modification A, were melted at a bath temperature of 115°–120° C. and maintained for 20 minutes at this temperature. The crystallisate obtained on cooling consisted mainly of modification B with traces of A in addition to polymer.
Example 26
2 g of I, modification A, were briefly melted at a bath temperature of ca. 140° C. and then rapidly cooled. The crystallisate consisted of an A/B modification mixture together with polymer.
Example 27
400 ml of acetone were added to a solution of 3 g of I, modification A, in 8 ml of water and the whole was cooled at −5° to −8° C. (2 hours)
Yield: 1.8 g (60% of theory) of I, modification mixture (B>A).
Example 28
80 ml of acetone were added to a solution of 3 g of I, modification A, in 12 ml of dimethylformamide. The solution was cooled to −5° and stirred for 90 minutes at this temperature.
Yield: 2.75 g (91.3% of theory) of I, modification B together with traces of A.
Example 29
20 g of I, modification A, and 2 g of sodium sulfite were dissolved or suspended at 50°–55° C. in 50 ml of ethanol (96%). After the addition of 1 g of Diacel the solution was suction filtered until clear, slowly cooled to −6° to −8° C. and stirred for 2 hours at this temperature.
Yield: 15.9 g (79.5% of theory) of I, modification mixture (B>A).
Example 30
10 g of I, modification A, and 0.25 g of 6,8-dimercapto-octanoic acid were dissolved at 50°–55° C. in 85 ml of ethanol (anhydrous). After the addition of 1 g of Diacel the solution was suction filtered until clear, slowly cooled to −8° to −12° C., and stirred for 2 hours in this temperature range.
Yield: 1.9 g (19% of theory) of I, modification mixture (B>A).
6.1 g (61% of theory) of modification B were obtained by concentration by evaporation of the mother liquor to ca. 50% followed by cooling.
Example 31
100 g of R-thioctic acid (produced according to process b) were dissolved in a mixture consisting of 760 ml of cyclohexane and 40 ml of water-saturated ethyl acetate (water content: 3.2%) at 40°–42° C. After addition of 5 g of Diacel the solution was suction filtered until clear, slowly cooled to −5°, stirred for 1 hour at this temperature, suction filtered, washed with cyclohexane and dried at 30° C.
Yield: 87.5 g (87.5% of theory) of pure R-thioctic acid.
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10870157
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viatris gmbh & co kg
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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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549/39
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Apr 1st, 2022 05:10PM
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Apr 1st, 2022 05:10PM
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Viatris
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