Process for the preparation of triple-bond-containing optically active carboxylic acids, carboxylate salts and carboxylic acid derivatives

Abstract

The invention provides a new enzimatic process for the preparation of chiral carboxylic acids, their salts and acid derivatives of the general formula (I) by enzymatic hydrolysis of racemic carboxylic acid ester of the general formula (II) and optionally subsequent esterification or acylation.

Claims

1. Process for the preparation of chiral carboxylic acids of general formula (I), ##STR00019## where R is H or methyl group, wherein a racemic carboxylic acid ester of general formula (II), ##STR00020## where R′ is Me, Et, Pr, i-Pr, Bu, and R is as defined above, is enzymatically hydrolysed using a hydrolase enzyme, thereby obtaining the chiral carboxylic acid of general formula (I).

2. The process as defined in claim 1, wherein as hydrolase enzyme Candida rugosa lipase enzyme is applied.

3. The process as defined in claim 1, wherein the hydrolysis is carried out in the presence of a solvent.

4. The process as defined in claim 3, wherein the solvent is selected from the group of ethers, hydrocarbon-type and aromatic solvents, and mixtures thereof.

5. The process as defined in claim 4, wherein as solvent methyl tert-butyl ether is applied.

6. The process as defined in claim 1, wherein depending on the amount and activity of the enzyme, the reaction time is 2-48 hours.

7. The process as defined in claim 1, wherein the reaction is performed at 20-40° C.

8. The process as defined in claim 2, wherein depending on the amount and activity of the enzyme, the reaction time is 2-48 hours.

9. The process as defined in claim 3, wherein depending on the amount and activity of the enzyme, the reaction time is 2-48 hours.

10. The process as defined in claim 4, wherein depending on the amount and activity of the enzyme, the reaction time is 2-48 hours.

11. The process as defined in claim 2, wherein the reaction is performed at 20-40° C.

12. The process as defined in claim 3, wherein the solvent is selected from the group of diisopropyl ether, methyl tert-butyl ether, n-hexane, toluene, and mixtures thereof.

13. The process as defined in claim 1, where in a subsequent step, the chiral acid of general formula (I) is converted into a salt with a metal ion, protonated ammonia, or an amine.

14. The process as defined in claim 1, further comprising a subsequent step (a), wherein the chiral acid of general formula (I) is converted into a chiral ester of general formula (III) ##STR00021## where R′ and R are as defined in claim 1, and optionally, in a subsequent step (b) the chiral ester of general formula (III) obtained in step (a) is converted into a chiral compound of general formula (IV), ##STR00022## where Y is Me or Et and R is as defined in claim 1.

15. The process as defined in claim 14, wherein the chiral ester of general formula (III) obtained in step (a) is enzymatically hydrolysed by the process of claim 1, to obtain the chiral carboxylic acid of general formula (I) with increased enantiomeric purity, and optionally, the esterification process of said step (a) and the hydrolysis process of claim 1 are repeated, to obtain the chiral carboxylic acid of general formula (I) with further increased enantiomeric purity.

16. The process as defined in claim 5, wherein depending on the amount and activity of the enzyme, the reaction time is 2-48 hours.

17. The process as defined in claim 3, wherein the reaction is performed at 20-40° C.

18. The process as defined in claim 4, wherein the reaction is performed at 20-40° C.

19. The process as defined in claim 5, wherein the reaction is performed at 20-40° C.

20. The process as defined in claim 6, wherein the reaction is performed at 20-40° C.

Description

EXAMPLES

1.) Preparation of (S)-2-Methyl-4-Hexynoic Acid

(1) ##STR00013##

(2) 841 g of racemic 2-methyl-4-hexynoic acid methyl ester is dissolved in 8.4 L of methyl tert-butyl ether, 30 L demi water and 126 g of Candida rugosa lipase (activity: 1200 U/mg) are added. The reaction mixture is agitated at 25-30° C. until approx. 45% conversion is reached, while the pH is adjusted to around 6 by addition of 1 M NaHCO.sub.3 solution. At the end of the reaction 1 M NaHCO.sub.3 solution is added, the phases are separated, the aqueous phase is washed twice with methyl tert-butyl ether, then 1 M NaHSO.sub.4 solution is added and the mixture is extracted with methyl tert-butyl ether. The united aqueous phase is washed with saturated NaCl solution, dried over sodium sulfate. The drying material is filtered off, the filtrate solution which contains the product is evaporated.

(3) Yield: 366.06 g (48.4%) (S)-2-methyl-4-hexynoic acid, enantiomeric purity: 70.2%.

2.) Preparation of (S)-2-Methyl-4-Hexynoic Acid Methyl Ester

(4) ##STR00014##

(5) 347 g of (S)-2-methyl-4-hexynoic acid (enantiomeric purity 70.2%) is dissolved in 2 L of dimethylformamide, 536 g of water-free potassium carbonate, and 457 ml of methyl iodide are added. The reaction mixture is agitated at 25-35° C. while esterification proceeds, then it is destroyed by addition of water and 1 M NaHSO.sub.4 solution. The aqueous phase is extracted with methyl tert-butyl ether:n-hexane mixture, the united organic phase is washed with saturated salt solution, dried over sodium sulfate. The drying material is filtered off, the liquid filtrate is evaporated.

(6) Yield: 369.93 g (96.0%) (S)-2-Methyl-4-hexynoic acid methyl ester, enantiomeric purity: 70.2%.

3.) Preparation of (S)-2-Methyl-4-Hexynoic Acid

(7) 369.9 g (S)-2-Methyl-4-hexynoic acid methyl ester (enantiomeric purity: 70.2%) is dissolved in 3.7 L of methyl tert-butyl ether, 13.2 L demi water and 55 g of Candida rugosa lipase (activity: 1200 U/mg) are added. The reaction mixture is agitated at 25-30° C. until reaching approx. 80% conversion, while adjusting the pH around 6 by addition of 1 M NaHCO.sub.3 solution. At the end of the reaction 1 M NaHCO.sub.3 solution is added, the phases are separated, the aqueous phase is washed twice with methyl tert-butyl ether, then 1 M NaHSO.sub.4 solution is added and the mixture is extracted with methyl tert-butyl ether. The united aqueous phase is washed with saturated NaCl solution, dried over sodium sulfate. The drying material is filtered off, the filtrate solution which contains the product is evaporated.

(8) Yield: 255.80 g (76.8%) (S)-2-Methyl-4-hexynoic acid, enantiomeric purity: 93.0%.

4.) Preparation of (S)-2-Methyl-4-Hexynoic Acid Methyl Ester

(9) 252 g (S)-2-methyl-4-hexynoic acid (enantiomeric purity 93.0%) is dissolved in 1.47 L of dimethylformamide, 390 g of water-free potassium carbonate and 332 ml of methyl iodide are added. The reaction mixture is agitated at 25-35° C. while esterification proceeds, then it is destroyed by addition of water and 1 M NaHSO.sub.4 solution. The aqueous phase is extracted with methyl tert-butyl ether:n-hexane mixture, the united organic phase is washed with saturated salt solution and dried over sodium sulfate. The drying material is filtered off, the liquid filtrate is evaporated.

(10) Yield: 272.28 g (97.1%) (S)-2-Methyl-4-hexynoic acid methyl ester, enantiomeric purity: 93.0%.

5.) Preparation of (S)-2-Methyl-4-Hexynoic Acid

(11) 272.3 g (S)-2-Methyl-4-hexynoic acid methyl ester (enantiomeric purity: 93.0%) is dissolved in 2.7 L of methyl tert-butyl ether, 9.7 L demi water and 41 g of Candida rugosa lipase (activity: 1200 U/mg) are added. The reaction mixture is agitated at 25-30° C. until reaching approx. 90% conversion, while adjusting the pH around 6 by addition of 1 M NaHCO.sub.3 solution. At the end of the reaction 1 M NaHCO.sub.3 solution is added, the phases are separated, the aqueous phase is washed twice with methyl tert-butyl ether, then 1 M NaHSO.sub.4 solution is added and the mixture is extracted with methyl tert-butyl ether. The united aqueous phase is washed with saturated NaCl solution, dried over sodium sulfate. The drying material is filtered off, the filtrate solution which contains the product is evaporated.

(12) Yield: 209.16 g (85.4%) (S)-2-methyl-4-hexynoic acid, enantiomeric purity: 97.6%.

6.) Preparation of (S)-2-Methyl-4-Hexynoic Acid Methyl Ester

(13) 200 g of (S)-2-methyl-4-hexynoic acid (enantiomeric purity 97.6%) is dissolved in 1.2 L of dimethylformamide, 309 g of water-free potassium carbonate and 264 ml of methyl iodide are added. The reaction mixture is agitated at 25-35° C. while esterification proceeds, then it is destroyed by addition of water and 1 M NaHSO.sub.4 solution. The aqueous phase is extracted with methyl tert-butyl ether:n-hexane mixture, the united organic phase is washed with saturated salt solution, dried over sodium sulfate. The drying material is filtered off, the liquid filtrate is evaporated.

(14) Yield: 200.32 g (90.2%) (S)-2-Methyl-4-hexynoic acid methyl ester, enantiomeric purity: 97.6%.

7.) Preparation of (S)-Dimethoxyphosphoryl-3-methyl-hex-5-yn-one

(15) ##STR00015##

(16) To 1.3 L of distilled toluene, under nitrogen atmosphere, 666 ml of 1.6 M butyl lithium solution is added and the mixture is cooled to −80±5° C. While keeping that temperature, the solution of 123 ml of dimethyl methylphosphonate in 495 ml of distilled toluene is added. After 15 minutes of agitation the solution of 82 g (S)-2-methyl-4-hexynoic acid methyl ester (enantiomeric purity 97.6%) in 405 ml of distilled toluene is added at −80±5° C. The reaction mixture is agitated at that temperature for another 30 minutes. After proceeding of the acylation reaction the mixture is poured onto acid solution. The phases are separated, the aqueous phase is extracted with ethyl acetate, the united organic phase is washed with saturated salt solution and evaporated.

(17) The crude product is purified by gravity chromatography using gradient mixtures of n-hexane: ethyl acetate.

(18) Yield: 127.45 g (94.0%) (S)-Dimethoxyphosphoryl-3-methyl-hex-5-yn-one, enantiomeric purity: 97.8%.

8.) Preparation of (S)-2-Methyl-4-Heptynoic Acid

(19) ##STR00016##

(20) 4.270 g of racemic 2-methyl-4-heptynoic acid methyl ester is dissolved in 43 ml of methyl tert-butyl ether, 152 ml of demi water and 0.534 g of Candida rugosa lipase (activity: 1300 U/mg) are added. The reaction mixture is agitated at 25-30° C. until reaching approx. 45% conversion, while adjusting the pH around 6 by addition of 1 M NaHCO.sub.3 solution. At the end of the reaction 1 M NaHCO.sub.3 solution is added, the phases are separated, the aqueous phase is washed twice with methyl tert-butyl ether, then 1 M NaHSO.sub.4 solution is added and the mixture is extracted with methyl tert-butyl ether. The united aqueous phase is washed with saturated NaCl solution, dried over sodium sulfate. The drying material is filtered off, the filtrate solution which contains the product is evaporated.

(21) Yield: 1.499 g (38.6%) (S)-2-Methyl-4-heptynoic acid, enantiomeric purity: 68.6%.

9.) Preparation of (S)-2-Methyl-4-Heptynoic Acid Methyl Ester

(22) ##STR00017##

(23) 1.460 g (S)-2-methyl-4-heptynoic acid (enantiomeric purity 68.6%) is dissolved in 8 ml of dimethylformamide, 2.030 g of water-free potassium carbonate and 1.7 ml of methyl iodide are added. The reaction mixture is agitated at 25-35° C. till esterification proceeds, then it is destroyed by addition of water and 1 M NaHSO.sub.4 solution. The aqueous phase is extracted with methyl tert-butyl ether:n-hexane mixture, the united organic phase is washed with saturated salt solution, dried over sodium sulfate. The drying material is filtered off, the liquid filtrate is evaporated.

(24) Yield: 1.366 g (85.1%) (S)-2-methyl-4-heptynoic acid methyl ester, enantiomeric purity: 68.6%.

10.) Preparation of (S)-2-Methyl-4-Heptynoic Acid

(25) 1.366 g of (S)-2-methyl-4-heptynoic acid methyl ester (enantiomeric purity: 68.6%) is dissolved in 14 ml of methyl tert-butyl ether, 49 ml demi water and 0.171 g of Candida rugosa lipase (activity: 1300 U/mg) are added. The reaction mixture is agitated at 25-30° C. until reaching approx. 45% conversion, while adjusting the pH around 6 by addition of 1 M NaHCO.sub.3 solution. At the end of the reaction 1 M NaHCO.sub.3 solution is added, the phases are separated, the aqueous phase is washed twice with methyl tert-butyl ether, then 1 M NaHSO.sub.4 solution is added and the mixture is extracted with methyl tert-butyl ether. The united aqueous phase is washed with saturated NaCl solution, dried over sodium sulfate. The drying material is filtered off, the filtrate solution which contains the product is evaporated.

(26) Yield: 0.646 g (52.0%) (S)-2-Methyl-4-heptynoic acid, enantiomeric purity: 91.0%.

11.) Preparation of (S)-2-Methyl-4-Heptynoic Acid Methyl Ester

(27) 0.592 g of (S)-2-methyl-4-heptynoic acid (enantiomeric purity 91.0%) is dissolved in 3.0 ml of dimethylformamide, 0.820 g of water-free potassium carbonate and 0.70 ml of methyl iodide are added. The reaction mixture is agitated at 25-35° C. while esterification proceeds, then it is destroyed by addition of water and 1 M NaHSO.sub.4 solution. The aqueous phase is extracted with methyl tert-butyl ether:n-hexane mixture, the united organic phase is washed with saturated salt solution, dried over sodium sulfate. The drying material is filtered off, the liquid filtrate is evaporated.

(28) Yield: 0.569 g (87.4%) (S)-2-methyl-4-heptynoic acid methyl ester, enantiomeric purity: 91.0%.

12.) Preparation of (S)-Dimethoxyphosphoryl-3-methyl-hept-5-yn-one

(29) ##STR00018##

(30) To 17 ml of distilled toluene, under nitrogen atmosphere, 8.1 ml of 1.6 M butyl lithium solution is added and the mixture is cooled to −80±5° C. While keeping that temperature, the solution of 1.5 ml of dimethyl methylphosphonate in 3.3 ml of distilled toluene is added. After 15 minutes of agitation the solution of 0.549 g of (S)-2-methyl-4-heptynoic acid methyl ester (enantiomeric purity 91.0%) in 3.0 ml of distilled toluene is added at −80±5° C. The reaction mixture is agitated at that temperature for another 30 minutes. After proceeding of the acylation reaction the mixture is poured onto acid solution. The phases are separated, the aqueous phase is extracted with ethyl acetate, the united organic phase is washed with saturated salt solution and evaporated.

(31) The crude product is purified by gravity chromatography using gradient mixtures of n-hexane: ethyl acetate

(32) Yield: 0.782 g (89.2%) (S)-Dimethoxyphosphoryl-3-methyl-hept-5-yn-one, enantiomeric purity: 96.7%.