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, carboxylate salts and carboxylic acid derivatives of the general formula I, ##STR00019## where in the formulae R=H or methyl group Z=OH, OM, OR or P(O)(OY).sub.2-group, wherein M=metal ion, protonated ammonia or amine, R=Me, Et, Pr, i-Pr, Bu, and Y=Me or Et, characterized by that a racemic carboxylic acid ester of the general formula II, ##STR00020## where Z=OR and the meaning R is as defined above, is enzymatically hydrolyzed, if desired, for the preparation of the compounds of the general formula I, wherein Z stands for OR group the obtained compound of the general formula I, wherein Z stands for OH group is esterified, if desired, for the preparation of the compound of the general formula I, wherein Z stands for P(O)(OY).sub.2 group the resulting ester is acylated, and if desired the obtained compound of the general formula I is transformed into its salt or liberated from its salt.

2. Process as defined in claim 1, wherein the enzymatic hydrolysis is carried out with hydrolase enzyme.

3. Process as defined in claim 2, wherein as hydrolase enzyme lipase enzyme, such as Candida rugosa, Pseudomonas fluorescens, Candida antarctica A, Candida antarctica B, Burkholderia cepacia, Rhizopus arrhizus, Rhizomucor miehei, Pseudomonas cepacia lipase or pig pancrease lipase, calf pancrease lipase are applied.

4. Process as defined in claim 3, wherein as lipase enzyme Candida rugosa enzyme is applied.

5. Process as defined in claim 1, wherein the hydrolysis is carried out in the presence of solvent.

6. Process as defined in claim 5, wherein as solvent ethers, hydrocarbon-type and aromatic solvents, such as diisopropyl ether, methyl tert.-butyl ether, n-hexane, toluene are applied.

7. Process as defined in claim 6, wherein as solvent methyl tert.-butyl ether is applied.

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

9. Process as defined in claim 1, wherein the reaction is performed at 20-40 C.

10. Process as defined in claim 2, wherein the hydrolysis is carried out in the presence of solvent.

11. Process as defined in claim 3, wherein the hydrolysis is carried out in the presence of solvent.

12. Process as defined in claim 4, wherein the hydrolysis is carried out in the presence of solvent.

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

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

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

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

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

18. Process as defined in claim 2, wherein the reaction is performed at 20-40 C.

19. Process as defined in claim 3, wherein the reaction is performed at 20-40 C.

20. Process as defined in claim 4, wherein the reaction is performed at 20-40 C.

Description

EXAMPLES

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

[0107] ##STR00013##

[0108] 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.

[0109] 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

[0110] ##STR00014##

[0111] 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.

[0112] 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

[0113] 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.

[0114] 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

[0115] 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.

[0116] 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

[0117] 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.

[0118] 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

[0119] 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.

[0120] 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-Hept-5-Yn-2-One

[0121] ##STR00015##

[0122] 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 805 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 805 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.

[0123] The crude product is purified by gravity chromatography using gradient mixtures of n-hexane: ethyl acetate.

[0124] Yield: 127.45 g (94.0%) (S)-dimethoxyphosphoryl-3-methyl-hept-5-yn-2-one, enantiomeric purity: 97.8%.

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

[0125] ##STR00016##

[0126] 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.

[0127] 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

[0128] ##STR00017##

[0129] 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.

[0130] 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

[0131] 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.

[0132] 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

[0133] 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.

[0134] 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-Oct-5-Yn-2-One

[0135] ##STR00018##

[0136] 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 805 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 805 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.

[0137] The crude product is purified by gravity chromatography using gradient mixtures of n-hexane: ethyl acetate

[0138] Yield: 0.782 g (89.2%) (S)-Dimethoxyphosphoryl-3-methyl-oct-5-yn-2-one, enantiomeric purity: 96.7%.