JPH1175889A - Production method and purification method of optically active α-trifluoromethyl lactic acid and its enantiomer ester - Google Patents

Abstract

(57) [Summary] General formula (I): (Wherein R is a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms), a racemic α-trifluoromethyl lactate represented by the following formula: Asymmetric hydrolysis in the presence of an enzyme-immobilized product, a microorganism, a culture of bacterial cells, or a processed product of bacterial cells, a method for producing optically active α-trifluoromethyllactic acid and its enantiomer ester; The optically active α-trifluoromethyl lactic acid obtained by the method or the enantiomeric optically active α-trifluoromethyl lactic acid obtained by hydrolyzing the enantiomeric ester obtained by the method is recrystallized to collect crystals. A method for purifying optically active α-trifluoromethyl lactic acid, comprising: According to the present invention, optically active α-trifluoromethyl lactic acid and its esters useful as raw materials for pharmaceuticals, agricultural chemicals and the like or synthetic intermediates can be produced without using an optical resolving agent. Further, if the optically active α-trifluoromethyl lactic acid obtained by the present invention is recrystallized, purification (improvement of optical purity) by a simple method is possible.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing optically active α-trifluoromethyl lactic acid and its enantiomer ester, which are useful as raw materials or intermediates for pharmaceuticals, agricultural chemicals and the like.

[0002]

2. Description of the Related Art It has been reported that racemic α-trifluoromethyl lactic acid and esters thereof are conventionally synthesized from 1,1,1-trifluoroacetone and sodium cyanide as raw materials (Journal of Chemical Society, 2329, 195
1) The report also reports a method for producing optically active α-trifluoromethyl lactic acid from racemic α-trifluoromethyl lactic acid by an optical resolution method using brucine. Further, WO93 / 23358 reports a method for producing optically active α-trifluoromethyl lactic acid from racemic α-trifluoromethyl lactic acid by an optical resolution method using (S)-(−)-α-methylbenzylamine. ing.

[0003] However, any of these methods requires an expensive resolving agent in order to increase the optical purity, resulting in high production costs. Furthermore, in these methods, it is necessary to repeat the recrystallization several times or more in the form of a salt with a resolving agent, and then to perform a de-splitting agent treatment, which makes the operation complicated. Further, in the above-mentioned literature, there is no mention of purification (improvement of optical purity) of optically active α-trifluoromethyl lactic acid by recrystallization, and it is not possible to improve optical purity by recrystallization. It was completely unknown.

[0004]

The object of the present invention is to provide an optically active α-α useful as a raw material or intermediate for pharmaceuticals, agricultural chemicals and the like.
An object of the present invention is to provide a method for producing trifluoromethyl lactic acid and its enantiomer ester without using an optical resolving agent, and a simple method for purifying an optically active substance obtained by the method (a method for improving optical purity).

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found an enzyme having an activity to optically hydrolyze racemic α-trifluoromethyl lactate. Further, the inventors have found that the optical purity is improved by recrystallizing optically active α-trifluoromethyl lactic acid, thereby completing the present invention. That is, the present invention includes the following inventions. (1) General formula (I):

[0006]

Embedded image

(Wherein, R is a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms).
Optically active, characterized in that trifluoromethyl lactate is asymmetrically hydrolyzed in the presence of an enzyme having ester asymmetric hydrolysis ability, an enzyme-immobilized product, a microorganism, a bacterial cell culture solution, or a processed product of bacterial cells. A method for producing α-trifluoromethyl lactic acid and its enantiomer ester. (2) Optically active α- obtained by the method described in (1) above.
Recrystallizing the enantiomeric optically active α-trifluoromethyl lactic acid obtained by hydrolyzing trifluoromethyl lactic acid or the enantiomeric ester obtained by the method described in the above (1), and collecting the crystals. A method for purifying optically active α-trifluoromethyl lactic acid.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
In the general formula (I), R is a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms. Specifically, a carbon atom having 1 to 12 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and an n-hexyl group.
An alkenyl group having 2 to 12 carbon atoms such as a vinyl group, a propenyl group, an isopropenyl group, a butenyl group, an isobutenyl group, and a hexenyl group; An alkynyl group; a cycloalkyl group having 3 to 12 carbon atoms, preferably 3 to 7 carbon atoms, such as a cyclohexyl group; a phenyl group, a tolyl group,
An aryl group such as a naphthyl group; an aralkyl group such as a benzyl group; In the hydrocarbon group, the hydrogen atom bonded to the carbon atom may be substituted with a substituent such as halogen.

Racemic α-trifluoromethyl lactate as a raw material is described, for example, in Journal of Chemical Societies.
ety, 2329 (1951) and the like. That is, to a 1,1,1-trifluoroacetone aqueous solution, a sodium cyanide aqueous solution is added dropwise under cooling, and then sulfuric acid is added and reacted at room temperature for 24 hours to synthesize α-trifluoromethyllactonitrile, Next, α-trifluoromethyl lactic acid is synthesized by hydrolyzing it with a strong acid such as sulfuric acid, and then esterified according to a conventional method.

The ester asymmetric hydrolase used in the present invention has the ability to asymmetrically hydrolyze racemic α-trifluoromethyl lactic acid ester to produce optically active α-trifluoromethyl lactic acid and its enantiomeric ester. The type of enzyme and its production source are not particularly limited as long as it is an ester asymmetric hydrolase having the following. Among them, enzymes generally called lipases, esterases and proteases are particularly effective.

As the ester asymmetric hydrolase, for example, it has an ability to produce optically active α-trifluoromethyl lactic acid and its enantiomer ester by asymmetric hydrolysis of racemic α-trifluoromethyl lactic acid ester. Crude or purified enzymes isolated from microorganisms can be used. Such microorganisms include the genus Bacillus (Bacillu
s), Aspergillus, Candida
(Candida), Pseudomonas (Pseudomonas), Rhizopus (Rhizopus), Mucor (Mucor), Humicola (H
umicola) and the like.

The microorganism belonging to the genus Bacillus includes Baci
llus subtilis, Bacillus licheniformus, Bacillus po
As microorganisms belonging to the genus Aspergillus, lymixa and the like, Aspergillus flavus, Aspergillus fumigatus, Asp
ergillus oryzae, Aspergillusfoetides, Aspergillus
niger, Aspergillus phoenics, Aspergillus saitoi, As
pergillus sojae and the like belong to the genus Candida as Candida rugosa, Candida antarcia, Candid
a utilus and the like, Pseudomonas fluorescence, Pseudomonas antarci
a, Pseudomonassp. MR-2301 (FERM BP-4870) and the like, as microorganisms belonging to the genus Rhizopus, Rhizopus juponicus
As microorganisms belonging to the genus Mucor, Mucor jupo
Examples of microorganisms belonging to the genus Humicola include Nicus, Mucor miehei and the like, and Humicola lanuginosa and the like.

As the ester hydrolase used in the present invention, a commercially available ester hydrolase can be used. Representative enzymes produced by microorganisms include, for example, NOVO Alcalase (from Bacillus sp.), NOVO Durazyme (from Bacillus sp.), NOVO
Esperase (from Bacillus sp.), NOVO Savinase (from Bacillus sp.), NOVO Neutrase (Bac
illus genus), NOVO lipolase (Humicola genus), NOVO flavozyme (from Aspergillus genus), Nagase Biochemical Co., Inc. AP-15 (both from the genus Aspergillus), Lipase 2G from Nagase Seikagaku Corporation (from Pseudomonas), Lipase P from Amano Pharmaceutical Co.
(Derived from the genus Pseudomonas), Lipase PS (Pse
udomonas sp.), Amano Pharmaceutical Co., Ltd.Neurase F (Rhizo
pus), Lipase MFL manufactured by Amano Pharmaceutical Co., Ltd., Lipase M manufactured by Amano Pharmaceutical Company (derived from the genus Mucor), Lipase AY manufactured by Amano Pharmaceutical Company (derived from the genus Candida), Lipase A (Asper
gillus genus), Lipase M-AP-1 manufactured by Amano Pharmaceutical Co., Ltd.
0, enzymes such as LP-015-S manufactured by Asahi Kasei Kogyo Co., Ltd., and examples of animal-derived ester hydrolases include pancreatin and trypsin derived from pig or bovine.

Furthermore, not only the crude enzyme or the purified enzyme isolated from the microorganism as described above, but also a culture obtained by culturing the microorganism in a culture medium as it is or by collecting the culture by centrifugation or the like. The optically active α is obtained by asymmetrically hydrolyzing the racemic α-trifluoromethyl lactate represented by the general formula (I) in the presence of a culture supernatant, cells, or processed cells obtained by the bacterial operation. -It is also possible to produce trifluoromethyl lactic acid and its enantiomeric esters. Examples of the treated cells include cells treated with acetone, toluene, and the like, crushed cells, cell-free extracts obtained by crushing cells, and the like. In the production method of the present invention, when the ester asymmetric hydrolase is subjected to the reaction, its use form is not particularly limited as long as the enzyme shows activity, and the enzyme may be immobilized on a suitable carrier and used. it can. By immobilizing the enzyme, the separation and recovery of the optically active α-trifluoromethyl lactic acid and its enantiomer ester and the enzyme after the reaction is completed, and the enzyme can be reused.

In the present invention, the optically selective hydrolysis of racemic α-trifluoromethyl lactate can be carried out by the following method. A racemic α-trifluoromethyl lactate as a substrate is dissolved or suspended in a reaction solvent. Before or after the addition of the substrate to the reaction solvent, an enzyme having the ability to perform asymmetric hydrolysis, an enzyme-immobilized product, a microorganism, a culture of bacterial cells, or a treated product of the bacterial cells is added as a catalyst. Then, while controlling the reaction temperature and, if necessary, the pH of the reaction solution, the reaction is carried out until about half of the α-trifluoromethyl lactate is hydrolyzed. In some cases, the reaction may be interrupted at an early stage of the reaction, or the reaction may be excessively performed.

The concentration of the substrate in the reaction solution is not particularly limited in the range of 0.1 to 80% by weight, but is preferably 1 to 50% by weight in consideration of productivity and the like. The enzyme concentration of the reaction solution is usually 0.01 to 10% by weight, preferably 0.05 to 10% by weight.
5% by weight. The pH of the reaction solution depends on the optimum pH of the enzyme used, but is generally in the range of pH 4 to 11. It is preferable to carry out the reaction at pH 5 to 9 from the viewpoint that a decrease in optical purity and a decrease in yield due to a chemical hydrolysis reaction can be suppressed. The pH decreases as the reaction proceeds. In this case, it is desirable to adjust the pH to an optimum value by adding a suitable neutralizing agent, for example, an aqueous solution of sodium hydroxide or potassium hydroxide. The reaction temperature is preferably 5 to 70 ° C, and 10
~ 50 ° C is more preferred.

As the reaction solvent, an aqueous medium such as ion-exchanged water or a buffer is usually used, but the reaction can be carried out in a system containing an organic solvent. Examples of the organic solvent include alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butyl alcohol, and t-amyl alcohol; and aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and octane. Benzene, toluene, xylene and other aromatic hydrocarbon solvents, methylene chloride, chloroform, carbon tetrachloride, dichloroethane and other halogenated hydrocarbon solvents, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and other ether solvents, acetic acid Ester solvents such as ethyl, propyl acetate and butyl acetate, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, acetonitrile, N, N-dimethylformamide and the like can be appropriately used. In addition, it is also possible to add these organic solvents to a solvent having a solubility equal to or higher than that of water to carry out the reaction in a two-layer system. Coexistence of an organic solvent in the reaction system often improves selectivity, conversion, yield, and the like.

The reaction time is generally 1 hour to 1 week, preferably 1 to 72 hours, and it is preferable to select reaction conditions under which the reaction is completed. The above-mentioned substrate concentration, enzyme concentration, pH, temperature, solvent, reaction time and other reaction conditions are most often the target optically active compounds in consideration of the reaction yield, optical yield, etc. under those conditions. It is desirable to select the conditions that can be collected as appropriate.

By the above reaction, racemic α-trifluoromethyl lactic acid ester is asymmetrically hydrolyzed to produce optically active α-trifluoromethyl lactic acid. In addition, the remaining substrate becomes the enantiomeric ester of the optically active α-trifluoromethyl lactic acid produced. Isolation of the resulting optically active α-trifluoromethyl lactic acid and optically active α-trifluoromethyl lactic acid ester (ie, the enantiomeric ester of optically active α-trifluoromethyl lactic acid) from the reaction mixture includes extraction, distillation, It can be carried out by a usual isolation method such as column separation.

For example, optically active α-trifluoromethyl lactate can be prepared, for example, by adjusting the pH of the reaction solution to near neutrality and then adding ethers such as diethyl ether and diisopropyl ether; esters such as ethyl acetate; hexane and octane. , Benzene, toluene and the like; and halogenated hydrocarbons such as methylene chloride and the like, and can be separated by extraction with a common organic solvent. On the other hand, optically active α-trifluoromethyl lactic acid can be extracted and separated with a common organic solvent as described above after adding a strong acid such as sulfuric acid or hydrochloric acid to the above-mentioned extraction residue.

Further, the optically active α-trifluoromethyl lactic acid ester can be converted into α-trifluoromethyl lactic acid by maintaining the optical activity by hydrolyzing in a usual manner. The optically active α-trifluoromethyl lactic acid can be converted into α-trifluoromethyl lactic acid ester while maintaining the optical activity by esterification by a usual method. Therefore, α-trifluoromethyl lactic acid and an ester thereof having an arbitrary configuration can be obtained. The optically active α-trifluoromethyl lactic acid obtained as described above can be further purified by recrystallization to improve its optical purity. Hereinafter, purification by recrystallization will be described in detail.

In the present invention, the optically active α-trifluoromethyl lactic acid to be subjected to recrystallization may be any of the R-form and the S-form. The optical purity thereof is not 0% ee, that is, as long as one of the R-form and the S-form is contained more than the other, there is no particular limitation. In addition, in this specification, optical purity is represented by enantiomeric excess (% ee). Optically active α obtained by asymmetric hydrolysis according to the present invention
-Trifluoromethyl lactic acid can be subjected to recrystallization in its original form. On the other hand, its enantiomer ester produced simultaneously with optically active α-trifluoromethyl lactic acid is
Before being subjected to recrystallization, it is necessary to hydrolyze the ester bond by an ordinary method.

The solvent used for recrystallization of the optically active α-trifluoromethyl lactic acid is not particularly limited as long as it does not react with the optically active α-trifluoromethyl lactic acid. Depending on the optical purity, etc.
It can be appropriately determined in consideration of the recovery rate of the target substance.
Examples of the solvent include aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and octane; benzene,
Aromatic hydrocarbon solvents such as toluene and xylene; halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ether solvents such as diethyl ether, isopropyl ether, tetrahydrofuran and dioxane; ethyl acetate, acetic acid Ester solvents such as propyl and butyl acetate; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; and acetonitrile and N, N-dimethylformamide. Among them, toluene is preferred in terms of versatility and economy. ,
Preferred are n-hexane, ethyl acetate, methylene chloride, chloroform, isopropyl ether, acetone and acetonitrile. Of these, toluene has a range of freezing point to boiling point (-95 ° C to 110.6 ° C at 1 atm) within an easy handling range. , And its range is particularly large. These recrystallization solvents can be used alone or in combination.

Alcohol solvents such as methanol, ethanol, propanol and butanol are:
As long as the amount does not cause an esterification reaction with the optically active α-trifluoromethyl lactic acid, it may be effective to use it as a mixed solvent in combination with another solvent in some cases. The recrystallization operation can be performed according to a general method, and there is no particular limitation. That is, the optically active α-trifluoromethyl lactic acid as a raw material can be dissolved in the above-mentioned recrystallization solvent under heating and then cooled to precipitate. Crystals may be precipitated by adding a poor solvent for optically active α-trifluoromethyl lactic acid. Furthermore, in order to smoothly and efficiently precipitate crystals,
Crystal seeds can also be seeded. Although there is no particular limitation on the crystal seed, it is preferable to use a crystal having high optical purity, a racemic crystal, or the like according to the purpose.

The temperature conditions for the recrystallization operation can be appropriately determined depending on the boiling point and the freezing point of the solvent used. Generally, the starting material is dissolved at room temperature (25 ° C.) to the boiling point of the solvent, and the temperature is from −80 ° C. to 50 ° C. Crystals can be precipitated at ° C. Toluene (1 atm, freezing point: -95 ° C, boiling point:
When using (110.6 ° C), it is preferable to dissolve the raw material at 90 ° C to 110 ° C and precipitate crystals at -20 ° C to 50 ° C. The amount relationship between the recrystallization solvent and the optically active α-trifluoromethyl lactic acid as the raw material is not particularly limited as long as it is within a range in which it is completely dissolved. Can be appropriately determined in consideration of the recovery rate of the target substance.

Next, recovery of the purified optically active α-trifluoromethyl lactic acid can be performed by a conventional method such as filtration and centrifugation. The optical purity of these optically active α-trifluoromethyl lactic acids can be easily measured by gas chromatography using a GC capillary column for optical resolution after esterification by a conventional method. Optical purity (enantiomeric excess;% ee) is generally determined by GC
The peak areas of (S) -α-trifluoromethyl lactic acid and (R) -α-trifluoromethyl lactic acid can be calculated by the following equations.

[0027]

## EQU1 ## When R> S: Optical purity (% ee) of R-isomer = (RS / R + S) × 10
0 In the case of S> R: Optical purity (% ee) of S-isomer = (SR / R + S) × 10
0 S: Peak area of (S) -α-trifluoromethyl lactic acid R: Peak area of (R) -α-trifluoromethyl lactic acid The optically active α-trifluoromethyl lactic acid obtained as described above is as described above. By repeating purification by recrystallization one or more times in the same manner, an optically active substance having a higher optical purity can be obtained.

[0028]

[Reference Example 1]

Synthesis of racemic α-trifluoromethyl lactic acid n-butyl ester To 65 ml of n-butanol, 60 g of racemic α-trifluoromethyl lactic acid and 1 ml of concentrated sulfuric acid were added, and the mixture was reacted for 15 hours under reflux. Next, excess butanol was removed by distillation. After the remaining solution was put in ice water, extraction was performed three times with 60 ml of diethyl ether each. The diethyl ether layers obtained by the three extraction operations were combined, purified by distillation under reduced pressure, and 64 g of racemic α-trifluoromethyl lactic acid n-butyl ester was obtained.

Example 1 In a reactor equipped with a pH controller, 300 ml of 0.1 M phosphate buffer, 15 g of racemic α-trifluoromethyl lactate n-butyl ester and 3 g of denazyme AP (manufactured by Nagase Seikagaku Corporation) Was added, and the mixture was reacted at 30 ° C. for 24 hours while adjusting the pH of the reaction solution to 7.0 with a 2N aqueous sodium hydroxide solution.

After completion of the reaction, extraction was performed three times using 100 ml of diisopropyl ether in each case. The diisopropyl ether layers obtained by the three extraction operations were combined, dehydrated by adding anhydrous magnesium sulfate, and then diisopropyl ether was removed by distillation. Α-trifluoromethyl lactic acid n-butyl ester thus obtained (4.
8g), an optical separation column (Chrompack Ch.
Analysis by capillary gas chromatography with an irasil-DEX CB column revealed that the optically active form (S
Body) and the optical purity was 96.5% ee.

To the optically active ester obtained above, 50 ml of a 5% aqueous sodium hydroxide solution was added, and a hydrolysis reaction was carried out at room temperature for 2 hours. Next, sulfuric acid was added to adjust the pH to 1.5, and extraction was performed three times with 50 ml of ethyl acetate each. The ethyl acetate layers obtained by the three extraction operations were combined, dehydrated with magnesium sulfate, and the solvent was removed. The α-trifluoromethyl lactic acid (2.3 g) thus obtained was esterified with diazomethane and analyzed by capillary gas chromatography equipped with an optical resolution column (Chirasil-DEX CB column manufactured by Chrompack). And optically active form (S form), and the optical purity was 96.5% ee.

Further, (S) -α-trifluoromethyllactic acid n-
The butyl ester extraction residue (aqueous layer) was concentrated to 100 ml.
After adding concentrated sulfuric acid to adjust the pH to 1.0,
Extraction was performed three times by adding ml of ethyl acetate. The ethyl acetate layers obtained by the three extraction operations were combined into one, dried over anhydrous magnesium sulfate, and the solvent was removed. The α-trifluoromethyl lactic acid thus obtained (3.3
g) was esterified with diazomethane, and analyzed by capillary gas chromatography equipped with an optical resolution column (Chirasil-DEX CB column manufactured by Chrompack). %
was ee.

Examples 2 to 45 In each example, 0.5 ml of a 0.1 M phosphate buffer (pH = 7.0) in which 1% by weight of racemic α-trifluoromethyl lactic acid n-butyl ester was suspended.
Then, 10 mg of each of the enzymes shown in Table 1 was added thereto, and the mixture was shaken at 30 ° C. for 24 hours, and then 0.5 ml of diisopropyl ether was added and stirred. The optically active α-trifluoromethyl lactate n-butyl ester contained in the diisopropyl ether layer was analyzed by gas chromatography equipped with an optical resolution column (Chroma-pack Chirasil-DEX CB column) in the same manner as in Example 1. Table 1 shows the results of measuring the configuration and the optical purity.

[0034]

[Table 1]

Example 46 10 g of peptone (manufactured by Difco),
A liquid medium having a composition consisting of 5 g of yeast extract (manufactured by Difco), 5 g of salt, and 1 L of distilled water was prepared, and the liquid medium was dispensed into 300 ml Erlenmeyer flasks in 50 ml portions.
Steam sterilized for minutes. Pseudomonas
One loopful of sp. MR-2301 (FERM BP-4870) was inoculated and cultured with shaking at 30 ° C for 1 day. Next, the cells were collected from the culture solution in each flask by centrifugation, washed with water, and suspended in 10 ml of 50 mM phosphate buffer (pH = 7.0). 0.5 ml of this cell suspension
2% by weight of racemic α-trifluoromethyl lactic acid n-butyl ester in 0.1M phosphate buffer (pH = 7.0)
After adding 4.5 ml, the mixture was reacted at 30 ° C. with shaking for 24 hours.

To the reaction solution, 5 ml of diisopropyl ether was added and stirred. Optically active α-trifluoromethyl lactic acid n-butyl ester contained in the diisopropyl ether layer was analyzed by gas chromatography equipped with an optical resolution column (Chirasil-DEX CB column manufactured by Chrompack) in the same manner as in Example 1. As a result of measuring the steric configuration and the optical purity, the product was R-form and the optical purity was 30% ee.

Examples 47 to 61 In the same manner as in Example 2, a 0.1 M phosphate buffer (pH = 7.0) in which 1% by weight of racemic α-trifluoromethyl lactate methyl ester was suspended.
To 0.5 ml, 10 mg of each of the enzymes shown in Table 2 was added, and 3
After shaking at 0 ° C. for 24 hours, 0.5 ml of diisopropyl ether was added and stirred. The optically active α-trifluoromethyl lactate methyl ester contained in the diisopropyl ether layer was analyzed by gas chromatography equipped with an optical resolution column (Chirasil-DEX CB column manufactured by Chrompack) in the same manner as in Example 1, and the configuration was determined. Table 2 shows the measurement results of the optical purity and the optical purity.

[0038]

[Table 2]

Example 62 96.5% obtained in Example 1
ee (S) -α-trifluoromethyl lactic acid 1.0 g
10 ml was added, dissolved at 100 ° C., and allowed to stand at room temperature overnight. When the precipitated crystals were recovered, more than 99% ee
0.8 g of (S) -α-trifluoromethyl lactic acid was obtained. The optical purity was measured as follows. An ether solution of diazomethane was added to the obtained crystals to perform methyl esterification. The solution was analyzed by gas chromatography (GC) under the following conditions, and (S) -α-trifluoromethyl lactic acid and (R) -α The optical purity (enantiomeric excess) was calculated from the peak area of trifluoromethyl lactic acid by the above formula. Column: CP-Chirasil DEX CB 0.25mm x 25m (manufactured by Chrome Pack) Column temperature: 70 ° C Detector: FID

Example 63 58.9% obtained in Example 1
To 1.0 g of (R) -α-trifluoromethyl lactic acid of ee, toluene
50 ml was added, dissolved at 100 ° C., and allowed to stand at 30 ° C. for 3 hours. When the precipitated crystals were collected, 79% ee of (R) -α
0.28 g of trifluoromethyl lactic acid was obtained. The optical purity was measured by the method described in Example 62.

Example 64 58.9% obtained in Example 1
To 1.0 g of (R) -α-trifluoromethyl lactic acid of ee, 500 ml of n-hexane was added and dissolved by heating near the boiling point, followed by standing at room temperature overnight. When the precipitated crystals were collected, 70%
0.4 g of (R) -α-trifluoromethyl lactic acid of ee was obtained. The optical purity was measured by the method described in Example 62.

Example 65 2.0 g of (S) -α-trifluoromethyllactic acid of 64% ee obtained in the same manner as in Example 1 except that the reaction time was reduced to half, was added to the solvent shown in Table 3. The mixture was dissolved by heating, and allowed to stand at room temperature for 3 hours to precipitate crystals.
Table 3 shows the solvent used, the amount of the solvent, the amount of crystal recovered, and the optical purity of the obtained crystal. The optical purity was measured by the method described in Example 62.

[0043]

[Table 3]

Example 66 2.0 g of (S) -α-trifluoromethyllactic acid of 64% ee obtained in the same manner as in Example 1 except that the reaction time was reduced to half, was dissolved in ethyl acetate or isopropyl ether. And further add n-hexane,
The solution was allowed to stand at 20 ° C. for 5 hours to precipitate crystals. Table 4 shows the solvent used, the amount of the solvent, the amount of crystal recovered, and the optical purity of the obtained crystal. The optical purity was measured by the method described in Example 62.

[0045]

[Table 4]

Example 67 2.0 g of 64% ee (S) -α-trifluoromethyllactic acid obtained in the same manner as in Example 1 except that the reaction time was reduced to half, was dissolved in acetonitrile or acetone. After further adding toluene at room temperature, -20
The solution was allowed to stand at 5 ° C. for 5 hours to precipitate crystals. Table 5 shows the solvent used, the amount of the solvent, the amount of crystal recovered, and the optical purity of the obtained crystal. The optical purity was measured by the method described in Example 62.

[0047]

[Table 5]

[0048]

According to the present invention, optically active α-trifluoromethyl lactic acid and its esters useful as raw materials for pharmaceuticals and agricultural chemicals or as synthetic intermediates can be produced without using an optical resolving agent. Further, if the optically active α-trifluoromethyl lactic acid obtained by the present invention is recrystallized, purification by a simple method (improvement of optical purity) is possible.

Claims (2)

[Claims] 1. A compound of the general formula (I): (Wherein R is a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms), a racemic α-trifluoromethyl lactate represented by the following formula: A process for producing optically active α-trifluoromethyl lactic acid and its enantiomer ester, comprising asymmetric hydrolysis in the presence of an enzyme-immobilized product, a microorganism, a culture of a bacterial cell, or a processed product of a bacterial cell. 2. An optically active α-trifluoromethyl lactic acid obtained by the method of claim 1, or an enantiomeric optically active α obtained by hydrolyzing an enantiomeric ester obtained by the method of claim 1. -A method for purifying optically active α-trifluoromethyl lactic acid, comprising recrystallizing trifluoromethyl lactic acid and collecting crystals.