JPH1014590A - Production of optically active 2-substituted-3-phenylpropionic acid and its ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently produce the subject compounds useful as a raw material, etc., for medicines by hydrolyzing an enantiomer mixture of a 2-substituted-3- phenylpropionic acid ester with an enzyme and separating the mixture into an optically active free acid and an ester of its antipode. SOLUTION: An eantiomer mixture of a 2-substituted-3-phenylpropionic acid ester represented by formula I (R is a 1-17C alkyl, a 2-17C alkenyl or a 6-25C aralkyl; A is a halogen except fluorine, an alkylsulfonyloxy or an arylsulfonyloxy) is hydrolyzed with an enzyme capable of asymmetrically hydrolyzing ester bond thereof. Thereby, the mixture is separated into a product comprising an (S)-2-substituted-3-phenylpropionic acid represented by formula II or an (R) 2-substituted-3-phenylpropionic acid represented by formula III and the unreacted substance comprising an (R)-2-substituted-3-phenylpropionic acid ester represented by formula IV or an (S)-2-substituted-3-phenylpropionic acid ester represented by formula V to afford the objective optically active compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active 2-substituted-3 compound.
A process for producing phenylpropionic acid and its esters.

[0002]

2. Description of the Related Art Optically active 2-substituted-3-phenylpropionic acids and esters thereof are useful intermediates of optically active bioactive compounds used in pharmaceuticals. For example, JP-A-7-48259 discloses (R) -2-bromo-3.
-Disclosed is the use of phenylpropionic acid for the production of dual or selective ACE inhibitors of NEP and ACE. For this reason, it is desired to establish an industrially superior production method capable of producing these with high optical purity.

As a method for producing optically active 2-bromo-3-phenylpropionic acid, for example, Bioorganic and Medicinal Chemistry Letters (Bio. Med. Chem. Lett.), 1783
Page (1994) describes a method of reacting D-phenylalanine with potassium bromide and sodium nitrite in a sulfuric acid solution.

However, such a conventionally known production method synthesizes optically active (R) -2-bromo-3-phenylpropionic acid by using optically active D-phenylalanine as a starting material, For industrial implementation, D-
There is a problem in terms of phenylalanine supply and economy.

[0005]

DISCLOSURE OF THE INVENTION In view of the above, the present invention provides a process for producing an optically active 2-substituted-3-phenylpropionic acid and an ester thereof which is industrially superior and has high optical purity. The purpose is to provide.

[0006]

The present invention provides a compound represented by the following general formula (1):

[0007]

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(Wherein, R represents a linear or branched alkyl group having 1 to 17 carbon atoms, an alkenyl group having 2 to 17 carbon atoms or an aralkyl group having 6 to 25 carbon atoms. A is fluorine. Represents a halogen, an alkylsulfonyloxy group or an arylsulfonyloxy group, excluding the above), and an enantiomeric mixture of a 2-substituted-3-phenylpropionic acid ester represented by the following formula: Is hydrolyzed by an enzyme capable of asymmetric hydrolysis to obtain the following general formula (2):

[0009]

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(Wherein A is the same as described above) and (S) -2-substituted-3-phenylpropionic acid represented by the following general formula (3):

[0011]

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Wherein A is the same as defined above, and a product comprising (R) -2-substituted-3-phenylpropionic acid; and the following general formula (4):

[0013]

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(Wherein R and A are the same as described above), and (R) -2-substituted-3-phenylpropionic acid ester represented by the following general formula (5):

[0015]

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Wherein (R) and (A) are the same as described above, a step (I) of obtaining an unreacted product comprising the (S) -2-substituted-3-phenylpropionic acid ester, When the content of the (S) -2-substituted-3-phenylpropionic acid in the product is larger than the content of the (R) -2-substituted-3-phenylpropionic acid, ) -2-Substituted-3-phenylpropionic acid is collected or (R) -2-substituted-3 in the above product
When the content of -phenylpropionic acid is larger than the content of (S) -2-substituted-3-phenylpropionic acid, the (R) -2-substituted-3-phenylpropionic acid is collected from the product. (II), and when the content of the (R) -2-substituted-3-phenylpropionic acid ester in the unreacted product is the above (S) -2-substituted-3
When the content is higher than the content of -phenylpropionate, the (R) -2-substituted-3-phenylpropionate is recovered from the unreacted material, or the (S) in the unreacted material is recovered. When the content of -2-substituted-3-phenylpropionic acid ester is the above (R) -2-substituted-3-
When the content is more than the content of the phenylpropionate, in the step (III) of recovering the (S) -2-substituted-3-phenylpropionate from the unreacted product, the step (I), and A method for producing an optically active 2-substituted-3-phenylpropionic acid and its enantiomer ester, which comprises one or both of the above step (II) and the above step (III). Hereinafter, the present invention will be described in detail.

[0017]

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The outline of the present invention is represented by the above reaction formula. That is, a product obtained by hydrolyzing an enantiomeric mixture of a 2-substituted-3-phenylpropionic acid ester represented by the general formula (1) by the action of an enzyme is represented by the general formula (2). (S) -2-Substituted-3-phenylpropionic acid or (R) -2-substituted-3-phenylpropionic acid represented by the above general formula (3) is collected and left without reacting. (R) -2-substituted-3-phenylpropionic acid ester represented by the above formula (4) or (S) -2-substituted-3-phenylpropionate represented by the above formula (5) from unreacted substances This is for recovering the onion ester.

In the present invention, first, in the step (I), the enantiomeric mixture of the above-mentioned 2-substituted-3-phenylpropionic acid ester is hydrolyzed with an enzyme to give the above-mentioned (S) -2-substituted-3-phenylpropionate. A product consisting of ononic acid and the above (R) -2-substituted-3-phenylpropionic acid is obtained. At this time, the above (R) -2-substitution-3
An unreacted product consisting of -phenylpropionic acid ester and the above (S) -2-substituted-3-phenylpropionic acid remains in the reaction mixture.

2-Substituted-3- used in the present invention
The enantiomer mixture of phenylpropionate is a compound represented by the above general formula (1). In the general formula (1), R is a linear or branched alkyl group having 1 to 17 carbon atoms, an alkenyl group having 2 to 17 carbon atoms, or an aralkyl group having 6 to 25 carbon atoms. Specifically, when R is an alkyl group, examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, a cyclohexyl group, an amyl group, and an isoamyl group. When R is an alkenyl group, examples thereof include a 2-propenyl group and a 3-butenyl group. When R is an aralkyl group, examples include a phenyl group and a benzyl group.

In addition to the above, Protective Groups in Organic Synthesis, 2nd edition (Pr.
active Groups in Organi
cSynthesis, 2nd Ed. ), Theodora
Theo Green W. Green
n), John Willie and Sons (John
Wiley & Sons) (1990) 2
Functional group derivatives described on pages 27 to 276, and the like. Preferably, it is a methyl group.

In the general formula (1), A is a halogen other than fluorine, an alkylsulfonyloxy group or an arylsulfonyloxy group. Preferably, when A is a halogen, it is bromine; when A is an alkylsulfonyloxy group, it is a methylsulfonyloxy group; when A is an arylsulfonyloxy group, p-toluene It is a sulfonyloxy group. The enantiomeric mixture ratio of the enantiomer mixture of the 2-substituted-3-phenylpropionic acid ester is not particularly limited, but a racemic form is preferable in that it is easily available.

The enzyme used in the present invention is not particularly limited as long as it can asymmetrically hydrolyze the ester bond of the 2-substituted-3-phenylpropionic acid ester. Examples include microorganisms and commercially available enzymes. Preferably, they are esterase and acylase.

In the present invention, microorganism-derived enzymes can be suitably used as the above enzymes. The enzyme derived from the microorganism is not particularly limited. For example, Rhizopus ( R
Hizopus) genus Mucor (Mucor) genus Penicillium (Penicillium) genus Candida (C
andida) genus Bacillus (Bacillus) genus,
Lipases derived from microorganisms belonging to the genus Pseudomonas are exemplified. In the present invention, lipases derived from microorganisms belonging to the genus Rhizopus, Mucor, Penicillium, Candida or Bacillus are particularly preferred. Can be used. Such a lipase is not particularly limited. For example, a lipase derived from the genus Rhizopus (L-057 Biocatalyst) and a lipase derived from the genus Mucor (Lipozyme)
Commercially available products such as IM Novo Nordisk, lipase derived from Candida (L-049, manufactured by Biocatalyst), and lipase derived from Penicillium (L-055P, manufactured by Biocatalyst) can be used. .

The utilization form of the above enzyme is not particularly limited, and may be any form such as a purified enzyme, a crude enzyme, a state contained in cells or tissues, and the like. Furthermore, it is also effective to use the enzyme immobilized on an inorganic carrier, an organic polymer carrier or the like, and it works particularly advantageously in repeated reactions.

The above-mentioned 2-
When performing hydrolysis of the enantiomer mixture of the substituted-3-phenylpropionic acid ester, it is preferable to carry out the hydrolysis in an aqueous solvent or buffer. In the enzymatic reaction, the concentration of the enantiomer mixture of the 2-substituted-3-phenylpropionic acid ester as a substrate is 0.1
~ 70% by weight is preferred. More preferably, it is 5 to 40% by weight. The temperature of the enzyme reaction is determined by the enzyme used, but is preferably from 0 to 60 ° C. More preferably, it is 20 to 50 ° C. The pH of the reaction solution in the above enzyme reaction is preferably 2 to 11. More preferably, it is 5-8.

When the enzyme is dispersed in the reaction solution and the reaction proceeds in a heterogeneous system, the enzyme reaction is preferably carried out with stirring or shaking, but may be carried out in a stationary state. . It is also possible to use a flow-through continuous reaction system. The amount of the enzyme used is the amount of 2-
It is preferably from 0.1 to 50% by weight based on the enantiomer mixture of the substituted-3-phenylpropionic acid ester.

After completion of the enzymatic reaction, the method for obtaining the product and the unreacted product from the reaction solution is not particularly limited. For example, ethyl acetate, chloroform, ether, etc. may be added to the reaction solution. Extraction with an organic solvent is performed, and the unreacted product is obtained by applying a conventional method such as distillation and column chromatography to the obtained organic layer. By lowering the pH of the aqueous layer after extraction to 3 or less, After converting (S) -2-substituted-3-phenylpropionic acid and (R) -2-substituted-3-phenylpropionic acid into free acids, the reaction product is extracted by extracting with an organic solvent such as ethyl acetate. Obtainable.

In the present invention, after performing the above step (I), the following steps (II) and (III)
Perform either one or both.

In the step (II), the content of the (S) -2-substituted-3-phenylpropionic acid in the product is reduced by the content of the (R) -2-substituted-3-phenylpropionic acid. If the amount is larger than the above, the (S) -2-substituted-3-phenylpropionic acid is collected from the product, and the content of the (R) -2-substituted-3-phenylpropionic acid in the product is determined. Is the above (S) -2-substituted-3-
When the content is higher than the content of phenylpropionic acid, the (R) -2-substituted-3-phenylpropionic acid is collected from the product.

From the above product, the above (S) -2-substituted-3
-Phenylpropionic acid or the above (R) -2-substituted-3
The method for collecting phenylpropionic acid is not particularly limited. For example, after removing unreacted substances by an operation such as extraction with a solvent such as ethyl acetate, the aqueous layer is adjusted to pH 2 and extracted with ethyl acetate or the like. Can be collected by concentration. In the case where the above (S) -2-substituted-3-phenylpropionic acid or the above (R) -2-substituted-3-phenylpropionic acid with higher purity is required, for example, the above-mentioned product excluding unreacted materials is used. Dicyclohexylamine is added to a solution of the above in ethyl acetate at 50 ° C., and it is cooled and crystallized to obtain a highly pure salt of the above product.

In the step (III), the content of the (R) -2-substituted-3-phenylpropionic acid ester in the unreacted product is reduced by the above (S) -2-substituted-3-phenylpropionic acid If the content is higher than the ester content,
The (R) -2-substituted-3-phenylpropionic acid ester is recovered from the unreacted material, and the content of the (S) -2-substituted-3-phenylpropionic acid ester in the unreacted material is as described above. When the content is higher than the content of (R) -2-substituted-3-phenylpropionate, the (S) -2-substituted-3-phenylpropionate is recovered from the unreacted product.

From the above unreacted product, the above (R) -2-substituted
3-phenylpropionic acid ester or the above (S) -2
The method for recovering the substituted 3-phenylpropionic acid ester is not particularly limited, and for example, can be obtained by extracting the reaction solution with ethyl acetate or the like and concentrating the organic layer. (R) -2-substituted-3 having a higher purity
-Phenylpropionic acid ester or the above (S) -2-
When a substituted -3-phenylpropionic acid ester is required, for example, the unreacted extract is acid-hydrolyzed with hydrochloric acid or the like to form a carboxylic acid, extracted with ethyl acetate, and added with dicyclohexylamine at 50 ° C. Cool crystallization,
A carboxylate. The obtained carboxylate is dissolved in methanol and acidified with an acid such as p-toluenesulfonic acid. Thereafter, the ester having high purity can be collected by heating and dehydrating.

In the present invention, when both the above-mentioned step (II) and the above-mentioned step (III) are carried out, the above-mentioned (S) -2-substituted-3-phenylpropionic acid is collected in the above-mentioned step (II). In the step (III), the (R) -2-substituted-3-phenylpropionate can be recovered. When the (R) -2-substituted-3-phenylpropionic acid is collected in the step (II), the (S) -2-substituted-3-phenylpropionic acid ester is collected in the step (III). Can be recovered.

The optically active 2-substituted-3-phenylpropionic acid and its enantiomer ester obtained as described above can be derived into an ester or a carboxylic acid, respectively, by a known method.

[0036]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Reference Example 1 Preparation of methyl 2-p-toluenesulfonyloxy-3-phenylpropionate 2.0 g (11.1 mmol) of racemic 2-hydroxy-3-phenylpropionic acid methyl ester was added to THF.
Dissolved in 20 ml and triethylamine 3.07 under ice-cooling.
ml and 3.17 g of p-toluenesulfonyl chloride
(16.6 mmol) were added sequentially. 10 under ice cooling
After stirring at room temperature for 1 hour and then at 30 ° C. for 1 hour, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and the ethyl acetate solution was added to a 1N aqueous solution of HCl and 5% NaHCO _3.
The extract was washed with an aqueous solution and saturated saline in this order, and dried over sodium sulfate. After concentrating the organic layer, it is applied to a silica gel column (hexane-ethyl acetate = 3: 1) to obtain racemic 2-p-toluenesulfonyloxy-3-phenylpropionic acid methyl ester (3.06 g, yield 82%). Was.

¹ H NMR (CDCl ₃ ); δ2.40
(S, 3H), 3.02 to 3.08 (dd, 1H),
3.12 to 3.17 (dd, 1H), 3.68 (s, 3
H), 4.92-4.95 (q, 1H), 7.04-
7.07 (dd, 2H), 7.17 to 7.19 (m, 5
H), 7.55 (dd, 2H) ppm Elemental analysis; C ₁₇ H ₁₈ SO ₅ Calculated (%); C, 61.06; H, 5.43; S,
9.59 actual value (%); C, 61.05; H, 5.32; S,
9.63

Example 1 Preparation of optically active 2-p-toluenesulfonyloxy-3-phenylpropionic acid and its enantiomer methyl ester Racemic 2-p-toluenesulfonyloxy-3-phenylpropionic acid methyl ester 20 0.0 mg of lipase (from Rhizopus javanicus, manufactured by Nagase & Co., Ltd.) 2
A 100 mM phosphate buffer solution (pH 7.0) containing 0.0 mg.
0) Added in 1000 μl. It was sealed and reacted in a shaking incubator at 30 ° C for 20 hours. After completion of the reaction, the enzyme was removed by filtration, and unreacted 2-p-toluenesulfonyloxy-3-phenylpropionic acid methyl ester was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain optically active methyl 2-p-toluenesulfonyloxy-3-phenylpropionate (10.2 mg, 51% recovery). . This optically active 2-p-toluenesulfonyloxy-3-phenylpropionic acid methyl ester was measured for optical purity using an optical resolution column (Chiral Cell OJ, manufactured by Daicel Chemical Industries, Ltd.). It was 3% ee. On the other hand, the pH of the aqueous layer was adjusted to 2.0 with dilute sulfuric acid, and ethyl acetate was added thereto to add 2-p-toluenesulfonyloxy-3.
-Phenylpropionic acid was extracted. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain optically active 2-p-toluenesulfonyloxy-3-phenylpropionic acid (9.4 mg, yield 49%). This optically active 2-p-toluenesulfonyloxy-3-phenylpropionic acid can be purified with an optical resolution column (Chiralcel OD).
-R, manufactured by Daicel Chemical Industries, Ltd.) and the optical purity was 89.6% ee for the (S) form.

¹ H NMR (CDCl ₃ ); δ2.40
(S, 3H), 3.04-3.10 (dd, 1H),
3.19-3.23 (dd, 1H), 4.97-5.0
0 (q, 1H), 7.07 (dd, 2H), 7.15-
7.22 (m, 5H), 7.52 (dd, 2H) ppm Elemental analysis; C ₁₆ H ₁₆ SO ₅ Calculated (%); C, 59.98; H, 5.03. S,
10.01 actual value (%); C, 60.01; H, 5.01; S, 1
0.04

Using the asymmetric hydrolases shown in Table 1,
The same experiment was performed and the results shown in the same table were obtained. In the table,
“−−” indicates that the measurement was not performed.

[0042]

[Table 1]

Example 2 Preparation of optically active 2-methylsulfonyloxy-3-phenylpropionic acid and its enantiomer methyl ester 20.0 mg of racemic 2-methylsulfonyloxy-3-phenylpropionic acid methyl ester was lipased. L
It was added to 1000 μl of 100 mM phosphate buffer (pH 7.0) containing 20.0 mg of −116P (derived from Mucor javanicus, manufactured by Biocatalyst). It was sealed and reacted in a shaking incubator at 30 ° C for 20 hours. After completion of the reaction, the enzyme was removed by filtration, and unreacted methyl 2-methylsulfonyloxy-3-phenylpropionate was extracted with ethyl acetate. The organic layer was dehydrated by adding anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain optically active methyl 2-methylsulfonyloxy-3-phenylpropionate (9.5 mg, recovery rate: 47.5%). .
When the optical purity of this optically active 2-methylsulfonyloxy-3-phenylpropionic acid methyl ester was measured using an optical resolution column (Chiral Cell OD-H, manufactured by Daicel Chemical Industries, Ltd.), the (R) form was 98. It was 9% ee. On the other hand, the pH of the aqueous layer was adjusted to 2.0 with dilute sulfuric acid, and ethyl acetate was added to extract 2-methylsulfonyloxy-3-phenylpropionic acid. The organic layer was dehydrated by adding anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
-Methylsulfonyloxy-3-phenylpropionic acid (9.9 mg, yield 52.5%) was obtained. This optically active 2-methylsulfonyloxy-3-phenylpropionic acid was derivatized to methyl ester with diazomethane,
When the optical purity was measured using an optical resolution column (Chiral Cell OD-H, manufactured by Daicel Chemical Industries, Ltd.), it was 76.3% ee for the (S) form. The same experiment was performed using the asymmetric hydrolase shown in Table 2, and the results shown in the table were obtained. In the table, “−−” indicates that no measurement was performed.

[0044]

[Table 2]

Example 3 Production of optically active 2-bromo-3-phenylpropionic acid and its enantiomer methyl ester. 20.0 mg of racemic 2-bromo-3-phenylpropionic acid methyl ester was added to Lipase L-057 (derived from Rhizopus arhidus, Biocatalyst) 20.0 mg
100 mM phosphate buffer (pH 7.0) containing 1 mg
Added in 000 μl. It was sealed and reacted in a shaking incubator at 30 ° C for 20 hours. After completion of the reaction, the enzyme was removed by filtration, and unreacted methyl 2-bromo-3-phenylpropionate was extracted with ethyl acetate. The organic layer was dehydrated by adding anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain optically active methyl 2-bromo-3-phenylpropionate (6.2 mg, 31% recovery). When the optical purity of this optically active 2-bromo-3-phenylpropionic acid methyl ester was measured using an optical resolution column (Chiral Cell OD-H, manufactured by Daicel Chemical Industries, Ltd.), the (S) form was 90.5%. ee. On the other hand, the pH of the aqueous layer was adjusted to 2.0 with diluted sulfuric acid, and ethyl acetate was added to extract 2-bromo-3-phenylpropionic acid. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain optically active 2-bromo-3-phenylpropionic acid (13.0 mg, yield 69%). This optical activity 2
-Bromo-3-phenylpropionic acid was derivatized to methyl ester with diazomethane, and the optical purity was measured using an optical resolution column (Chiral Cell OD-H, manufactured by Daicel Chemical Industries, Ltd.). 38.6% ee. Similar experiments were performed using the asymmetric hydrolases shown in Table 3 and the results shown in the same table were obtained. In the table, "-
"-" Indicates that the measurement was not performed.

[0046]

[Table 3]

[0047]

According to the present invention having the above-mentioned constitution, optically active 2-substituted-3-phenylpropionic acid having high optical purity and its enantiomer ester can be industrially and efficiently produced. .

Claims (7)

[Claims] 1. The following general formula (1): (In the formula, R is a linear or branched alkyl group having 1 to 17 carbon atoms, an alkenyl group having 2 to 17 carbon atoms, or 6 carbon atoms.
Represents up to 25 aralkyl groups. A represents a halogen other than fluorine, an alkylsulfonyloxy group or an arylsulfonyloxy group. A) enantiomer mixture of a 2-substituted-3-phenylpropionic acid ester represented by
The ester bond of the 2-substituted-3-phenylpropionic acid ester is hydrolyzed by an enzyme capable of asymmetric hydrolysis to obtain the following general formula (2): (In the formula, A is the same as described above.) (S) -2-
Substituted-3-phenylpropionic acid and the following general formula (3); (In the formula, A is the same as described above.) (R) -2-
A product comprising substituted -3-phenylpropionic acid, and the following general formula (4): (Wherein R and A are the same as described above).
-2-Substituted-3-phenylpropionic acid ester and the following general formula (5); (Wherein R and A are the same as described above) (S)
Step (I) of obtaining an unreacted product comprising -2-substituted-3-phenylpropionic acid ester, wherein the content of the (S) -2-substituted-3-phenylpropionic acid in the product is (R ) When the content of 2-substituted-3-phenylpropionic acid is higher than that of (S) -2,
-Substituted-3-phenylpropionic acid is collected, or the content of the (R) -2-substituted-3-phenylpropionic acid in the product is (S) -2-substituted-3-
When the content is more than the phenylpropionic acid content, the step (II) of collecting the (R) -2-substituted-3-phenylpropionic acid from the product, and the (R)-in the unreacted product When the content of the 2-substituted-3-phenylpropionate is higher than the content of the (S) -2-substituted-3-phenylpropionate, the unreacted product is converted to the (R) -2-substituted. -3-Phenylpropionate is recovered, or the content of the (S) -2-substituted-3-phenylpropionate in the unreacted product is reduced to the (R) -2-substituted-3- When the content of the phenylpropionate is higher than the content of the phenylpropionate, in the step (III) of recovering the (S) -2-substituted-3-phenylpropionate from the unreacted product, the step (I), and Wherein step (II) and the step (I
A method for producing an optically active 2-substituted-3-phenylpropionic acid and its enantiomer ester, which comprises one or both of II). 2. The method according to claim 1, wherein the step (II) comprises converting the product to (S) -2.
The step of collecting -substituted-3-phenylpropionic acid, wherein the step (III) is a step of recovering (R) -2-substituted-3-phenylpropionic acid ester from an unreacted product. A process for producing optically active 2-substituted-3-phenylpropionic acid and its enantiomer ester. 3. The method according to claim 1, wherein the step (II) comprises converting the product to (R) -2
The step of collecting -substituted-3-phenylpropionic acid, wherein the step (III) is a step of recovering (S) -2-substituted-3-phenylpropionic acid ester from unreacted products. A process for producing optically active 2-substituted-3-phenylpropionic acid and its enantiomer ester. 4. The enzyme capable of asymmetrically hydrolyzing an ester bond of a 2-substituted-3-phenylpropionic acid ester is an esterase or an acylase.
4. The method for producing the optically active 2-substituted-3-phenylpropionic acid and the enantiomer thereof according to 2 or 3. Enzymes 5. A 2-substituted-3 ester linkages phenylpropionic acid ester can be asymmetric hydrolysis is, Rhizopus (Rhizopus) genus Mucor (Mucor) genus Penicillium (Penicilli
um) genus Candida (Candida) genus or Bacillus (Bacillus) is a lipase derived from a microorganism belonging to the genus claim 1, wherein the optically active 2-substituted -3
-A process for producing phenylpropionic acid and its enantiomer ester. 6. The method according to claim 1, wherein A is bromine, a methylsulfonyloxy group, or a p-toluenesulfonyloxy group.
The process for producing an optically active 2-substituted-3-phenylpropionic acid and its enantiomer ester according to 2, 3, 4 or 5. 7. The method according to claim 1, wherein R is a methyl group.
7. The process for producing an optically active 2-substituted-3-phenylpropionic acid and its enantiomer ester according to 3, 4, 5 or 6.