JPS63112998A - Production of optically active ester - Google Patents

Abstract

PURPOSE:To efficiently obtain an optically active beta-acyloxyacid ester and beta- hydroxyacid ester, by biochemically carry out an asymmetric ester interchange reaction using (R, S)-beta-hydroxyacid ester of racemic modification as a raw material. CONSTITUTION:Ester interchange reaction is carried out in the presence of an enzyme, e.g. lipase, esterase, etc., having ability capable of reacting with a (R, S)-beta-hydroxyacid ester expressed by formula I (X is 1-20C alkyl group- and preferentially subjecting ester of either one of R- and S-configurations to ester interchange reaction under condition substantially free from water. Said ester is preferably triglyceride, etc. The racemic ester compound can be separated into optically active beta-hydroxyacid ester and beta-acyloxyacid ester rich in either one of R- and S-configurations by said reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing optically active esters using enzymes.

[Prior art and problems to be solved by the invention] Optically active β-hydroxy acid esters are very useful substances as optically active starting materials for physiologically active substances such as medicines and agricultural chemicals. A currently well-known production method involves stereoselectively reducing (R,S)-β-keto acid ester using baker's yeast (B,S).

Deol, D, D, R'1dley, G, Simp
son, Au5t, J, Chem.

29, 2459 (1976)). This method is simple and very useful at the laboratory level, but it requires several tens of liters of solvent to obtain several tens of grams of β-hydroxy acid ester, making it unsuitable for industrial or human production. Met.

[Means for solving problems]

The present inventors have conducted research to solve the above problems and obtain optically active β-hydroxy acid esters using an industrially advantageous method. As a result, instead of reducing β-keto acid esters, By using racemic (R,S)-β-hydroxy acid ester as a raw material and performing a biochemical asymmetric transesterification reaction, optically active β-acyloxy acid ester and β-hydroxy acid ester can be efficiently produced. I found out what I can get.

That is, the present invention provides a method for preparing a (R,S)-β-hydroxy acid ester represented by the general formula: (X represents an alkyl group having 1 to 10 carbon atoms) under conditions substantially free of water. An optically active ester is produced by carrying out a transesterification reaction with an ester and dividing it into an optically active β-hydroxy acid ester and a β-acyloxy acid ester that are rich in either the R-isomer or the S-isomer.

Next, the present invention will be described in detail.

Racemic (R,S)-β- which is a raw material in the present invention
Hydroxy acid esters are readily available and can be easily synthesized. For example, methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, etc. are commercially available. Also commercially available propyl acetoacetate, butyl acetoacetate, pentyl acetoacetate, hexyl acetoacetate,
Heptyl acetoacetate, octyl acetoacetate, isopropyl acetoacetate, isobutyl acetoacetate, isoamyl acetoacetate, tert-butyl acetoacetate, etc., with NaBII
They correspond to each other by reducing with 4 etc. (R, S
)-β-hydroxy acid ester.

Preferred suitable esters are triglycerides, which are easily available, such as triacetin, triplobionin, tributyrin, tristearin, trilaurin, trimistin, triolein, and the like. Other examples include methyl propionate, ethyl butyrate, propyl laurate, ethyl myristate, ethyl stearate, trichloroethyl acetate, trichloroethyl laurate, and ethylene glycol diacetate.

The enzyme used in the present invention is preferably lipase, lipoprotein lipase, or esterase, but it acts on racemic (R,S)-β-hydroxy acid ester and converts it into either R-body or S-body. Any type can be used as long as it has the ability to preferentially undergo a transesterification reaction with a suitable ester. Commercially available enzymes include
These include those shown in the table below.

In addition to these enzymes, any microorganism that produces an enzyme capable of carrying out the above reaction can be used regardless of its extraction pressure. Examples of such microorganisms include Arthrobacter genus, Achromobacter genus, Alcaligenes genus, Aspergillus genus, Chromobacterium E,
Candida spp., Mucor
) genus, Pseudomonas genus,
Examples include those belonging to the Rhizopus genus.

In practicing the present invention, racemic β-hydroxy acid esters and suitable esters such as triglycerides can all be used without special treatment.

The asymmetric transesterification reaction of racemic β-hydroxy acid ester is carried out by mixing (R,S)-β-hydroxy acid ester and an appropriate ester, preferably triglyceride, and bringing the mixture into efficient contact with an enzyme. be exposed.

The reaction temperature at this time is suitably 20°C to 70°C, particularly preferably 25°C to 45°C. Reaction times vary widely;
The time is from 5 hours to 2000 hours, and the reaction temperature is increased,
It is also possible to shorten the reaction time by using a highly active enzyme or by increasing or decreasing the substrate concentration.

The ratio of the substrate (R,S)-β-hydroxy acid ester and the appropriate ester is 1:0.5 to 1:5 (molar ratio).
and preferably 1:1-1:2.

After performing the asymmetric transesterification reaction in this manner, the enzyme can be removed by a normal filtration operation and can be reused as is. By distilling the reaction solution, which is a filtrate, under reduced pressure, optically active β-hydroxy acid ester and β-acyloxy acid ester can be separated and obtained.

〔Effect of the invention〕

The effects of the present invention are listed below.

(2) A highly pure optically active substance can be obtained through a −-step reaction.

■ Since no culture solution or buffer is required, there is no need for particularly large-capacity reaction vessels when synthesizing a target product in large quantities.

Moreover, no special equipment or materials are required.

■ Enzyme can be easily separated and reused after reaction.

〔Example〕

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 66 g of racemic ethyl β-hydroxybutanoate (0,
5 mol), tributyrin 166.3 g (0.6 m
ol), and lipase "Amano PJ 80g,
After stirring at 35°C for 1°, the reaction was stopped by filtering off the lipase.

The filtrate was distilled under reduced pressure to isolate ethyl S-(+)-β-hydroxybutanoate, yield ff14.7g, yield 44.5% ((
α) n= +17.3 @(C1,0,CHCl3)
) and R-(-)-β-butyryloxybutanoate ethyl isolated yield 1) 6.3 g, yield ff 132% ((α)n=-o,
3° (cl, 0° CHCl3)) were obtained, respectively.

Example 2 37.6 g (0,235 m
ol) and S-(+)-β-hydroxybutanoic acid ter to -butyl([α) n= +28.2°(c
l, 0. CHCh)) Isolated yield 7.8 g (yield 41%
) and R-(-)-β-butyryloxybutane fite
An isolated yield of 16.2 g (60% yield) of rt-butyl α8=-0.07° (neat, 10 cells) was obtained in each case.

Claims (2)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (X represents an alkyl group having 1 to 20 carbon atoms)
The (R,S)-β-hydroxy acid ester represented by the above general formula is converted into an (R,S)-β-hydroxy acid ester represented by the above general formula in the presence of an enzyme capable of transesterifying preferentially either the --form or the S-form with an appropriate ester. Perform a transesterification reaction with an appropriate ester under substantially water-free conditions to separate optically active β-hydroxy acid esters rich in either R-form or S-form and β-acyloxy acid esters. A method for producing an optically active ester, characterized by: (2) The method for producing an optically active ester according to claim 1, wherein the appropriate ester is a triglyceride.