JPS63123399A - Production of optically active alcohol and ester - Google Patents

Abstract

PURPOSE:To efficiently obtain the titled compound useful as an intermediate raw materials, etc., by reacting a specific (R,S)-alcohol with a carboxylic acid in the presence of an enzyme capable of acting the (R,S)-alcohol and forming an asymmetric ester with preferentially either R form or S form of the alcohol in an organic solvent. CONSTITUTION:An (R,S)-alcohol shown by formula I (X<1>-X<5> are H, halogen, cyano, trifluoromethyl, amino, group shown by formula II (Z<1>-Z<5> are H, halogen, cyano, 1-20C alkyl, etc.), 1-20C alkyl, etc.); Y is halogen, alkyl, cyano or trifluoromethyl; R is 1-20C alkylene; n is 0 or 1] is reacted with a carboxylic acid in the presence of an enzyme capable of acting on the (R,S)- alcohol and subjecting to preferentially either R-form or S-form of the alcohol and the carboxylic acid to asymmetric synthetic reaction under a water-free condition in an organic solvent and resolved into an optically active alcohol rich in either of R-form or S-form and an ester to give the aimed compound.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for producing optically active alcohols and esters by a biochemical method in which enzymes are used to act on alcohols having the above general formula.

[Problems to be solved by the prior art and the invention] The optically active alcohols of the above general formula are in great demand as physiologically active substances such as medicines and agricultural chemicals, or as intermediate raw materials thereof, or as intermediates for liquid crystal compounds. It is known as a compound with many

However, the general formula: % is selected from the group of halogen atom, cyano group, trifluoromethyl group, amino group, alkylamino group, alkyl group or alkoxy group, and Y is a halogen atom,
Zt, zz selected from the group of alkyl groups, cyano groups, and trifluoromethyl groups.

z3. z' and z' are selected from the group of hydrogen atom, halogen atom, cyano group, trifluoromethyl group, amino group, alkylamino group, and alkyl group or alkoxy group having 1 to 20 carbon atoms, and R is the number of carbon atoms 1 to 20 alkylene groups, and n is 0 or 1. ) Since alcohols such as those represented by the following exist optical isomers,
Unless it contains either the R-isomer or the S-isomer in high purity, it will not exhibit sufficient physiological activity in most cases.

Therefore, in order to obtain an optically active substance, it is necessary to optically resolve a racemate obtained by ordinary synthetic chemical production methods, perform asymmetric synthesis, or synthesize it from an optically active substance using stereochemical methods. However, the process was complicated and industrially disadvantageous.

Therefore, it has been desired to develop a technique for optical resolution using an industrially advantageous method.

Currently known optical resolution methods for alcohols such as the above general formula include biochemical methods such as hydrolyzing racemic esters with lipase as disclosed in Japanese Patent Application Laid-Open No. 59-205989, and There is a method to obtain an optically active alcohol.

In this case, the starting ester is often insoluble in water, and it is necessary to form it into an emulsion or to stir vigorously with a large amount of water. Furthermore, since enzymes are water-soluble and unstable with respect to water, it has been necessary to immobilize the enzymes in order to make them work stably and to easily remove or reuse them after the reaction.

In addition, Langland (G, Langland) et al.
Alcohols are synthesized and split into esters using enzymes (Tetrahedron Letters 26
．． 185', (1985)), the alcohols to be resolved are limited to substituted cyclohexanols.

[Means for solving problems]

The present inventors conducted research to find an industrially advantageous method for producing an optically active alcohol of the general formula, and found that using a racemic alcohol of the general formula as a raw material,
We synthesized an asymmetric ester biochemically and found that it could be efficiently separated into an optically active ester and its enantiomer, an optically active alcohol.

That is, the present invention acts on the (R,S)-alcohol represented by the above general formula to cause an asymmetric ester synthesis reaction with either the R-form or the S-form alcohol preferentially with a carboxylic acid. (R,S) using an enzyme having the ability to
- Performing an ester synthesis reaction with a carboxylic acid in an organic solvent using alcohol under conditions substantially free of water;
This is a method of splitting into optically active alcohol and ester that are enriched in either R or S.

The method of the present invention differs from conventional methods in that the reaction is carried out in the absence of moisture. Since this method does not require the use of water or a lower alcohol in place of water, it does not cause hydrolysis of the synthesized ester, keeps the enzyme stable in a solvent, and allows for easy separation and regeneration after the reaction. Usable. Furthermore, since microbial contamination does not occur because an electric element is used directly, there is no need for special equipment or preservatives, and the reaction can be carried out in an open system.

Next, the method of the present invention will be described in detail.

In the present invention, the (R,S)-alcohol used as a raw material is a compound that is available or can be easily synthesized.

Easily available commercially available carboxylic acids are sufficient, and examples include acetic acid, propionic acid, butyric acid, caproic acid, lauric acid, stearic acid, myristic acid, and oleic acid.

Preferred enzymes used in the present invention include lipase, ribotin lipase, and esterase. However, any type may be used as long as it has the ability to act on (R,S)-alcohol and cause an ester synthesis reaction with carboxylic acid preferentially with either the R-form or S-form alcohol. Commercially available products include the following.

In addition to these enzymes, any microorganism that produces an enzyme capable of carrying out the above reaction can be used, regardless of its type. Examples of such microorganisms include Arthrobacter
er) genus, Achromobacter - CAcroarobac
ter) Tels, Alcaligenes (Alcal i
Genes), Aspergillus
I 1us) genus, Chromobacterium (Chromobacterium
genus acterium, Candida
Genus, Mucor genus, Shutomonas (Ps
eudomonas), Rhizopus
) include those belonging to the genus etc.

The ester synthesis reaction of (R,S)-alcohol is (R,S)-alcohol ester synthesis reaction.
S)-alcohol with carboxylic acid, toluene, hexane,
This is done by mixing in an organic solvent such as heptane and efficiently (contacting) it with the enzyme.

At this time, the reaction temperature is suitably 20 to 70°C, particularly preferably 30 to 45°C. Many) using enzymes or base! The reaction time can also be shortened by lowering the concentration.

The ratio of the substrate (R,S)-alcohol to carboxylic acid is 1:0.5 to 1:5 (molar ratio), preferably 1:1.1 to 1:2 (molar ratio). .

After performing the asymmetric ester synthesis reaction in this manner, the enzyme can be removed by a normal filtration operation and can be reused as is. The optically active ester and alcohol can be separated and obtained from the reaction solution (filtrate) by vacuum distillation or column chromatography.
Furthermore, the ester produced in the synthesis reaction becomes an optically active alcohol, which is the enantiomer of the above-mentioned alcohol, by ordinary alkaline hydrolysis.

By the above operations, optically active alcohols can be obtained in both the R and S forms.

〔Effect of the invention〕

The effects of this invention are listed below.

■ Since the reaction is carried out in substantially no water, unnecessary hydrolysis of the ester hardly occurs.

■ Enzymes can be easily recovered and reused.

■ Since the reaction can be carried out at relatively low temperatures and in an open system, no special equipment or materials are required.

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

■ Since no water is required, the substrate concentration can be high despite the biochemical reaction, and a reaction vessel with a large capacity for the substrate is not required.

〔Example〕

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

- Example 1 Enzyme (Amano Pharmaceutical, lipase "Amano, 1P)" 20g,
(R,S)-1-phenylethyl alcohol 24.4
g (0.2 mol), and laurin a44.1 g
(0.22 mol) was placed in a three-ring flask and stirred at 35° C. for 9 days to carry out a reaction. After the reaction was terminated, the enzyme was removed by filtration, washed with toluene, and the washing liquid was added to the filtrate, followed by vacuum distillation under reduced pressure. Boiling point 52-62℃/3
16.7 g of 5-(-)-1-phenylethyl alcohol at mmHg (yield 68.5%, [α) D--28
, 9'' (neat)) was obtained.

The residue was subjected to column chromatography and R-(+)-
1-phenylethyl laurate was obtained.

Next, it was hydrolyzed in a usual manner, and 4.79 g of R-(+)-1-phenylethyl alcohol (yield 19.6%,
[α]. = 39.9'' (neat)) was obtained.

Example 2 According to the method of Example 1, (R,S)-4-(2-hydroxyethyl)-4'-octylbiphenyl 12
．． 4g was optically resolved by ester synthesis reaction using 8.8g of lauric acid, and the result was 5-(-)-4-(2-hydroxyethyl)-4'-octylbiphenyl: 4.6
g (yield 37.2%, [α)D=3.2'(cl
, o, )luene)), and R-(+)-4-(2-
5.4 g of (dodecanoyloxyethyl)-4'-octylbiphenyl was obtained. This was hydrolyzed in a conventional manner to obtain R-(+)-4-(2-hydroxyethyl)-4゛
-Octyl biphenyl 3.0g (yield 24.2%,
[α]. =” 15.4 @ (cl, Or) Luen)
) was obtained.

Claims (1)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼... (1) (X^1, X^2, X^3, X^4, X^5 are hydrogen atoms, halogen atoms, Cyano group, trifluoromethyl group,
Amino group, alkylamino group, aryloxy group, ▲numerical formula, chemical formula, table, etc.▼, and carbon number 1-20
Y is selected from the group of halogen atoms, alkyl groups, cyano groups, trifluoromethyl groups, Z^1, Z^2, Z^3, Z
^4, Z^5 are hydrogen atoms, halogen atoms, cyano groups,
trifluoromethyl group, amino group, alkylamino group,
and an alkyl group or alkoxy group having 1 to 20 carbon atoms, R is an alkylene group having 1 to 20 carbon atoms, and n is 0 or 1. ) represented by (R,
Substantially the presence of water in the presence of an enzyme that acts on S)-alcohol and has the ability to perform an asymmetric ester synthesis reaction with carboxylic acid preferentially with either R-form or S-form alcohol. The (R,S)-alcohol and the carboxylic acid are reacted in an organic solvent under conditions that do not contain the ester, and an ester synthesis reaction is carried out to produce an optically active alcohol rich in either the R-form or the S-form. A method for producing optically active alcohols and esters using a biochemical method characterized by separation into esters.