JP2542833B2 - Process for producing optically active alcohols and esters - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for producing an optically active alcohol or ester by a biochemical method, which comprises reacting an alcohol of the above general formula with an enzyme.

[Problems to be solved by conventional technology and invention]

The optically active alcohols of the above general formula are known to be very demanding compounds as physiologically active substances such as medicines and agricultural chemicals, or intermediate raw materials thereof, or intermediates of liquid crystal compounds.

However, the general formula: (X ¹ , X ² , X ³ , X ⁴ , X ⁵ are hydrogen atom, halogen atom, cyano group, trifluoromethyl group, amino group, alkylamino group, aryloxy group, And selected from the group consisting of alkyl or alkoxy group having a carbon number of 1 to 20, Y is a halogen atom, an alkyl group, a cyano group, selected from the group consisting of trifluoromethyl group, Z ^1, Z ^2,
Z ³ , Z ⁴ and Z ⁵ are selected from the group consisting of hydrogen atom, halogen atom, cyano group, trifluoromethyl group, amino group, alkylamino group, and alkyl or alkoxy group having 1 to 20 carbon atoms, and R Is an alkylene group having 1 to 20 carbon atoms,
n is 0 or 1. The alcohols represented by) have R-form and S-form because they have optical isomers.
In many cases, the body does not exhibit sufficient physiological activity unless it contains either the body or the body in high purity.

Therefore, in order to obtain an optically active substance, the racemate obtained by a general synthetic chemical production method must be optically resolved, asymmetrically synthesized, or synthesized from an optically active substance by a stereochemical method. However, the process is complicated and industrially disadvantageous.

Therefore, it has been desired to develop a technique of performing optical division by an industrially advantageous method.

As an optical resolution method for alcohols such as the above-mentioned general formula currently known, as a biochemical method, for example, hydrolysis of a racemic ester by lipase as in JP-A-59-205989, There is a method for obtaining the desired optically active alcohol. In this case, the ester of the starting material is often insoluble in water, and it is necessary to make an emulsion or to stir vigorously with a large amount of water. In addition, since the enzyme is water-soluble and unstable to water, it is necessary to immobilize the enzyme for stable action, and for easy removal or reuse of the enzyme after the reaction.

In addition, G. Langrand et al. Used an enzyme to synthesize alcohols into alcohols for resolution (Tetr
ahedron Letters 26 , 1857 (1985)), alcohols to be resolved are limited to substituted cyclohexanols.

[Means for solving problems]

The present inventors have conducted research to find a method for producing an optically active alcohol of the above general formula by an industrially advantageous method. It was found that the enantiomeric ester synthesis was performed and the optically active ester and its antipodal optically active alcohol were efficiently resolved.

That is, the present invention acts on the (R, S) -alcohol represented by the above general formula to preferentially react with either the R-form or the S-form alcohol with a fatty acid and an asymmetric ester synthesis reaction. An enzyme having the ability is used, the (R, S) -alcohol is used, and an ester synthesis reaction is carried out in a fatty acid and an organic solvent under conditions substantially free of water to obtain either an R-form or an S-form. It is a method of dividing into optically active alcohol and ester rich in one side.

Unlike the conventional method, the method of the present invention carries out the reaction in the absence of water. Since this method does not require the use of water or lower alcohols in place of water, it does not cause hydrolysis of the synthesized ester, keeps the enzyme stable in an organic solvent, and allows easy separation and reuse after the reaction. It is possible. Furthermore, since the enzyme is directly used, microbial contamination does not occur, so there is no need for special equipment or preservatives, and the reaction can be performed in an open system.

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

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

As for fatty acids, commercially available products that are easily available are sufficient, and examples thereof include acetic acid, propionic acid, butyric acid, caproic acid,
Examples include lauric acid, stearic acid, myristic acid, oleic acid and the like.

As the enzyme used in the present invention, lipases derived from the genus Pseudomonas are particularly preferable, and the following are commercially available products thereof.

In addition to these enzymes, any microorganism can be used as long as it produces an enzyme capable of carrying out the above reaction, regardless of its type. Examples of such microorganisms include those belonging to the genus Pseudomonas.

The ester synthesis reaction of (R, S) -alcohol is (R, S)
It is carried out by mixing an alcohol with a fatty acid in an organic solvent such as toluene, hexane or heptane and efficiently contacting with an enzyme.

At this time, the reaction temperature is suitably 20 to 70 ° C, particularly preferably 30 to 45 ° C. Wide reaction time 5
The reaction time can be shortened by increasing the reaction temperature, using a highly active enzyme (having a large number of units), or decreasing the substrate concentration.

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

After carrying out the asymmetric ester synthesis reaction in this manner, the enzyme can be removed by a usual filtration operation and can be reused as it is. The reaction solution, which is a filtrate, can be obtained by separating the optically active ester and alcohol from each other by distillation under reduced pressure or column chromatography, and the ester produced by the synthetic reaction is subjected to the usual alkaline hydrolysis to obtain the above-mentioned alcohol. It becomes an optically active alcohol that is the antipode to.

By the above operation, optically active alcohol can be obtained in each of R-form and S-form.

〔The invention's effect〕

 The effects of the present invention are listed below.

Since the reaction is carried out under the substantially absence of water, unnecessary hydrolysis of the ester hardly occurs.

 The enzyme can be easily recovered and reused.

Since the reaction can be performed at a relatively low temperature and in an open system, no special equipment or materials are required.

A highly pure optically active substance can be obtained by a one-step reaction.

Since water is not required, the substrate concentration can be increased despite the biochemical reaction, and a large-capacity reaction container for the substrate is not required.

〔Example〕

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

Example 1 20 g of enzyme (Amano Pharmaceutical Co., lipase "Amano" P), (R,
S) -1-Phenylethyl alcohol 24.4 g (0.2 mol),
And 44.1 g (0.22 mol) of lauric acid were placed in a three-necked flask, and the reaction was carried out by stirring at 35 ° C for 9 days. After stopping the reaction,
The enzyme was removed by filtration, this was washed with toluene, the washing liquid was added to the filtrate, and then vacuum distillation was performed. Boiling point 52-62 ℃
S-(-)-1-phenylethyl alcohol 1 at 3mmHg
6.7 g (yield 68.5%, [α] _D = -28.9 ° (neat)) was obtained. The kettle residue is subjected to column chromatography and R-
(+)-1-Phenylethyl laurate was obtained.

Next, hydrolysis was carried out by an ordinary method to give 4.79 g of R-(+)-1-phenylethyl alcohol (yield 19.6%, [α] _D =
−39.9 ° (neat) was obtained.

Example 2 According to the method of Example 1, 12.4 g of (R, S) -4- (2-hydroxyethyl) -4'-octylbiphenyl was optically resolved by ester synthesis reaction with 8.8 g of lauric acid. 4.6 g of-(-)-4- (2-hydroxyethyl) -4'-octylbiphenyl (yield 37.2%,
[Α] _D = -3.2 ° (c1.0, toluene)), and R-
(+)-4- (2-dodecanoyloxyethyl) -4 '
-5.4 g of octylbiphenyl are obtained. This was hydrolyzed by a usual method to give R-(+)-4- (2-hydroxyethyl) -4'-octylbiphenyl 3.0 g (yield 24.2%,
[Α] _D = + 15.4 ° (c1.0, toluene)) was obtained.

Claims (1)

(57) [Claims] 1. A general formula: (X ¹ , X ² , X ³ , X ⁴ , X ⁵ are hydrogen atom, halogen atom, cyano group, trifluoromethyl group, amino group, alkylamino group, aryloxy group, And selected from the group consisting of alkyl or alkoxy group having a carbon number of 1 to 20, Y is a halogen atom, an alkyl group, a cyano group, selected from the group consisting of trifluoromethyl group, Z ^1, Z ^2,
Z ³ , Z ⁴ and Z ⁵ are selected from the group consisting of hydrogen atom, halogen atom, cyano group, trifluoromethyl group, amino group, alkylamino group, and alkyl or alkoxy group having 1 to 20 carbon atoms, and R Is an alkylene group having 1 to 20 carbon atoms,
n is 0 or 1. A lipase derived from the genus Pseudomonas having the ability to act on an (R, S) -alcohol represented by In the presence of a substantially water-free condition, the (R, S) -alcohol and the fatty acid are reacted in an organic solvent to carry out an ester synthesis reaction.
A method for producing an optically active alcohol or ester by a biochemical method, characterized in that it is divided into optically active alcohol and ester rich in either one of the bodies.