JP2542838B2 - Process for producing optically active secondary alcohol and ester - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an optically active secondary alcohol and ester by a biochemical method in which a carboxylic acid is allowed to act on a secondary alcohol using an enzyme. Is.

[Problems to be solved by conventional technology and invention]

Optically active alcohols 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 is an alkyl group having 2 to 20 carbon atoms, Y represents an alkyl group having 1 to 3 carbon atoms or -CF _3, or -CN,. However,
X ≠ Y. The secondary alcohols represented by) have optical isomers, and therefore R-form and S-form.
In many cases, it does not exhibit sufficient physiological activity unless it contains one of the bodies 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. Inevitably, the process was complicated and industrially disadvantageous.

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

The optical resolution method of secondary alcohol as currently known also requires a complicated process and an expensive optical activator. For example, in order to split 2-butanol or 2-octanol, it is necessary to make a salt with brucine after forming a monophthalic acid ester and recrystallize it many times. (Org.Syntheses,
Coll. Vol.I, 418, 2nd ed., 1941).

There are also known some methods of obtaining optically active substances by performing optical resolution by biochemical methods. For example, Krivanov (Kl
ibanov) et al. (J. Am. Chem. Soc., 106 , 2687 (198
4), J. Am. Chem. Soc., 107 , 7072 (1985) are known, but they are different from the method of the present invention, and the former uses a buffer solution to carry out the reaction, and Unnecessary hydrolysis of triglycerides due to their presence is unavoidable, and moreover the enzyme is water soluble and unstable towards water,
The enzyme must be immobilized for stable use. Further, the latter does not require immobilization of an enzyme, but a transesterification reaction for resolution is limited, so a special ester for alcohol is required. In addition, G. Langrand et al. Divide alcohols by ester synthesis using enzymes (Tetrahedron Letter).
s 26, 1857 (1985)) is, alcohols of the split subject has been limited to the replacement cyclohexanol.

[Means for solving problems]

The present inventors have conducted research to find out a method for producing an optically active alcohol of the above general formula by an industrially advantageous method, and as a result, the racemic alcohol of the above general formula was used as a raw material and biochemically unsuitable. It was found that the compound can be efficiently separated into optically active ester and its enantiomer, optically active alcohol, by performing simultaneous ester synthesis.

That is, the present invention has the general formula (X is an alkyl group having 2 to 20 carbon atoms, Y represents an alkyl group having 1 to 3 carbon atoms or -CF _3, or -CN,. However,
X ≠ Y. And an enzyme having the ability to react preferentially with either an R- or S-alcohol to a carboxylic acid and an asymmetric ester synthesis reaction, particularly a microorganism. Using lipase derived from
The (R, S) -alcohol is reacted with a carboxylic acid, and the ester synthesis reaction is carried out directly under an essentially water-free condition or in an organic solvent to give either R-form or S-form. It is a method of resolving optically active alcohols and esters rich in water.

The method of the present invention does not require the use of lower alcohols in place of water or water, and thus does not cause hydrolysis of the synthesized ester and keeps the enzyme stable in an organic solvent,
It can be easily separated and reused after the reaction. Furthermore, since microbial contamination does not occur, there is no need for special equipment, preservatives, etc., and the reaction can be carried out in an open system.

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

In the present invention, the raw material (R, S) -alcohol is a compound that can be obtained or easily synthesized. For example, 2-butanol, 2-pentanol, 2-hexanol, 2-heptanol, 2-
Commercially available octanol, 2-nonanol, 2-decanol and the like are sufficient. The (1) If Y = -CF ₃ in formula, Campbell (Campbell) et al. Method (J.Am.Chem.Soc, 72, 4380 (1950)) can be synthesized by. Y = -CN can also be synthesized by reacting an aldehyde with hydrogen cyanide. As for the carboxylic acid, it is sufficient that it is easily available.
Acetic acid, propionic acid, butyric acid, caproic acid, lauric acid,
Stearic acid, myristic acid, oleic acid, etc. are commercially available.

The enzyme used in the present invention is preferably one called lipase, lipoprotein lipase, or esterase, but it acts on (R, S) -alcohol to give R-
Any type of alcohol may be used as long as it has the ability to preferentially react with the carboxylic acid and the asymmetric ester synthesis reaction with either the alcohol of the body or S-body. The commercially available products include those listed in the table below.

In addition, any microorganism can be used regardless of its race, as long as it is a microorganism that produces an enzyme capable of carrying out the above reaction. An example of such a microorganism is Arthrobacter (Ar
throbacter) genus, Achromobacter
Genus, Alcali-genes genus, Asperigillus genus, Chromobacterium
Examples thereof include those belonging to the genus bacterium, the genus Candida, the genus Mucor, the genus Pseudomonas, the genus Rhizopus, and the like.

The ester synthesis reaction of (R, S) -alcohol is (R, S)
The alcohol directly with the carboxylic acid, or toluene,
It is carried out by mixing in an organic solvent such as hexane or heptane and efficiently contacting with the enzyme. At this time, the reaction temperature is appropriately 20 to 70 ° C, particularly preferably 30 to 45 ° C.
Is. The reaction time is wide, 5 to 1000 hours, and the reaction time can be shortened by increasing the reaction temperature, using an enzyme with high activity (having a large number of units), or decreasing the substrate concentration.

The ratio of the substrate (R, S) -alcohol to the carboxylic acid is 1: 0.5 to 1: 5 (molar ratio), preferably 1: 1.
It is 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 liquid, which is a filtrate, can be distilled under reduced pressure to separately obtain an optically active ester and an alcohol, and the ester is an enantiomer with the alcohol by subjecting to ordinary alkali hydrolysis. Becomes an optically active alcohol.

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 carried out 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 regardless of 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),
A solution prepared by dissolving 26 g (0.2 mol) of (R, S) -2-octanol and 50.2 g (0.22 mol) of myristic acid in 400 ml of heptane was placed in a three-necked flask and reacted at 35 ° C. for 6 days with stirring. . After the reaction was stopped, the enzyme was removed by filtration, washed with toluene, the washing solution was added to the filtrate, and then vacuum distillation was performed to obtain S-(+)-2-octanol (yield 57%,
[Α] _D = + 7.4 ° (neat) was taken out at a boiling point of 52 to 62 ° C./3 mmHg. Next, the residue in the kettle was subjected to column chromatography to obtain 2-octyl R-(-)-myristate. This ester undergoes normal hydrolysis to give R-(-)-2-
Octanol (50% yield, [α] _D = -6.3 ° (nea
t)).

The obtained compound was identified by structural analysis by an NMR chart and optical rotation measurement by a polarimeter.

Example 2 Using the enzyme (Amano Pharmaceutical Co., lipase “Amano” P) 40 g, 2-decanol 31.7 g (0.2 mol) as the secondary alcohol, and lauric acid 44.1 g (0.22 mol) as the carboxylic acid, The operation according to the method was performed. S-
13.2 g of (+)-2-decanol (yield 83.4%, [α] _D
= + 69.5 ° (neat), R-(-)-2-decanol 7.8g
(Yield 49.3%, [α] _D = −5.60 ° (neat)) were obtained.

The obtained compound was identified according to the method of Example 1.

Claims (1)

(57) [Claims] 1. A general formula: (X is an alkyl group having 2 to 20 carbon atoms, Y represents an alkyl group having 1 to 3 carbon atoms or -CF _3, or -CN,. However,
X ≠ Y. ) A lipase derived from a microorganism, which has the ability to act on an (R, S) -alcohol represented by In the presence of, the (R, S) -alcohol represented by the above (1) is reacted with a carboxylic acid, and an ester synthesis reaction is carried out directly or in an organic solvent under substantially no water. R
A method for producing an optically active secondary alcohol and ester by a biochemical method, characterized by dividing into an optically active alcohol and an ester which are rich in either one of the -form and the S-form.