JPH08149994A - Production of optically active alcohol containing phenyl group - Google Patents

Abstract

PURPOSE: To produce the subject compound useful as a raw material for pharmaceuticals, agrochemicals, etc., in high efficiency by carrying out the transesterification reaction of a dibasic acid diester of a racemic alcohol containing phenyl group with a higher alcohol in the presence of a thermostable enzyme under specific condition and separating the optically active compound. CONSTITUTION: The objective optically active alcohol containing phenyl group is produced in high efficiency by carrying out the transesterification reaction of (A) a diester of a racemic alcohol having phenyl group and expressed by formula (D1 to D5 are each H, a halogen, a 1-3C alkyl or a 1-3C alkoxy; A is a 1-3C alkyl, CF3 or CN), etc. [e.g. (R,S)-1-phenyi-1-ethanol] and a dibasic acid (e.g. 1,14-tetradecadicarboxylic acid) with (B) a >=16C optically inactive non-racemic alcohol (e.g. oleyl alcohol) in the presence of a thermostable lipase originated from microorganisms belonging to the genus Alcaligenes, etc., under anhydrous condition and normal pressure at >=81 deg.C without using a solvent for the raw materials and separating the optically active alcohol from the reaction product.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing an optically active alcohol which is important as a raw material or intermediate raw material for pharmaceuticals, agricultural chemicals and the like, and a synthetic intermediate in the field of fine chemicals such as liquid crystals.

[0002]

2. Description of the Related Art Optically active alcohols have been used as raw materials and synthetic intermediates for pharmaceuticals, agricultural chemicals, fine chemical products such as ferroelectric liquid crystals, etc., and in recent years, various compounds have been developed with increasing demand. For example, in an optically active alcohol having a phenyl group, 1-phenyl-1
-Ethanol, 1-phenyl-1-pentanol, 1-
Many are useful such as (p-chlorophenyl) -1-ethanol. Further, the optically active alcohol is required to have not only a high purity as a substance but also a high optical purity in order to exhibit its sufficient function.

Known methods such as solvent extraction, fractionation, recrystallization, simple distillation, azeotropic distillation, molecular distillation, and column chromatography are used to increase the substance purity of the optically active alcohol. On the other hand, in order to increase the optical purity, it is effective to split the optically active alcohol, which is its enantiomer (enantiomer), from the racemic alcohol using an enzyme (lipase, lipoprotein lipase, esterase, protease, etc.). is there. That is, it is difficult to separate the enantiomer from the racemic alcohol by a usual chemical reaction involving high temperature, but the reaction using the enzyme makes it possible to identify it. Therefore, a method for producing an optically active alcohol utilizing such an enzymatic reaction has been intensively studied.

As a method for separating an optically active alcohol from a racemic alcohol by using the above-mentioned enzyme, (i) hydrolysis of an ester of the racemic alcohol (JP-A-1-
137996, JP-A-1-257484, etc.), (ii) transesterification of racemic alcohol and triglyceride (JP-A-62-166898, JP-B-6-34752), (iii) racemic It has been proposed to transesterify an ester of a body alcohol with an alcohol (Japanese Patent Laid-Open No. 63-173597).

Since the method (i) is a reaction using a large amount of water, a desired optically active alcohol is prepared from a racemic alcohol ester having a high affinity with water, such as a lower 2-alkanol, as a raw material. High purity (meaning that both material purity and optical purity are high. The same applies hereinafter)
If a large amount of a solvent having a selective solubility for the target substance is used, the operation such as extraction, fractionation and / or azeotropic distillation, molecular distillation or preparative liquid chromatography is complicated. In addition, it is necessary to use a refining means which makes the manufacturing cost expensive. In addition, in this method, the enzyme is easily deactivated due to the fact that it is an aqueous reaction and, for example, carboxylic acid is produced as a reaction by-product, and it is practically difficult to recover and reuse it from the reaction product by using a powdery enzyme. is there.

In the methods (ii) and (iii), the amount of water in the reaction system is very small, and a substance that causes the inactivation of the enzyme is not by-produced by the reaction. There is no need to extract and separate the target product from the product,
It is also possible to recover and reuse the enzyme. However, when a lipase is used in such an enzymatic reaction, the conventional reaction temperature is usually about 20 to 70 ° C, substantially 20 to 50 ° C.
Since the temperature is 0 ° C., the raw materials are limited to those that become liquid in this temperature range, or it is necessary to dissolve the raw materials in an organic solvent to cause a reaction. Moreover, the reaction time is particularly low in racemic alcohols having a substituent having a large molecular size such as a phenyl group due to steric hindrance due to its chemical structure. It needed a period.

When the transesterification reaction of (ii) and (iii) is carried out in a solventless system in the conventional method, as described above, the practically usable raw materials (racemic alcohol, its ester, triglyceride, alcohol, etc.) are It is necessary that its melting point be equal to or lower than the enzyme reaction temperature, and therefore it is unavoidable to adopt those having similar physical properties such as melting point and boiling point of raw materials, solubility in a solvent and the like. Even when the reaction (iii) is carried out in an organic solvent system (for example, JP-A-63-173597), the alcohol, which is one of the starting materials, has 1 to 10 carbon atoms, and the other racemic material is the other starting material. The melting point is similar to that of body alcohol ester. When a raw material having similar physical properties is used, the optically active alcohol is usually efficiently separated and recovered from the transesterification reaction product in which the raw material component and the reaction component have a complicated equilibrium composition, and As a refining means for increasing the purity and the optical purity, it is difficult to utilize the difference in the physical properties of each component, and eventually (i
The methods i) and (iii) also have a problem that they have to rely on complicated and expensive purification methods and means as in the method (i).

[0008]

In view of such a situation, in the present invention, in the method for producing an optically active alcohol having a phenyl group, the enzymatic reaction is carried out in a short time, and the desired product is separated into highly pure by a simple operation, The aim was to develop such a method that could be purified.

[0009]

[Means for Solving the Problems] The present inventors have conducted earnest studies to solve the above problems and obtain an optically active alcohol having a phenyl group by an industrially simple and advantageous method. As a result, by using a diester obtained by esterifying a specific racemic alcohol with a dibasic acid and a specific alcohol as a raw material, and subjecting this to a transesterification reaction at a high temperature using a thermostable lipase, the reaction is completed in a short time. Then
Moreover, they have found that a highly pure optically active alcohol can be easily isolated from the reaction product in a high yield, and completed the present invention.

That is, the gist of the present invention is to prepare a heat-resistant lipase using a) a diester of a racemic alcohol having a phenyl group and a dibasic acid and b) a non-optically active non-racemic alcohol having 16 or more carbon atoms as a raw material. Using the raw material solvent, a transesterification reaction is carried out at 81 ° C. or higher under atmospheric pressure under conditions substantially free of water, and then an optically active alcohol having a phenyl group is obtained from the reaction product. A method for producing a phenyl group-containing optically active alcohol, which comprises separating.

The present invention will be described in detail below. First, in the present invention, a) a diester of a racemic alcohol having a phenyl group (hereinafter referred to as phenyl group substitution) and a dibasic acid and b) a non-optically active non-racemic alcohol having 16 or more carbon atoms are used as raw materials. The diester of a) is a known chemical ester synthesis method using a phenyl group-substituted racemic alcohol and a dibasic acid, for example, inorganic acids such as sulfuric acid, hydrochloric acid and paratoluenesulfonic acid, metals such as zinc, tin and nickel,
The phenyl group-substituted racemic alcohol and the dibasic acid are heated to 100 to 250 ° C. by using an oxide or chloride of the metal as a catalyst to remove water by-produced from the reaction system for esterification and esterification. If necessary, the reaction product is deoxidized with an alkali (sodium hydroxide, sodium carbonate, etc.), decolorized with an adsorbent (activated carbon, activated clay, etc.),
It can be obtained by performing deodorizing treatment by sucking water vapor or nitrogen gas under reduced pressure.

The phenyl group-substituted racemic alcohol here means a racemic straight-chain or side-chain, saturated or unsaturated halogen (chlorine, chlorine, chlorine, having at least a phenyl group or a phenyl group substituted with a functional group). Bromine, fluorine), oxygen, nitrogen, phosphorus, sulfur and the like, and primary or secondary alcohols which may be substituted with atoms. And preferably, the following general formula (1)

Embedded image [In Formula (1), D ₁ , D ₂ , D ₃ , D ₄ and D ₅
Is a substituent represented by hydrogen, a halogen atom, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, and A is an alkyl group having 1 to 3 carbon atoms or CF ₃ or CN]. Is a compound.

Examples of the phenyl group-substituted racemic alcohol include 1-phenyl-1-ethanol and 1-phenyl-1-ethanol.
Phenyl-1-propanol, 2-phenyl-1-propanol, 1-phenyl-2-propanol, 1-phenyl-1-butanol, 3-phenyl-1-butanol, 2-phenyl-2-butanol, 3-phenyl- Two
-Butanol, 4-phenyl-2-butanol, 1-phenyl-1-pentanol, 4-phenyl-1-pentanol, 2-phenyl-2-pentanol, 3-phenyl-2-pentanol, 4-phenyl 2-Pentanol, 5-phenyl-2-pentanol, 1-hexanol in which 1- or 5-position carbon is substituted with a phenyl group, and 2 in which any one of 2-position to 6-position carbon is substituted with a phenyl group 2
-Hexanol, 1-heptanol in which 1- or 6-position carbon is substituted with a phenyl group, 2-heptanol in which any one of 2- and 7-position carbons is substituted with a phenyl group, 1- or 7-position carbon is a phenyl group Substituted with 1-octanol, 2-octanol in which any one of 2-position to 8-position carbon is substituted with a phenyl group, 1-nonanol in which 1-position or 8-position carbon is substituted with a phenyl group, 2-positions to 9 2-nonanol in which any one of the position carbons is substituted with a phenyl group, and 1-in which the position 1 or 9 carbons are substituted with a phenyl group
Decanol, 2-decanol in which any one of 2-position to 10-position carbon is substituted with a phenyl group, ethyl 3-hydroxy-3-phenyl-propionate, 1-phenyl-
1,3-propanediol, 2-phenyl-1-cyclohexanol, 1-phenyl-2,2,2-trifluoro-1-ethanol, 1- (2-chlorophenyl) -1
-Ethanol, 1- (4-chlorophenyl) -1-ethanol, 1- (2,4-dichlorophenyl) -1-ethanol, 1- (2-bromophenyl) -1-ethanol, 1- (4-bromophenyl) -1-Ethanol, 1
-(2,4-dibromophenyl) -1-ethanol, 1
-(2-Fluorophenyl) -1-ethanol, 1-
(4-Fluorophenyl) -1-ethanol, 1-
(2,4-difluorophenyl) -1-ethanol, 1
-(2-Methylphenyl) -1-ethanol, 1- (4
-Methylphenyl) -1-ethanol, 1- (2,4-
Dimethylphenyl) -1-ethanol, 1- (2-ethylphenyl) -1-ethanol, 1- (4-ethylphenyl) -1-ethanol, 1- (2,4-diethylphenyl) -1-ethanol, 1 -(2-n-Propylphenyl) -1-ethanol, 1- (2-methoxyphenyl) -1-ethanol, 1- (2-ethoxyphenyl)
-1-Ethanol, 1-propanol substituted with the phenyl group, 2-propanol, 1-butanol, 2-
Butanol, 1-pentanol, 2-pentanol, 1
In hexanol, 2-hexanol, 1-heptanol, 2-heptanol, 1-octanol, 2-octanol, 1-nonanol, 2-nonanol, 1-decanol and 2-decanol, the phenyl group is 2-chlorophenyl group, 4-chlorophenyl. Group, 2,4-dichlorophenyl group, 2-bromophenyl group, 4-bromophenyl group, 2,4-dibromophenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2 -Methylphenyl group, 4-methylphenyl group, 2,4-dimethylphenyl group, 2-ethylphenyl group, 4-ethylphenyl group, 2,4-diethylphenyl group, 2-n-propylphenyl group, 4-n -Propylphenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 2- There are Tokishifeniru group or racemic alcohols such as those replaced by any one group of 4-ethoxyphenyl group. Among these, 1-phenyl-1-ethanol, 1-phenyl-1-propanol, 1-phenyl-1-butanol, 1-phenyl-1-pentanol, 1- (4-chlorophenyl) is preferable.
-1-Ethanol, 1- (2-bromophenyl) -1-
Ethanol, most preferably 1-phenyl-1-
Ethanol, 1-phenyl-1-propanol, 1-
It is (4-chlorophenyl) -1-ethanol.

On the other hand, as the dibasic acid, a linear or side chain saturated one can be arbitrarily used, and specifically, dodecamethylene dicarboxylic acid, tetradecamethylene dicarboxylic acid, hexadecamethylene dicarboxylic acid, heptadeca. Methylenedicarboxylic acid, octadecamethylenedicarboxylic acid,
Nonadecamethylenedicarboxylic acid, eicosamethylenedicarboxylic acid, docosamethylenedicarboxylic acid, tetracosamethylenedicarboxylic acid, hexacosamethylenedicarboxylic acid, octacosamethylenedicarboxylic acid, etc., and a dimer of oleic acid, erucic acid, etc. Examples thereof include acids. These dibasic acids may be used alone or as a mixture, and in addition to the above, a long wax dibasic acid separated from a wax, a sesame crude oil precipitate, or the like may be used.

In the present invention, the transesterification temperature is 130 ° C. as described below, so that the phenyl group-substituted racemic alcohol and the dibasic acid are such that their diesters are liquid at that temperature. It is important to combine From the viewpoint of simplicity in the purification step of separating the optically active alcohol of interest from the transesterification reaction product, the dibasic acid has 14 or more, preferably 16 to 30, and more preferably 18 carbon atoms among the above-mentioned dibasic acids.
It is desirable to be a linear saturated dibasic acid of ˜28, most preferably 20 to 28. With dibasic acids having less than 14 carbon atoms, unsaturated dibasic acids, and the like, the purification conditions for isolating the optically active alcohol with high purity and high yield tend to require strictness. Dibasic acids having more than 45 carbon atoms are difficult to obtain as industrial raw materials. The dibasic acid diester used in the present invention preferably has a high melting point (preferably 60 ° C. or higher, more preferably 70 ° C. or higher).

Specific examples of b) the non-optically active non-racemic alcohol having 16 or more carbon atoms, which is the other raw material of the present invention, include 1-hexadecanol (cetanol) and 1-hexadecanol.
Heptadecanol, 1-octadecanol (stearyl alcohol), oleyl alcohol, 1-eicosanol, 1-docosanol (behenyl alcohol), 1-tetracosanol, 1-hexacosanol, 1-octacosanol, 1-nonacosanol, myricil Alcohol (C30), Melisyl alcohol (C31),
Lasserole (having 32 carbon atoms) and the like can be mentioned.
Of these, linear saturated alcohols having 16 to 30, and more preferably 18 to 28 carbon atoms are desirable. If the number of carbon atoms is less than 16, it is difficult to separate the target optically active alcohol in the purification step, and the alcohol having more than 34 carbon atoms is difficult to obtain industrially.

The transesterification reaction of the present invention is characterized by using a thermostable lipase. As a result, the raw materials a) and b) can be maintained in a liquid state at a high temperature, a solvent for dissolving the raw materials unlike the conventional method is not required, and the transesterification reaction can be rapidly progressed. Since it becomes possible to use esters and alcohols having a melting point, separation and purification of the optically active alcohol become easy.

The thermostable lipase of the present invention means one having transesterification activity even at 81 ° C. or higher. For example, Alcaligenes sp. PL-266 described in Japanese Patent Publication No. 58-36953 (Ministry of Industrial Science and Technology) No. 3187) produced by Lipase PL-266, and the lipase PL-679 produced by Alcaligenes sp. PL-679 described in Japanese Examined Patent Publication No. 60-15312 (Microtechnology Research Institute No. 3783). And lipases originating from Rhizopus chinensis described in JP-B-59-156282, and the like, of which the former two are preferred. In carrying out the present invention, it is convenient to use Lipase QL and Lipase PL (both are trade names of the same company) manufactured by Meito Sangyo Co., Ltd. as the lipase derived from Alcaligenes SP, and Lipase QL is particularly preferable. The heat-resistant lipase may be immobilized on a known carrier such as activated carbon, celite, an adsorptive resin, an ion-exchange resin, glass beads, and ceramics, but it should be coexisted with the raw material in a powder state as described later. Is desirable.

In the transesterification reaction, the diester of the phenyl group-substituted racemic alcohol of a) and the alcohol of b) are used in a ratio of 1: 5 or less, preferably 1: 5.
The raw material is mixed at a molar ratio of 5 to 3 without using an organic solvent for dissolving the raw material, and is substantially free of water (that is, the equilibrium water content of the raw material of about 0.1). The powder of the thermostable lipase is preferably dispersed in a reaction system (wt% or less, preferably 0.05 wt% or less), and the reaction is performed with stirring or shaking.
At this time, 90% or more of the particles of the heat resistant lipase powder are 1 to
It is desirable to control the transesterification reaction so that the size is 100 μm, preferably 20 to 50 μm. This particle size can be adjusted by dispersing the heat-resistant lipase powder in the raw material that has been heated and dissolved, if necessary, and then sonicated, filtered with a precision membrane or ultrafiltration membrane of the dispersion, and subjected to centrifugal sedimentation. It may be subjected to a treatment or the like, but is preferably below the reaction temperature, 20 to 150 kHz, 10
Irradiation with ultrasonic waves for 1 to 30 minutes under conditions of 0 to 250 W is convenient.

The reaction temperature is 81 ° C or higher, more preferably 9 ° C.
The temperature is set to 1 to 130 ° C, most preferably 101 to 120 ° C, and the reaction rate is checked by, for example, gas chromatography while gently stirring or shaking under normal pressure, and the reaction is performed for a predetermined period of time, preferably several hours. The transesterification reaction is carried out for 100 hours. When the reaction temperature is lower than 81 ° C, the reaction proceeds slowly and requires a long time.
If it exceeds, even if it is a thermostable lipase, the tendency to be inactivated increases.

The transesterification reaction product of the present invention has the following reaction formula:

Embedded image [However, (a): dibasic acid diester of racemic alcohol, (b): non-optically active non-racemic alcohol,
(C): dibasic acid diester of optically active alcohol,
(D): non-optically active non-racemic alcohol dibasic acid diester, (e): optically active alcohol. ]
As shown in, the diester of the racemic alcohol as a raw material is non-optically active and, as it were, is subjected to alcoholysis by the non-racemic alcohol, and the optically active alcohol of either the R-form or the S-form is released and the non-optically-active and non-optical A new dibasic acid diester of a racemic alcohol is newly formed, and an unreacted dibasic acid diester of an optically active alcohol in either the R form or the S form is also present. The composition is composed of the components. Moreover, in the conventional method, since the physical properties of each component in the reaction product are similar to each other, a complicated purification step was required to recover the optically active alcohol. It is characterized by using a non-optically active and non-racemic alcohol, and its physical properties (melting point, boiling point, solubility in a solvent, etc.) are significantly different from those of the above-mentioned racemic alcohol, which facilitates isolation of the optically active alcohol. Become.

That is, the transesterification reaction product is obtained by first removing the lipase powder using a microfiltration membrane such as filter paper, and then performing distillation under reduced pressure, fractionation in the presence or absence of a solvent, recrystallization, silica gel column chromatography and the like. Highly pure optically active alcohol can be isolated in a high yield by a relatively simple method, more preferably, only vacuum distillation is carried out. In the method of the present invention, unreacted enantiomers that remain as monoesters or diesters are separated from the reaction product by a known method such as column chromatography, and then the acid (hydrochloric acid, sulfuric acid, etc.) or alkali (sodium hydroxide) is used. ,
Similarly, it can be isolated with high purity by hydrolysis with potassium hydroxide or the like. Further, the thermostable lipase used in the reaction can be used in a new similar transesterification reaction after recovery.

[0023]

EXAMPLES The substance purity of the compounds obtained in the following Examples and Comparative Examples was measured by gas chromatography (GC-14A, manufactured by Shimadzu Corporation), and the optical purity was measured by a polarimeter (JASCO ( Co., Ltd., DIP-370), and the calculated values were calculated by comparing the measured values with those of standard samples.

Example 1 10 g of lipase PL (manufactured by Meito Sangyo Co., Ltd.) derived from Alcaligenes sp., (R, S)
50 g of 1,14-tetradecadicarboxylic acid (dodecamethylenedicarboxylic acid) diester of -1-phenyl-1-ethanol and 300 g of oleyl alcohol were added.
Place in a 0 ml separable flask and use an ultrasonic generator (manufactured by Shimadzu Corporation, SUS-103) at 80 ° C for 4
Ultrasonic irradiation was performed at 5 kHz for 1 minute. After that, at normal pressure,
Stirring was carried out at a stirring speed of 350 rpm at 85 ° C., and a transesterification reaction was carried out for 48 hours. Water content of reaction system (Karl Fischer method): 0.03% by weight, size of lipase particles (particle size distribution measuring device manufactured by Coulter Electronics Co .: measured by Multisizer): 95% or more is 30 to
It was 70 μm. After completion of the reaction, the reaction product was measured by gas chromatography to find that 50 mol% of 1,14-tetradecadicarboxylic acid diester of (R, S) -1-phenyl-1-ethanol was transesterified.
After removing the lipase by filtration using a membrane filter 0.5 μm (manufactured by Advantech), 90
Distillation was carried out under the condition of 3 ° C. and 3 mmHg to obtain (R) -1-phenyl-1-ethanol (yield: 90%, material purity: 100
%, Optical purity: 100% ee). On the other hand, 1,14-tetradecadicarboxylic acid diester of 1-phenyl-1-ethanol remaining in the reaction product is separated by silica gel column chromatography and alkali-hydrolyzed to (S) -1-phenyl-1-ethanol. (Yield: 95
%, Material purity: 100%, optical purity: 100% ee).

Example 2 10 g of lipase QL (manufactured by Meito Sangyo Co., Ltd.) derived from Alcaligenes sp., (R, S)
100 g of 1,20-eicosadicarboxylic acid (octadecamethylenedicarboxylic acid) diester of -1-phenyl-1-propanol and 300 g of stearyl alcohol
Was placed in a 500 ml separable flask, subjected to ultrasonic treatment at 105 ° C. in the same manner as in Example 1, and then subjected to normal pressure, 105
Stirring was carried out at a stirring speed of 350 rpm at 24 ° C., and a transesterification reaction was carried out for 24 hours. The water content of the reaction system measured by the method described in Example 1 was 0.05% by weight, and the size of lipase particles: 95% or more was 20 to 60 μm. After the completion of the reaction, the reaction product was measured by gas chromatography to find that 49 mol% of 1,20-eicosadicarboxylic acid diester of (R, S) -1-phenyl-1-propanol was transesterified. Lipase was removed by filtration using a membrane filter of 0.5 μm (same as in Example 1), and then distilled under conditions of 95 ° C. and 2 mmHg to obtain (R) -1-phenyl-1-propanol (yield:
90%, material purity: 100%, optical purity: 99% ee or more). On the other hand, 1-phenyl-remaining in the reaction product
The 1,20-eicosadicarboxylic acid diester of 1-propanol was separated by silica gel column chromatography and alkali-hydrolyzed to give (S) -1-phenyl-1-
Propanol (yield: 92%, material purity: 100%, optical purity: 99% ee or more) was obtained.

Example 3 10 g of lipase QL as described in Example 2, (R, S) -2
100 g of 1,28-octacosadicarboxylic acid (hexacosamethylenedicarboxylic acid) diester of-(2,4-difluorophenyl) -2-octanol and 330 g of behenyl alcohol were placed in a 500 ml separable flask and sonicated in the same manner as in Example 1. After the treatment, the mixture was stirred at 110 ° C. under normal pressure at a stirring speed of 250 rpm, and a transesterification reaction was performed for 20 hours. The water content of the reaction system measured by the method described in Example 1 was 0.02% by weight, and the size of lipase particles: 95% was 20 to 50 μm. After completion of the reaction, the reaction product was measured by gas chromatography to find that (R, S) -2- (2,4-difluorophenyl)
50 mol% of the 1,28-octacosadicarboxylic acid diester of 2-octanol was transesterified.
Lipase was applied to a membrane filter of 0.5 μm (Example 1
Same as above) and then filtered off at 95 ° C., 2
Distillation was carried out under the condition of mmHg to obtain (R) -2- (2,4-difluorophenyl) -2-octanol (yield: 93
%, Material purity: 99%, optical purity: 100% ee). On the other hand, the 1,28-octacosadicarboxylic acid diester of 2- (2,4-difluorophenyl) -2-octanol remaining in the reaction product is separated by silica gel column chromatography and alkali-hydrolyzed (S)- Two
-(2,4-difluorophenyl) -2-octanol (yield: 93%, material purity: 100%, optical purity: 10
0% ee) was obtained.

Example 4 Lipase QL15g, (R, S) -1 described in Example 2
1,20 of-(p-chlorophenyl) -1-ethanol
100 g of eicosadicarboxylic acid (octadecamethylene dicarboxylic acid) diester and 320 g of n-hexadecanol were placed in a 500 ml separable flask and subjected to ultrasonic treatment in the same manner as in Example 1, and then at atmospheric pressure, 103 ° C.
At a stirring speed of 350 rpm, the transesterification reaction was carried out for 25 hours. Water content of reaction system measured by the method described in Example 1: 0.03% by weight, size of lipase particles:
95% or more had a thickness of 20 to 60 μm. After the reaction was completed, the reaction product was measured by gas chromatography,
(R, S) -1- (p-chlorophenyl) -1-ethanol 1,20-eicosadicarboxylic acid diester 5
0 mol% was transesterified. Lipase was removed by filtration using a membrane filter of 0.5 μm (same as in Example 1), and then distilled under conditions of 95 ° C. and 3 mmHg to give (R) -1- (p-chlorophenyl) -1-
Ethanol (yield: 95%, material purity: 99% or more, optical purity: 100% ee) was obtained. On the other hand, 1- (p-chlorophenyl) -1-ethanol, which remains in the reaction product,
20-Eicosadicarboxylic acid diester was separated by silica gel column chromatography and alkali-hydrolyzed to give (S) -1- (p-chlorophenyl) -1-ethanol (yield: 87%, substance purity: 99%, optical Purity: 10
0% ee) was obtained.

COMPARATIVE EXAMPLE 1 In Example 4, when 300 g of myristyl alcohol was used in place of 320 g of n-hexadecanol and treated under the same conditions, (R) -1- (p-chlorophenyl) -1- was separated. Yield of the component equivalent to ethanol: 93
%, Substance purity: 95%, optical purity: 93% ee,
The (S) -1- (p-chlorophenyl) -1-ethanol equivalent component had a yield of 81%, a substance purity of 93%, and an optical purity of 91%.

[0029]

INDUSTRIAL APPLICABILITY According to the present invention, when an optically active alcohol is separated from an ester of a racemic alcohol substituted with a phenyl group, a thermostable lipase is used to use a raw material having a high melting point without using a solvent as the raw material. You can
It becomes possible to carry out a transesterification reaction at a high temperature which has not been heretofore possible, and the reaction time can be shortened. Furthermore, since a long-chain alcohol having a high melting point and a high boiling point can be used as a raw material, an optically active alcohol of either the R isomer or the S isomer can be obtained from the reaction product by utilizing the difference in the physical properties in the transesterification reaction product. It can be separated with high purity, high yield, and simple purification means. Further, the optically active alcohol in either the R form or the S form which is an antipode to the optically active alcohol can be easily isolated with high purity.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location (C12N 9/20 C12R 1:05) C07M 7:00

Claims (6)

[Claims] 1. A raw material comprising: a) a diester of a racemic alcohol having a phenyl group and a dibasic acid; and b) a non-optically active non-racemic alcohol having 16 or more carbon atoms,
A thermostable lipase is used and a transesterification reaction is carried out at 81 ° C. or higher under normal pressure under conditions substantially free of water without using the solvent of the raw material, and then the reaction product has a phenyl group. A process for producing a phenyl group-containing optically active alcohol, which comprises separating the optically active alcohol. 2. A racemic alcohol having a phenyl group is represented by the following general formula (1): [In Formula (1), D ₁ , D ₂ , D ₃ , D ₄ and D ₅
Is a substituent represented by hydrogen, a halogen atom, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, and A is an alkyl group having 1 to 3 carbon atoms or CF ₃ or CN]. The method according to claim 1, wherein the compound is a compound. 3. The method according to claim 1, wherein the dibasic acid is a linear saturated dibasic acid having 14 or more carbon atoms. 4. The method according to claim 1, wherein the thermostable lipase is obtained from a microorganism belonging to the genus Alcaligenes. 5. The method according to claim 1, wherein the thermostable lipase is in the form of powder, and 90% or more of its particles have a size of 1 to 100 μm. 6. The production method according to claim 1, wherein the transesterification reaction temperature using thermostable lipase is 101 to 120 ° C.