JPH07303494A - Production of optically active alcohol - Google Patents

Abstract

PURPOSE:To easily obtain in a short time the subject high-purity compound by reaction between a racemic alcohol and e.g. a higher saturated dicarboxylic lower alcohol ester in the presence of a heat-resistant lipase in the absence of solvent and water followed by resolution of the resultant optically active product. CONSTITUTION:A transesterification is conducted at >=81 deg.C in the presence of a heat-resistant lipase such as derived from Alcaligenes microbes in the absence of solvent and water between a racemic alcohol of e.g. of formula I [A is phenyl or a substituent of formula II (D1-D5 each is a halogen, a 1-3C alkyl or 1-3C alkoxyl); B is a l-3C alkyl, CF3 or CN] and an ester such as a >=14C saturated dicarboxylic lower monohydric alcohol diester, >=16C saturated fatty acid-derived triglyceride, or >=18C saturated fatty acid lower monohydric monoester, and an optically active alcohol rich in either the R-form or S-form is resolved from the reaction product, thus obtaining the objective high-purity optically active alcohol in high efficiency.

Description

Detailed Description of the Invention

[0001]

The present invention relates to raw materials for pharmaceuticals, agricultural chemicals, etc.
The present invention relates to a method for producing an optically active alcohol, which is important as a synthetic intermediate for fine chemicals such as liquid crystals.

[0002]

BACKGROUND OF THE INVENTION Optically active alcohols are important substances as raw materials or intermediates for pharmaceuticals, agricultural chemicals, etc., and synthetic intermediates in the field of fine chemicals such as ferroelectric liquid crystals, but in order to exert sufficient physiological activity and properties. Quite high precision is required for both the purity of the physical properties themselves and the optical purity. On the other hand, in a reaction using an enzyme such as lipase, lipoprotein lipase or esterase, it is possible to identify an enantiomer, which is difficult in a normal chemical reaction involving high temperature. Therefore, the enzyme reaction is useful as a means for increasing optical purity, that is, for performing optical resolution, and in recent years, a method for producing an optically active alcohol using this has been earnestly studied.

However, in the enzymatic reaction currently performed, the reaction must be carried out over a very long period of several days to several tens of days or longer (for example, JP-A-62-16).
6898, JP-A-63-273499). Moreover, the temperature range in which the enzymatic reaction can be carried out is at most about 20 to 70 ° C., preferably 30 to 50 ° C. For example, the ester to be transesterified with the racemic alcohol is dissolved in a liquid or a solvent in the temperature range and reacted. Must be done (JP-A-62-166898, JP-A-63-1638).
284184, JP-A-4-349894).

Therefore, the ester to be transesterified and the racemic alcohol have substantially similar physical properties such as boiling point and melting point, and usually the reaction product containing various components such as unreacted products and by-products. As a purification means for efficiently separating and recovering the target substance from the inside and increasing the substance purity and optical purity, it is difficult to use the difference in physical properties, and other complicated and expensive steps must be taken. That is, after the completion of the enzymatic reaction, in order to recover the desired optically active alcohol from the reaction product, it is the actual situation that the substance purity is increased by using azeotropic distillation, molecular distillation, preparative liquid chromatography or the like.

[0005]

As described above, the present method for producing an optically active alcohol has a drawback that the enzymatic reaction must be carried out for a very long period of time. Furthermore, since the enzyme reaction temperature is substantially limited to 30 to 50 ° C. and a raw material suitable for this is selected, it is difficult to utilize the difference in physical properties such as melting point and boiling point in the separation and purification step of the target substance after the reaction. However, there is a problem in that a complicated method and means have to be selected and an excessive cost is required to efficiently recover the target optically active alcohol from the reaction product. Therefore, an object of the present invention is to develop a method for producing an optically active alcohol, in which an enzymatic reaction is carried out in a short time, and a desired product can be separated and purified by a simple operation.

[0006]

[Means for Solving the Problems] The present inventors have conducted extensive studies to solve the above problems and obtain an optically active alcohol by an industrially simple and advantageous method. As a result, a racemic alcohol and a specific ester shown below are subjected to transesterification reaction at a high temperature in the presence of a thermostable lipase, whereby the reaction is completed in a short time, and an optically active alcohol is obtained from the reaction product. The inventors have found that can be easily isolated in high yield, and have completed the present invention.

That is, the gist of the present invention is to include a racemic alcohol, a) a lower monohydric alcohol diester of a saturated dicarboxylic acid having 14 or more carbon atoms, b) a triglyceride composed of a saturated fatty acid having 16 or more carbon atoms, and c). A condition in which an ester selected from the group consisting of lower monohydric alcohol monoesters of saturated fatty acids having 18 or more carbon atoms is used in the coexistence of a heat resistant lipase, without using the solvent of the raw material, and containing substantially no water. In the method for producing an optically active alcohol, a transesterification reaction is performed at 81 ° C. or higher under the conditions described below, and the optically active alcohol enriched in either the R form or the S form is resolved from the reaction product.

In the present invention, the racemic alcohol to be optically resolved is not particularly limited, but 2-alkanol is easily resolved, and the following general formula (1)

[Chemical 3] [Wherein A ≠ B in the formula (1), A is a phenyl group or the following general formula (2)

[Chemical 4] (In the formula (2), D ₁ , D ₂ , D ₃ , D ₄ and D ₅
Is a substituent represented by a halogen atom, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, and B
Is an alkyl group having 1 to 3 carbon atoms or CF ₃ or CN]
If the racemic alcohol is represented by the following formula, the optical resolution can be efficiently carried out by the method of the present invention described below.

Specifically, 2-butanol, 2-pentanol, 2-hexanol, 2-heptanol, 2-octanol, 2-nonanol, 2-decanol, 1-phenylethanol, 1-phenyl-1-propanol, ethyl. 3-hydroxy-butanate, ethyl 3-hydroxy-3-phenyl-propionate, methyl 3-hydroxy-pentanate, 1-phenyl-1,3-propanediol, 2-phenyl-1-cyclohexanol, 1
-Pentin-3-ol, 1- (2-bromophenyl)
Ethanol, 1-parachlorophenylethanol, 1-
(4-chlorophenyl) ethanol, 1-chloro-2-
There are racemic alcohols such as octanol, 1,1-difluoro-2-octanol, 1- (2,4-dichlorophenyl) ethanol. Of these, preferably 2-
Octanol, 1-phenylethanol, 1-phenyl-1,3-propanediol, 2-phenyl-1-cyclohexanol, most preferably 1-phenylethanol, 2-octanol, 1- (2-bromophenyl) ethanol. Is.

The ester used in the present invention includes a) a lower monohydric alcohol diester of a saturated dicarboxylic acid having 14 or more carbon atoms, b) a triglyceride composed of a saturated fatty acid having 16 or more carbon atoms, and c) 18 carbon atoms. An ester selected from the group consisting of lower monohydric alcohol monoesters of saturated fatty acids described above, wherein the lower monohydric alcohol is a linear or branched monohydric alcohol having 1 to 3 carbon atoms (methanol, ethanol, n-propanol). , Isopropanol). All of the a), b) and c) type esters are characterized by a high melting point (preferably 60 ° C. or higher, more preferably 70 ° C. or higher). Thus, there is an advantage that the objective optically active alcohol can be efficiently obtained from the transesterification product of the present invention.

Examples of diesters of a) type dicarboxylic acids and lower alcohols include tetradecadicarboxylic acid,
Pentadecadicarboxylic acid, hexadecadicarboxylic acid, heptadecadicarboxylic acid, octadecadicarboxylic acid, nonadecadicarboxylic acid, eicosadicarboxylic acid, docosadicarboxylic acid, tetracosadicarboxylic acid, hexacosadicarboxylic acid and octacosadicarboxylic acid, and also Specific examples thereof include dimethyl, diethyl, di-n-propyl and diisopropyl esters of any of saturated dicarboxylic acids represented by dimer acid obtained by duplexing oleic acid, erucic acid and the like, and among them, those having 20 to 28 carbon atoms. The lower monohydric alcohol diesters of the above-mentioned linear saturated dicarboxylic acids are preferable, and the lower monohydric alcohols of the dicarboxylic acids having 22 carbon atoms (docosadicarboxylic acid) and the dicarboxylic acids having 28 carbon atoms (octacosadicarboxylic acid) are also preferable. More preferred alcohol diester . The dicarboxylic acid has 1 carbon atom.
If it is less than 4, the target product cannot be efficiently separated in the purification step of the present invention, and if it has more than 45 carbon atoms, it is difficult to obtain industrially. Further, the lower monohydric alcohol is not preferable for the purpose of the present invention because it may have a racemic mixture when the carbon number exceeds 3.

Examples of fatty acid triglycerides of type b) are tripalmitin (C ₁₆ : triglyceride of palmitic acid), tri-2-hexyldecane (C ₁₆ : triglyceride of 2-hexyldecanoic acid), tristearin (C ₁₈ : of stearic acid). Triglyceride), triisostearin (C ₁₈ : triglyceride such as 2-heptylundecanoic acid, isostearic acid manufactured by Emery Co., Ltd.), triarachidin (C ₂₀ : triglyceride of arachidic acid), tribehen (C ₂₂ : triglyceride of behenic acid), trilignoserine. (C ₂₄ : triglyceride of lignoceric acid),
Tricerotene (C ₂₆ : triglyceride of cerotic acid),
Trimontan (C ₂₈ : triglyceride of montanic acid),
Trimericin (C ₃₀ : triglyceride of mericinic acid),
Trilacselone (C ₃₂ : triglyceride of laxellonic acid), trigeda (C ₃₄ : triglyceride of gedic acid)
Etc. can be given.

Further, these fatty acids may be not only a single type of triglyceride but also a mixed fatty acid triglyceride in an arbitrary ratio, and the single type of fatty acid triglyceride may be mixed in an arbitrary ratio. Furthermore, in each hydrogenated product of fish oil, animal fat and oil and vegetable fat (hardened fat), the main component of the constituent fatty acids is the above fatty acid,
It can be used as is in the present invention. As an example of this, sardine oil,
Herring oil, saury oil, squid oil, cod liver oil, menhaden oil, seal oil, beef tallow, lard, sheep fat, linseed oil, eno oil, walnut oil, sunflower oil, safflower oil, soybean oil, cottonseed oil, corn oil, There are hydrogenated substances such as sesame oil, rapeseed oil, rice bran oil, peanut oil, olive oil, camellia oil, tea seed oil, castor oil, palm oil and the like. In the present invention, the above-mentioned linear saturated fatty acid triglyceride is desirable.

In the present invention, among the fatty acid triglycerides, the fatty acid triglycerides having 16 to 30 carbon atoms, hydrogenated products of fish oils and animal and vegetable oils and fats are preferable, and tristearin, tribehen, soybean extremely hardened oils and fats and rapeseed extremely hardened oils and fats are preferable. More preferred is tribehen, and most preferred is rapeseed extremely hardened oil and fat. A triglyceride of a fatty acid having less than 16 carbon atoms is not preferable because the target product cannot be efficiently separated in the purification step, and a fatty acid having more than 34 carbon atoms is industrially difficult to obtain.

Specific examples of the c) type monoesters of fatty acids and lower alcohols include stearic acid, isostearic acid (2-heptylundecanoic acid, isostearic acid manufactured by Emery Co., Ltd.), arachidic acid, behenic acid, lignoceric acid, Cerotic acid, montanic acid, melissic acid, laxeronic acid, gedic acid, etc., and mixed fatty acids in any proportion thereof, such as hydrolyzed fatty acids of hydrogenated products of the above-mentioned fish oil, animal fats and vegetable fats or oils Methyl, ethyl, hydrogenated products of each hydrolyzed fatty acid,
Examples thereof include n-propyl and isopropyl esters, of which lower monohydric alcohols each having 18 to 30, more preferably 20 to 28, and most preferably 22 to 28 straight chain saturated fatty acids. Monoesters are preferred. With a fatty acid having less than 18 carbon atoms, it is difficult to separate the target product in the purification step of the present invention, and conversely, a fatty acid having more than 34 carbon atoms is industrially difficult to obtain.

In the present invention, a) type diester> c) type monoester> b) type triglyceride can be preferably used in this order. In addition, examples of the high melting point ester that can be used in the present invention include various waxes which are esters of higher fatty acids and higher alcohols, for example, montan wax, carnauba wax, rice wax, candelilla wax, sunflower wax, beeswax, whale wax. , Shellac wax, insect white wax, poppy wax, cotton wax, sugar cane wax and the like.

The transesterification reaction of the present invention is characterized by using a thermostable lipase. Thereby, the transesterification reaction between the racemic alcohol and the ester can be rapidly proceeded by maintaining the temperature at a high temperature, and the high temperature reaction is made possible. High melting point esters can be used without the need for.

As the heat-resistant lipase, Japanese Patent Publication No. 58-3
Alcaligenes described in Japanese Patent No. 6953
) Genus-derived lipase, Rhizopus chinensi described in JP-A-59-156282.
s) etc. can be illustrated. In the present invention, in particular,
Alkagenes sp described in JP-36953-A (Alcaligenes sp. PL-266) (Ministry of Industrial Science and Technology No. 3187), lipase PL-266, JP-A-60-15312
The lipase PL-679 produced by SP (Alcaligenes sp. PL-679) (Microtechnical Laboratory No. 3783) is preferable, and further, the lipase QL manufactured by Meito Sangyo Co., Ltd. is preferable. Such heat-resistant lipase includes activated carbon, Celite,
Although it may be immobilized on a known carrier such as an adsorptive resin, an ion exchange resin, or a ceramics, it is preferably coexisted with the raw material in a powder state as described later.

In the transesterification reaction, the above-mentioned racemic alcohol and ester are mixed as a raw material in a molar ratio of 1: 1 or less, preferably 1: 0.5 to 0.25, based on the racemic alcohol, It is preferable for a reaction system which does not use a solvent as a raw material and contains substantially no water (that is, an equilibrium water content of the raw material of about 0.1% by weight or less, desirably 0.01% by weight or less). Disperse the lipase powder and carry out the reaction with stirring.
At this time, 90% or more of the particles of the lipase powder are 1 to 100
It is desirable to control the transesterification so that the size is μm, preferably 20 to 50 μm.
As means for homogenizing the particle size, the lipase powder is dispersed in the raw material which is heated and dissolved as necessary, and then ultrasonicated, filtered with a precision membrane or ultrafiltration membrane of the dispersion, and centrifuged to settle. The treatment may be carried out, but it is convenient to irradiate ultrasonic waves for 1 to 30 minutes under the reaction temperature of 20 to 150 kHz and 100 to 250 W.

The reaction temperature is 81 ° C or higher, more preferably 9 ° C.
1 to 130 ° C., most preferably 101 to 120 ° C., the reaction rate is checked by, for example, gas chromatography while gently stirring or shaking, and transesterification is performed for a predetermined time, preferably 10 minutes to 10 hours. Allow the reaction to take place. When the reaction temperature is lower than 81 ° C, the reaction proceeds slowly, and when it is higher than 130 ° C, the lipase is inactivated. Note that, depending on the type of the ester as the raw material, a lower alcohol is produced along with the transesterification reaction, so that the transesterification reaction can be carried out more efficiently by carrying out the reaction while distilling this out under reduced pressure.

The transesterification reaction product is obtained by removing the lipase using a microfiltration membrane such as filter paper, and then simply distilling the optically active alcohol of either R form or S form which is present as an unreacted product in the presence of a solvent. Alternatively, it is treated by a relatively simple method such as fractionation, recrystallization or silica gel column chromatography in the absence of the residue, and the residue is subjected to alkaline hydrolysis with sodium hydroxide or potassium hydroxide or with hydrochloric acid or sulfuric acid. By acid hydrolysis and, if necessary, fractionation treatment using acetone, methyl ethyl ketone, ethyl acetate, hexane or the like, the other optically active alcohols remaining can be separated and purified by increasing both the substance purity and the optical purity.

[0022]

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 specific optical rotation. (Manufactured by JASCO Corporation, DIP-37
0) was used for each measurement, and the calculated value was calculated by comparing with the value of the standard sample.

Example 1 300 g of lipase QL derived from Alcaligenes sp. (Manufactured by Meito Sangyo Co., Ltd., the same applies hereinafter) and 60 g of (R, S) -1-phenylethanol were used.
It was placed in a ml separable flask, and was placed at room temperature using an ultrasonic generator (Shimadzu Corporation SUS-103) at 45.
Ultrasonic waves were applied for 1 minute at kHz. Next, 140 g of tetradecadicarboxylic acid dimethyl ester was added to this, and 95
Stirring was carried out at a stirring speed of 350 rpm at 0 ° C., and transesterification reaction was carried out for 20 hours while evaporating the by-produced methanol. Water content in reaction system (Karl Fischer method):
0.02% by weight, particle size of lipase particles (measured by Coulter Electronics Co., Ltd. particle size distribution measuring apparatus: Multisizer): 90% was 10 to 50 μm. The reaction product was measured by gas chromatography to find that it was 45 mol% of (R, S) -1-phenylethanol.
Was transesterified to 1- (1-phenylethyl), 14-methyltetradecadicarboxylic acid diester and 1,14-di (1-phenylethyl) tetradecadicarboxylic acid diester.

After removing the lipase using Toyo Filter Paper No. 5A, simple distillation was performed under the conditions of 85 ° C. and 5 mmHg (S).
-(-)-1-Phenylethanol (yield 97%, substance purity 99.9%, optical purity 82.3% ee) was obtained. On the other hand, the residue, that is, 1- (1-phenylethyl), 14-
Methyl tetradecadicarboxylic acid diester, 1,14-
A mixture of di (1-phenylethyl) tetradecadicarboxylic acid diester and unreacted tetradecadicarboxylic acid dimethyl ester was refluxed in a 10% aqueous sodium hydroxide solution for 1 hour to undergo alkaline hydrolysis, and then acetone 1000 was added.
After adding ml and cooling to 5 ° C, sodium tetradecadicarboxylate precipitated was filtered off in the same manner as above, and methanol was distilled off under reduced pressure to obtain (R)-(+)-1-phenylethanol (yield: Yield 83%, substance purity 99.9%, optical purity 98.3% ee).

Example 2 Using 2 g of lipase QL, 40 g of (R, S) -1-phenylethanol and 160 g of docosadicarboxylic acid diethyl ester, a transesterification reaction was carried out for 25 hours under the same conditions as in Example 1. The water content in the reaction system was 0.02% by weight, and the lipase particle size: 96% was 5 to 60 μm. The reaction product was measured by gas chromatography to find that it was 49 mol% of (R, S) -1-phenylethanol.
Was converted to 1- (1-phenylethyl), 20-ethyldocosadicarboxylic acid diester and 1,20-di (1-phenylethyl) docosadicarboxylic acid diester. The reaction is treated as in Example 1 (S)-
(−)-1-Phenylethanol (yield 98%, substance purity 99.9%, optical purity 98.9% ee) was obtained. on the other hand,
Residue, namely 1- (1-phenylethyl), 20-ethyldocosadicarboxylic acid diester, 1,20-di (1-
A mixture of phenylethyl) docosadicarboxylic acid diester and unreacted docosadicarboxylic acid diethyl ester was refluxed with 10% hydrochloric acid for 1 hour to acid-hydrolyze, 1000 ml of acetone was added, and the mixture was cooled to 5 ° C. to precipitate the precipitated docosadicarboxylic acid. Similarly, it was filtered off and ethanol was distilled off under reduced pressure to obtain (R)-(+)-1-phenylethanol (yield 87%, substance purity 99.9%, optical purity 98.4% ee).
Got

Example 3 3 g of lipase PL (manufactured by Meito Sangyo Co., Ltd.) derived from Alcaligenes sp. And (R,
S) -1-Phenylethanol (50 g) was placed in a 300 ml separable flask, and an ultrasonic generator (Example 1) was used at room temperature.
The same as the above) was used for ultrasonic wave irradiation at 20 kHz for 20 minutes. After that, 150 g of tripalmitin was added, and the transesterification reaction was carried out at 85 ° C. at a stirring speed of 100 rpm for 30 hours. The water content in the reaction system was 0.05% by weight, and the lipase particle size: 93% was 15 to 40 μm. The reaction product was measured by gas chromatography to find that it was 46 mol% of (R, S) -1-phenylethanol.
Had been converted to 1-phenylethyl palmitate.
Add 1500 ml of acetone to the reaction mixture and cool to 10 ° C.
Lipase and unreacted products of tripalmitin, dipalmitin, monopalmitin and palmitic acid were separated by filtration using Toyo Roshi Kaisha No. 5A. Then, simple distillation was performed under the conditions of 95 ° C. and 5 mmHg, and (S)-(−)-1-phenylethanol (yield 87%, substance purity 99.9%, optical purity 86.3).
% Ee). On the other hand, the residual (R)-(+)-1-
Example 1 A palmitate ester of phenylethanol was used.
Alkaline hydrolysis treatment is performed in the same manner as in (R)-(+)-1
-Phenylethanol (yield 82%, substance purity 99.5
%, Optical purity 98.0% ee) was obtained.

Example 4 Using 3 g of lipase QL, 50 g of (R, S) -1- (2-bromophenyl) ethanol and 150 g of tribehen, a transesterification reaction was carried out at 105 ° C. for 20 hours in the same manner as in Example 3. . The water content in the reaction system was 0.01% by weight, and the lipase particle size: 90% was 30 to 50 μm. When the reaction product was measured by gas chromatography, 45 mol% of (R, S) -1- (2-bromophenyl) ethanol was converted to 1- (2-bromophenyl) ethylbehenate. The reaction product was treated in the same manner as in Example 3 and subjected to simple distillation under the conditions of 110 ° C. and 5 mmHg,
(S)-(-)-1- (2-bromophenyl) ethanol (yield 82%, substance purity 99.9%, optical purity 81.
5% ee) was obtained. On the other hand, the residual (R)-(+)-1
The behenic acid ester of-(2-bromophenyl) ethanol was subjected to acid hydrolysis treatment in the same manner as in Example 2 to obtain (R)-.
(+)-1- (2-Bromophenyl) ethanol (yield 75.6%, substance purity 99.8%, optical purity 99.0%
ee).

Example 5 Lipase QL 3 g, (R, S) -2-octanol 50
g and 150 g of tribehen were transesterified at 120 ° C. for 22 hours in the same manner as in Example 3. The water content in the reaction system was 0.03% by weight, and the lipase particle size: 91% was 20 to 40 μm. When the reaction product was measured by gas chromatography, (R, S) -2-
64 mol% of the octanol had been converted to 2-octyl behenate. The reaction was treated as in Example 3 and 6
Perform simple distillation under the conditions of 5 ° C and 5 mmHg to obtain (S)-(+)
-2-Octanol (34% yield, substance purity 99.9)
%, Optical purity 98.2% ee) was obtained. On the other hand, the residual behenic acid ester of (R)-(−)-2-octanol was subjected to alkaline hydrolysis treatment in the same manner as in Example 1 to obtain (R)-.
(−)-2-Octanol (yield 85%, substance purity 9
9.6%, optical purity 62% ee) was obtained.

Example 6 Lipase QL1g and (R, S) -2-decanol 4
0 g was placed in a 300 ml separable flask and irradiated with ultrasonic waves at 90 kHz for 1 minute using an ultrasonic generator (same as in Example 1) at room temperature. After that, 60 g of isopropyl stearate was added, and the mixture was stirred at 95 ° C. at a stirring speed of 250 rpm while distilling off by-product isopropanol under reduced pressure.
The transesterification reaction was carried out for an hour. Water content in the reaction system:
0.02% by weight, lipase particle size: 96% is 10%
It was 40 μm. When the reaction product was measured by gas chromatography, 58 mol% of (R, S) -2-decanol was converted to 2-decanoyl stearate.
Lipase was filtered off in the same manner as in Example 1, and simple distillation was performed under the conditions of 70 ° C. and 5 mmHg, and (S)-(+)-2-decanol (yield 73.5%, substance purity 99.9%). , Optical purity 9
8.5% ee) was obtained. On the other hand, the residual (R)-(-)
A mixture of 2-decanol stearic acid ester and unreacted isopropyl stearate was acid-hydrolyzed in the same manner as in Example 2, 1000 ml of acetone was added, the mixture was cooled to 5 ° C., and stearic acid deposited was filtered off in the same manner. Further, methanol was distilled off under reduced pressure to obtain (R)-(-)-2-decanol (yield 72%, substance purity 99.6%, optical purity 84% e
e) got.

Example 7 Using lipase QL (1 g), (R, S) -1-phenylethanol (40 g) and ethyl behenate (60 g) at 95 ° C.
In the same manner as in Example 6, the transesterification reaction was carried out for 20 hours. The water content in the reaction system was 0.03% by weight, and the lipase particle size: 95% was 20 to 40 μm. When the reaction product was measured by gas chromatography, (R, S)
47 mol% of -1-phenylethanol was converted to 1-phenylethyl behenate. The reaction product was used in Example 6.
Is treated in the same manner as above and subjected to simple distillation under the conditions of 85 ° C. and 5 mmHg to obtain (S)-(−)-1-phenylethanol (yield 97%, substance purity 99.9%, optical purity 88.9). % Ee)
Got On the other hand, the residual behenic acid ester of (R)-(+)-1-phenylethanol and unreacted ethyl behenate were alkali-hydrolyzed in the same manner as in Example 1, 1000 ml of acetone was added, and the mixture was cooled to 5 ° C. The precipitated behenic acid was filtered off in the same manner, and (R)-(+)-1-phenylethanol (yield 88%, substance purity 99.9%, optical purity 9
8.5% ee) was obtained.

Comparative Example 1 Tributyrin 1 was used instead of tribehen in Example 4.
The same reaction was carried out for 25 hours at 40 ° C. using 50 g (water content in reaction system: 0.05% by weight, lipase particle size: 93% was 20 to 40 μm). The reaction product was fractionated into an alcohol, a monoester, a fatty acid, a monoglyceride, a diglyceride, and a triglyceride by thin-layer chromatography, and the reaction rate was measured by gas chromatography. As a result, (R, S) -1- (2-bromophenyl ) 37 mol% of ethanol had been converted to 1- (2-bromophenyl) ethyl butyrate. Treat the reactants in the same way,
(S) -by simple distillation under the conditions of 110 ° C and 5 mmHg
An attempt was made to recover (-)-1- (2-bromophenyl) ethanol, but it was impossible because other components were mixed and distilled.

Comparative Example 2 Using 60 g of ethyl laurate instead of ethyl behenate in Example 7, the same reaction was carried out for 25 hours at 40 ° C. (water content in reaction system: 0.03% by weight, lipase particle size). : 94% is 10 to 50 μm). When the reaction product was measured by gas chromatography, 46 mol% of (R, S) -1-phenylethanol was converted to 1-phenylethyl laurate. Treat the reactants in the same way,
(S)-(-) by simple distillation under the conditions of 85 ° C and 5 mmHg
As a result of collecting -1-phenylethanol, the substance purity of the obtained alcohol was 32%. Then, when (S)-(-)-1-phenylethanol was separated by liquid chromatography, the yield was 5% and the optical purity was 8%.
It was 9% ee.

[0033]

INDUSTRIAL APPLICABILITY According to the present invention, a racemic alcohol and a high melting point ester can be transesterified with a heat resistant lipase at a high temperature in an extremely short time,
As a result, one of the racemates remains unreacted and the other becomes a high-melting point and high-boiling point transesterification product, so by utilizing this difference in physical properties, simple distillation, solvent fractionation, etc. By using such a simple and inexpensive purification means, an optically active alcohol having both high material purity and high optical purity can be resolved in good yield.

Claims (7)

[Claims] 1. A racemic alcohol and a) 14 carbon atoms
Selected from the group consisting of the above-mentioned lower monohydric alcohol diesters of saturated dicarboxylic acids, b) triglycerides composed of saturated fatty acids having 16 or more carbon atoms, and c) lower monohydric alcohol monoesters of saturated fatty acids having 18 or more carbon atoms. The ester is allowed to undergo a transesterification reaction at 81 ° C. or higher in the coexistence of a thermostable lipase, without using the solvent of the raw material, and under a condition substantially containing no water,
A process for producing an optically active alcohol, which comprises splitting an optically active alcohol enriched in either the R form or the S form from the reaction product. 2. The method according to claim 1, wherein the thermostable lipase is obtained from a microorganism belonging to the genus Alcaligenes. 3. The production method according to claim 1, wherein the thermostable lipase is in the form of powder, and 90% or more of the particles have a particle size of 1 to 100 μm. 4. The production method according to claim 1, wherein the transesterification reaction temperature using thermostable lipase is 101 to 120 ° C. 5. The production method according to claim 1, wherein the saturated dicarboxylic acid and the saturated fatty acid are linear. 6. The method according to claim 1, wherein the racemic alcohol is a 2-alkanol. 7. A racemic alcohol is represented by the following general formula (1): [Wherein A ≠ B in the formula (1), A is a phenyl group or the following general formula (2): (In the formula (2), D ₁ , D ₂ , D ₃ , D ₄ and D ₅
Is a substituent represented by a halogen atom, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, and B
Is an alkyl group having 1 to 3 carbon atoms or CF ₃ or CN]
The production method according to claim 1, which is a compound represented by: