JPH08116987A - Resolving of optically active alcohol - Google Patents

Abstract

PURPOSE: To resolve the subject compound in high purity and good yield by reacting a racemic alcohol with a specific saturated dicarboxylic acid diester, etc., in the presence of an enzyme to separate either one isomer and separating another isomer by reaction with a non-optically active alcohol. CONSTITUTION: A racemic alcohol expressed by formula I [A is phenyl or a group of formula II (D1 to D5 are each a halogen, a 1-3C alkyl or a 1-3C alkoxy); B is a 1-3C alkyl, CF3 or CN] is subjected to transesterification with one kind of an ester selected from a lower monohydric alcohol diester of a >=14C saturated dicarboxylic acid, >=16C saturated fatty acid triglyceride, a lower monohydric alcohol diester of >=18C saturated fatty acid, etc., using a lipase catalyst in the presence (or absence) of a solvent under conditions not containing water to separate either one as an enantiomer, and a non- optically active non-racemic alcohol different from the racemic alcohol in boiling point is added to the residual part and the mixture is subjected to transesterification under same conditions as above. Thereby, another one as its enantiomer is separated to resolve the optically active alcohol in high purity and good yield.

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art 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 exhibit sufficient physiological activity and properties. Is required to have considerably high accuracy in terms of both material purity and 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 enzymatic reaction is effective as a means for increasing the 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, the enzymatic reaction currently carried out must be carried out for a very long time of several days to several tens of days or longer (for example, JP-A-62-166898 and JP-A-63-273499, JP-A-2-86797). In the case of lipase, the temperature range in which the enzymatic reaction can be carried out is at most about 20 to 70 ° C, preferably 30 to 5 ° C.
The temperature is 0 ° C. For example, the ester to be transesterified with the racemic alcohol must be dissolved in a liquid or a solvent in that temperature range to react (Japanese Patent Laid-Open No. 62-62-62).
166898, JP-A-63-284184, JP-A-2-182340, JP-A-4-349894).

Therefore, the ester to be transesterified and the racemic alcohol are often close to each other in physical properties such as boiling point and melting point. Usually, various components such as unreacted products and by-products are used. As a purification means for efficiently separating and recovering the target substance from the contained reaction product 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 completion of the transesterification reaction, a treatment such as a hydrolysis reaction is required to recover the target optically active alcohol from the reaction product, and azeotropic distillation, molecular distillation or preparative liquid chromatography is used. The reality is that the substance purity is increased.

[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 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 optically resolving an optically active alcohol, in which the enzymatic reaction is carried out in a short time, and the 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, in the first-step reaction, a racemic alcohol and a specific ester shown below are subjected to transesterification in the presence of lipase in a solvent or in the absence of a solvent, whereby one of the enantiomers is obtained from the reaction product. Of the optically active alcohol can be easily isolated in high yield, and then in the second reaction,
By adding a non-optically active non-racemic alcohol to the residue obtained by separating the optically active alcohol and carrying out a transesterification reaction in the presence of lipase as in the first step reaction, the other optically active alcohol of the enantiomer is increased. The present invention has been completed by finding that it can be isolated with high purity and convenience.

That is, the gist of the present invention is a method of resolving an optically active alcohol, which comprises the following first step and second step. First step: racemic alcohol and a) a lower monohydric alcohol diester of a saturated dicarboxylic acid having 14 or more carbon atoms,
1 selected from the group consisting of b) a triglyceride composed of a saturated fatty acid having 16 or more carbon atoms, and c) a lower monohydric alcohol monoester of a saturated fatty acid having 18 or more carbon atoms.
The ester is used as a starting material, lipase is used as a catalyst, and the ester exchange reaction is carried out in the presence or absence of a solvent for the starting material under conditions substantially free of water. A step of separating unreacted optically active alcohol rich in either one of Second step: To the residue obtained by separating the unreacted optically active alcohol obtained in the first step, a non-optically active non-racemic alcohol having a boiling point different from that of the racemic alcohol is added, and lipase is used as a catalyst for the raw material solvent. Which is rich in either the R-form or the S-form which was not separated in the first step from the reaction product by transesterification in the presence or absence of benzene, and under conditions containing substantially no water. Separating the active alcohol.

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

Embedded image [However, in the formula (1), A ≠ B, and 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 performed 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-propionate, methyl 3-hydroxy-pentanate, 1-phenyl-1,3-propanediol, 2-
Phenyl-1-cyclohexanol, 1-pentyne-3
-Ol, 1- (2-bromophenyl) ethanol, 1
-Parachlorophenylethanol, 1- (4-chlorophenyl) ethanol, 1-chloro-2-octanol,
1,1-difluoro-2-octanol, 1- (2,4
There are racemic alcohols such as -dichlorophenyl) ethanol. Of these, preferably 2-octanol, 1
-Phenylethanol, 1-phenyl-1,3-propanediol and 2-phenyl-1-cyclohexanol, most preferably 1-phenylethanol, 2-octanol and 1- (2-bromophenyl) ethanol.

The ester used in the first step of the present invention is
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 lower monohydric alcohol monoester of a saturated fatty acid having 18 or more carbon atoms An ester selected from the group consisting of
The monohydric alcohol is a linear or branched monohydric alcohol having 1 to 3 carbon atoms (methanol, ethanol, n-propanol,
Isopropanol). It is desirable that all of the a), b) and c) type esters have a high melting point (preferably 60 ° C. or higher, more preferably 70 ° C. or higher). This has the advantage that the target optically active alcohol can be efficiently obtained from the transesterification reaction 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, Any one of eicosadicarboxylic acid, docosadicarboxylic acid, tetracosadicarboxylic acid, hexacosadicarboxylic acid, octacosadicarboxylic acid, and saturated dicarboxylic acid represented by dimer acid obtained by dimerizing oleic acid, erucic acid, etc. Specific examples thereof include dimethyl, diethyl, di-n-propyl and diisopropyl esters. Of these, lower monohydric alcohol diesters of the linear saturated dicarboxylic acid having 20 to 28 carbon atoms are preferable, and further 22 carbon atoms are preferable. Dicarboxylic acid (docosadicarboxylic acid) and Wherein each lower monovalent alcohol diesters of dicarboxylic acids primes 28 (octa co spoon carboxylic acid) is more preferable. If the carbon number is less than 14, the desired product cannot be efficiently separated in the purification step of the present invention, and if the carbon number exceeds 45, it is difficult to obtain industrially. Further, the lower monohydric alcohol is not preferable in view of the gist of the present invention when the number of carbon atoms exceeds 3, since a racemic mixture may be present.

Examples of fatty acid triglycerides of type b) are tripalmitin (C ₁₆ : palmitic acid triglyceride), tri-2-hexyldecane (C ₁₆ : 2-hexyldecanoic acid triglyceride), tristearin (C ₁₈ : stearic acid triglyceride). Triglyceride), triisostearin (C ₁₈ : triglyceride such as 2-heptylundecanoic acid, isostearic acid manufactured by Emery Co.), 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 above-mentioned 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 monoester of fatty acid and lower alcohol 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 fatty acids having less than 18 carbon atoms, it is difficult to separate the target product in the refining process, and conversely, fatty acids having more than 34 carbon atoms are difficult to obtain industrially.

In the present invention, diesters of type a)>
C) type monoester> b) type triglyceride can be preferably used in this order. In addition, as the ester which can be used in the present invention, various waxes which are esters of higher fatty acid and higher alcohol, 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 so on.

In the first step of the present invention, the raw material is transesterified using lipase as a catalyst. Known lipases can be used, for example, porcine pancreatic lipase, Pseudomonas fluoresc
ens), Pseudomonas sp.
), Candida cylindora
cea), Aspergillus niger
), Mucor miehei, Mucor javanicus, Rhizopus delemar, Rhizop
us niveus), Rhizopus javicas
anicus), Humicola lanugin
osa), Chromobacterium viscosham (Chromobact)
erium viscosum), Geotrichum candy dam (Ge
otrichum candidum), penicillium cyclopium (Penicillium cyclopium), and other lipases derived from microorganisms. Also, the Alcaligenes s described in JP-B-58-36953.
p. PL-266) (Ministry of Industrial Science and Technology, No. 3187), Lipase PL-266, Alcaligenes described in Japanese Patent Publication No. 60-15312.
sp. PL-679) (Ministry of Industrial Science, No. 3783), lipase PL-679, JP-A-59-156282.
Rhizopus chinesis (Rhizopus chine)
nsis) is a heat-resistant lipase, especially the former two are 81 ℃ or more, more preferably 91 ~ 130 ℃,
Most preferably, the reaction can be catalyzed even at a high temperature of 101 to 120 ° C. Such a lipase can be used as it is in a powder state, or can be immobilized on a known carrier such as activated carbon, celite, an adsorptive resin, an ion exchange resin, glass or ceramics before use.

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, and the raw material is mixed. Solvent such as hexane,
Cyclohexane, heptane, octane, isooctane,
Without adding or using a non-aqueous organic solvent such as carbon tetrachloride, diethyl ether, diisopropyl ether, petroleum ether, etc., and containing substantially no water (that is, an equilibrium water content of about 0.1% by weight in the raw material). % Or less, preferably 0.01% by weight or less), preferably the powder of the lipase is dispersed in the reaction system, and the reaction is carried out with stirring. At this time, it is desirable to control the transesterification reaction so that 90% or more of the particles of the lipase powder have a size of 1 to 100 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. 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 set in the range of 20 to 130 ° C in consideration of the heat resistance of lipase, the boiling point of the solvent, etc., and the reaction rate is checked by, for example, gas chromatography while gently stirring or shaking. The transesterification reaction is performed for a predetermined time, preferably several hours to 100 hours. If the reaction temperature is lower than 20 ° C, the reaction proceeds slowly,
On the contrary, when the temperature exceeds 130 ° C, the inactivation of lipase is caused.

The optically active alcohol rich in either the R form or the S form present as an unreacted substance in the transesterification reaction product is subjected to lipase removal using a microfiltration membrane such as filter paper, High purity can be obtained by treatment by distillation, fractionation in the presence or absence of a solvent, recrystallization, silica gel column chromatography, or the like, more preferably by simple distillation alone.

The residue obtained by the first step as described above, which is obtained by separating the unreacted optically active alcohol from the transesterification reaction product, is subsequently used as a raw material for the second step described below. That is, in the second step of the present invention, a non-optically active non-racemic alcohol having a boiling point different from that of the racemic alcohol is added to the residue, and the same conditions as in the first step (using lipase as a catalyst, in the presence of a solvent or An optically active alcohol which is rich in either the R form or the S form which has not been separated in the first step in the reaction product by performing a transesterification reaction under the presence of a substantially water-free reaction condition). Is produced in a free state and separated in the same manner as in the first step.

The non-optically active non-racemic alcohol is not particularly limited as long as it has a boiling point different from that of the racemic alcohol used as the raw material in the first step and does not contain an enantiomer, and various Although a monohydric alcohol that is commonly used as an industrial raw material can be used, it is convenient. Specifically, n-butanol, n-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octanol, n-nonanol, n-decanol, lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, Examples include isostearyl alcohol (2-heptylundecanol), oleyl alcohol, behenyl alcohol, octacosanol and the like. These non-optically active non-racemic alcohols have a boiling point different from the boiling point of the racemic alcohol, and one or more of them may be used as the first
Mixing is carried out at a molar ratio of 1: 1 or less, preferably 1: 0.5 to 0.25, based on the ester in the residue obtained in the step, and the transesterification reaction is carried out using lipase as in the first step. The optically active alcohol enriched in either the R isomer or the S isomer (enantiomer not separated in the first step) in a free state is separated from the reaction product.

[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 specific optical rotation. (D1P-37 manufactured by JASCO Corporation)
0) was used for each measurement, and the calculated value was calculated by comparing with the value of the standard sample.

Example 1 Candida cylindracea
Origin lipase OF (manufactured by Meito Sangyo Co., Ltd.) 10 g,
80 g of (R, S) -1-phenylethanol, 140 g of octadecadicarboxylic acid dimethyl ester and 420 ml of hexane were put in a 1000 ml separable flask, and an ultrasonic generator (manufactured by Shimadzu Corporation, SUS-1) was added at room temperature.
03) was used and ultrasonic waves were applied at 45 kHz for 1 minute. Then, the mixture was stirred at 50 ° C. at a stirring speed of 350 rpm, and a transesterification reaction was carried out for 72 hours. Moisture content in the reaction system (Karl Fischer method): 0.05% by weight, size of lipase particles (measured by Coulter Electronics Co. particle size distribution analyzer: Multisizer): 95% or more is 2
It was 0 to 50 μm. After completion of the reaction, the reaction product was measured by gas chromatography to find that 49 mol% of (R, S) -1-phenylethanol was converted to octadecadicarboxylic acid ester. Membrane filter 0.
After removing the lipase by filtration using 5 μm (manufactured by Advantech), the hexane was distilled off under reduced pressure and further 90
Unreacted (S)-
(-)-1-Phenylethanol (yield 98%, material purity 100%, optical purity 98% ee) was separated.

Then, 270 g of n-tetradecanol, 450 ml of hexane and 10 g of lipase OF were added to the residue after the simple distillation treatment, and the particle size of the enzyme was adjusted by sonication in the same manner as above, followed by stirring at 50 ° C. Speed 350rpm
The mixture was stirred at 72 ° C. for transesterification for 72 hours. Hexane was distilled off from this reaction product under reduced pressure, and then at 90 ° C. for 3 mm.
When simple distillation was carried out under the condition of Hg, liberated high-purity (R)-(+)-1-phenylethanol (yield 87
%, Material purity 100%, optical purity 100% ee).

Comparative Example 1 Under the same conditions as in Example 1 except that 150 g of sebacic acid dimethyl ester was used in place of octadecadicarboxylic acid dimethyl ester, the transesterification reaction was carried out at 50 ° C.
It was carried out for 2 hours (water content in reaction system: 0.07% by weight, size of lipase particles: 87% was 25 to 60 μm). After the completion of the reaction, the reaction product was analyzed by gas chromatography to find that 32 mol% of (R, S) -1-phenylethanol had been converted to sebacic acid ester. This reaction product was treated in the same manner as in Example 1 to remove lipase and hexane, and then simple distillation was carried out under the conditions of 90 ° C. and 3 mmHg, but unreacted (S)-(- ) -1-Phenylethanol is mixed with other components such as ester, and S
It was impossible to divide the body. Further, 220 g of nonanol and 10 g of the lipase described in Example 1 were added to the distillation residue, and the transesterification reaction was carried out at 50 ° C. for 72 hours in the same manner. After the reaction product was treated, it was heated at 90 ° C. under 3 mmHg. Although simple distillation was performed, other components such as unreacted nonanol and ester were mixed together with (R)-(+)-1-phenylethanol, and separation was impossible.

Example 2 4.5 g of lipase QL (manufactured by Meito Sangyo Co., Ltd.) derived from Alcaligenes sp.
90 g of S) -2-octanol and 134 g of tetradecadicarboxylic acid dimethyl ester were placed in a 300 ml separable flask, and ultrasonic waves were irradiated at 45 kHz for 1 minute using an ultrasonic wave generator at room temperature as in Example 1. Then 1
The transesterification reaction was carried out for 25 hours while the methanol produced by stirring at 05 ° C. at a stirring speed of 350 rpm was evaporated. Water content in reaction system measured by the method described in Example 1: 0.02% by weight, size of lipase particles: 90%
The above was 20 to 50 μm. After completion of the reaction, the reaction product was measured by gas chromatography to find that (R, S)
48 mol% of the 2-octanol had been converted to the tetradecadicarboxylic acid ester. After removing the lipase by filtration using a membrane filter 0.5 μm (manufactured by Advantech), simple distillation was performed under the conditions of 95 ° C. and 3 mmHg to obtain unreacted (S)-(+)-2-octanol (yield). 95%, substance purity 100.2%, optical purity 95
% Ee) was separated.

Then, 180 g of oleyl alcohol and 8 g of lipase QL were added to the residue after the above single distillation treatment,
After aligning the particle size of the enzyme by ultrasonic treatment in the same manner as above,
Stirring was carried out at a stirring speed of 350 rpm at 105 ° C. for transesterification for 48 hours. The reaction product was heated at 95 ° C for 3
When simple distillation was carried out under the condition of mmHg, liberated high-purity (R)-(-)-2-octanol (yield 92%, substance purity 100.9%, optical purity 100% ee) was obtained. .

Comparative Example 2 Under the same conditions as in Example 2, except that 140 g of decamethylenedicarboxylic acid dimethyl ester was used in place of tetradecadicarboxylic acid dimethyl ester, the transesterification reaction was carried out at 80 ° C. for 25 hours (in the reaction system) Water content: 0.
04 wt%, lipase particle size: 95% is 20-6
0 μm). When the reaction product was measured by gas chromatography, it was found that 58 mol% of (R, S) -2-octanol had been converted to decamethylene dicarboxylic acid ester.
This reaction product was treated in the same manner as in Example 2 to remove lipase, and then subjected to simple distillation under the conditions of 95 ° C. and 3 mmHg, whereby other components were co-distilled, and (S)-(−)-2 It was not possible to separate octanol with high purity. Further, 300 g of n-decanol and 10 g of the lipase described in Example 2 were added to the distillation residue, and the transesterification reaction was carried out at 80 ° C. for 48 hours in the same manner, and the reaction product was treated at 95 ° C. and 3 mmHg. By simple distillation under the conditions (R)-
Although (+)-2-octanol was recovered, the purity of the substance was low at 61% and the optical purity was 78% ee.

Example 3 Pseudomonas fluo
rescens) -derived lipase (lipase P) (manufactured by Amano Pharmaceutical Co., Ltd.) 5 g, (R, S) -1- (2-bromophenyl) ethanol 10 g, tribehen 30 g, and cyclohexane 450 ml. The same treatment as in Example 1 was performed and a transesterification reaction was carried out for 72 hours. Water content in reaction system: 0.01% by weight, size of lipase particles: 9
0% was 30 to 50 μm. The reaction product was measured by gas chromatography to find that (R, S) -1- (2-
48 mol% of bromophenyl) ethanol is 1- (2-
It had been converted to bromophenyl) ethyl behenate.
The reaction product was treated in the same manner as in Example 1 and subjected to simple distillation under the conditions of 110 ° C. and 5 mmHg to obtain unreacted (S)-(−)-1-
(2-Bromophenyl) ethanol (yield 82%, substance purity 99.9%, optical purity 98% ee) was obtained.

Then, 30 g of lauryl alcohol, 350 ml of cyclohexane and 3 g of lipase P (mentioned above) were added to the residue after the simple distillation treatment, and the particle size of the enzyme was adjusted by sonication in the same manner as above, and then the temperature was raised to 50 ° C. And transesterification was performed for 68 hours. This reaction product was heated at 110 ° C. for 5
After simple distillation under the condition of mmHg, high purity (R)-(+)-1- (2-bromophenyl) ethanol liberated (yield 75.6%, substance purity 99.8%, optical Purity 99% ee or more) was obtained.

Example 4 1 g of lipase PL (manufactured by Meito Sangyo Co., Ltd.) derived from Alcaligenes sp., (R, S)-
40 g of 2-decanol was placed in a 300 ml separable flask and irradiated with ultrasonic waves at 90 kHz for 1 minute using an ultrasonic generator (the same as in Example 1) at room temperature. Thereafter, 60 g of isopropyl stearate was added, and the stirring speed was 2 at 85 ° C.
Stirring was carried out at 50 rpm and transesterification was carried out for 30 hours. The amount of water in the reaction system was 0.02% by weight, and the size of lipase particles: 96% was 10 to 40 μm. When the reaction product was measured by gas chromatography, (R, S)
57 mol% of the 2-decanol had been converted to the 2-decanoylsurearate. 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 to obtain unreacted (S)-(+)-2-decanol (yield 73.5.
%, Substance purity 99.9%, optical purity 93% ee).

On the other hand, a mixture of stearic acid ester of (R)-(-)-2-decanol and unreacted isopropyl stearate, which is the residue after the above simple distillation treatment, was added to 90 g of stearyl alcohol and Lipase PL (supra).
After adding 3 g and adjusting the particle size of the enzyme by sonication in the same manner as described above, a transesterification reaction was carried out at 85 ° C. for 48 hours. High-purity (R)-(-)-2-decanol (yield 72%, substance purity 99.6%, optical purity 84%) liberated by simple distillation of this reaction product under the conditions of 90 ° C. and 3 mmHg.
ee).

[0034]

According to the present invention, since the transesterification reaction of the racemic alcohol is carried out twice, each of the optically active alcohols of the R-form and the S-form can be separated in high purity with high yield and easily. it can. That is, in the first step, the transesterification reaction between the racemic alcohol and the ester is carried out by a simple means such as simple distillation to remove the unreacted optically active alcohol in the R or S form among the racemates. By this, both the substance purity and the optical purity can be increased, and these can be separated. Further, in the subsequent second step, an optically active alcohol of either R-isomer or S-isomer, which cannot be obtained in the first step, is obtained by a transesterification reaction between the residue of the step and the non-optically active non-racemic alcohol. It can be liberated, and the substance and optical purity can be increased and separated by the same simple means as in the above step. Further, if a thermostable lipase is used in the transesterification reaction, the solvent of the raw material becomes unnecessary and the reaction time can be shortened.

Claims (5)

[Claims] 1. A method for resolving an optically active alcohol, which comprises the following first step and second step. First step: racemic alcohol and a) a lower monohydric alcohol diester of a saturated dicarboxylic acid having 14 or more carbon atoms,
1 selected from the group consisting of b) a triglyceride composed of a saturated fatty acid having 16 or more carbon atoms, and c) a lower monohydric alcohol monoester of a saturated fatty acid having 18 or more carbon atoms.
The ester is used as a starting material, lipase is used as a catalyst, and the ester exchange reaction is carried out in the presence or absence of a solvent for the starting material under conditions substantially free of water. A step of separating unreacted optically active alcohol rich in either one of Second step: To the residue obtained by separating the unreacted optically active alcohol obtained in the first step, a non-optically active non-racemic alcohol having a boiling point different from that of the racemic alcohol is added, and lipase is used as a catalyst for the raw material solvent. Which is rich in either the R-form or the S-form which was not separated in the first step from the reaction product by transesterification in the presence or absence of benzene, and under conditions containing substantially no water. Separating the active alcohol. 2. The resolution method according to claim 1, wherein the saturated dicarboxylic acid and the saturated fatty acid are linear. 3. The lipase is in the form of powder, and 9 of its particles are used.
The particle size of 0% or more is 1 to 100 μm.
The division method described in. 4. The resolution method according to claim 1, wherein the racemic alcohol is 2-alkanol. 5. 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 method for resolution according to any one of claims 1 to 3, which is a compound represented by: