JP2798893B2 - Resolution method of optically active alcohol - Google Patents

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 the like, 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 as raw materials or intermediate materials for pharmaceuticals and agricultural chemicals, and synthetic intermediates in the field of fine chemicals such as ferroelectric liquid crystals. Requires a very high degree of accuracy in both purity and optical purity as a substance. On the other hand, in a reaction using an enzyme such as lipase, lipoprotein lipase or esterase, it becomes possible to distinguish enantiomers which are difficult to carry out by ordinary chemical reactions involving high temperatures. For this reason, the enzymatic reaction is effective as a means for increasing the optical purity, that is, as a means for performing optical resolution. In recent years, methods for producing optically active alcohols utilizing this are being studied intensively.

[0003] However, the enzymatic reaction currently carried out requires a very long reaction of several days to several tens of days (for example, JP-A-62-166898, JP-A-63-273499, JP-A-2-86797). In addition, 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. in the case of lipase.
0 ° C., for example, the ester to be transesterified with a racemic alcohol must be reacted in a liquid state or dissolved in a solvent in that temperature range (Japanese Patent Laid-Open No. Sho 62-62).
JP-A-166898, JP-A-63-284184, JP-A-2-282340, JP-A-4-349894, etc.).

[0004] Therefore, the ester to be transesterified and the racemic alcohol often have almost similar physical properties such as boiling point and melting point, and 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 reactants and increasing the purity of the substance and the optical purity, it is difficult to utilize the difference in physical properties, and other complicated and expensive steps must be taken. That is, after the transesterification reaction, further 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 fact is that the material purity is increased.

[0005]

As described above, the current method for producing an optically active alcohol has the disadvantage 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 suitable raw material is selected, it is difficult to use a difference in physical properties such as a melting point and a boiling point in a separation and purification step of a target product after the reaction. There is a problem that a complicated method and means must be selected, and an excessive cost is required for efficiently recovering the desired optically active alcohol from the reaction product. Accordingly, an object of the present invention is to develop a method for resolving an optically active alcohol in which an enzymatic reaction can be performed in a short time and the target substance can be separated and purified by a simple operation.

[0006]

Means for Solving the Problems The present inventors have made intensive studies to solve the above problems and to obtain an optically active alcohol by an industrially simple and advantageous method. As a result, in the first-stage reaction, a transesterification reaction between a racemic alcohol and a specific ester shown below is carried out in a solvent or in the absence of a solvent in the presence of lipase, whereby one of the enantiomers is obtained from the reaction product. That the optically active alcohol can be easily isolated in a high yield.
By adding a non-optically active non-racemic alcohol to the residue obtained by separating the optically active alcohol and subjecting it to a transesterification reaction in the presence of a lipase in the same manner as in the first step reaction, the other optically active alcohol of the enantiomer is highly purified. They have found that they can be isolated with high purity and ease, and have completed the present invention.

That is, the gist of the present invention is a method for resolving an optically active alcohol, which comprises the following first step and second step. First step: racemic alcohol and 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.
A transesterification reaction under the conditions of the above-mentioned raw material, lipase as a catalyst, lipase as a catalyst, in the presence or absence of a solvent of the raw material and under a condition substantially free of water, to obtain an R-form or an S-form from the reaction product. Separating the unreacted optically active alcohol rich in any one of the above. Second step: A non-optically active non-racemic alcohol having a boiling point different from that of the racemic alcohol is added to the residue obtained by separating the unreacted optically active alcohol obtained in the first step, and the solvent of the raw material is produced using lipase as a catalyst. The transesterification reaction is carried out in the presence or absence of and under conditions substantially free of water, and the optical product enriched in either the R-form or the S-form which was not separated in the first step from the reaction product A step of separating active alcohol.

[0008]

In the present invention, 2-alkanol is easily split, and specifically, 2-butanol, 2-pentanol, 2-hexanol, 2-heptanol, 2-octanol, 2-nonanol, 2-decanol, 1-chloro-2-octanol and 1,1-difluoro-2-octanol. Most preferably, 2-
Octanol.

The ester used in the first step of the present invention is
a) lower monohydric alcohol diester of a saturated dicarboxylic acid having 14 or more carbon atoms, b) triglyceride composed of a saturated fatty acid having 16 or more carbon atoms, and c) lower monohydric alcohol monoester of a saturated fatty acid having 18 or more carbon atoms. One type of ester selected from the group consisting of
The dihydric alcohol is a linear or branched monohydric alcohol having 1 to 3 carbon atoms (methanol, ethanol, n-propanol,
Isopropanol). It is desirable that the esters of types a), b) and c) all have a high melting point (preferably at least 60 ° C, more preferably at least 70 ° C). This has the advantage that the desired optically active alcohol can be efficiently obtained from the transesterification product of the present invention.

The diesters of dicarboxylic acids of the type a) with lower alcohols include tetradecadicarboxylic acid, pentadecadicarboxylic acid, hexadecadicarboxylic acid, heptadecadicarboxylic acid, octadecadicarboxylic acid, nonadecadicarboxylic acid, Eicosadicarboxylic acid, docosadicarboxylic acid, tetracosadicarboxylic acid, hexacosadicarboxylic acid, octacosadicarboxylic acid, or oleic acid, any of saturated dicarboxylic acids represented by dimer acids such as erucic acid, etc. Dimethyl, diethyl, di-n-propyl and diisopropyl esters can be specifically exemplified, and among them, lower monohydric alcohol diesters of the above-mentioned linear saturated dicarboxylic acids having 20 to 28 carbon atoms are preferable, and furthermore, those having 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. When the number of carbon atoms of the dicarboxylic acid is less than 14, the desired product cannot be efficiently separated in the purification step of the present invention, and when the number of carbon atoms exceeds 45, it is difficult to obtain industrially. If the number of carbon atoms exceeds 3, the lower monohydric alcohol may be mixed with a racemic body, which is not preferable from the gist of the present invention.

Examples of type b) fatty acid triglycerides include tripalmitin (C ₁₆ : triglyceride of palmitic acid), tri-2-hexyldecane (C ₁₆ : triglyceride of 2-hexyldecanoic acid), and tristearin (C ₁₈ : triglyceride of stearic acid). triglycerides) triisostearate (C _18: 2-heptyl undecanoic acid, triglycerides such as emery Co. isostearic acid), Toriarakijin (C _20: triglycerides of arachidic acid), tribehenate (C _22: triglycerides of behenic acid), tri lignoceric (C ₂₄ : triglyceride of lignoceric acid),
Triserotin (C ₂₆ : triglyceride of serotoic acid),
Trimontan (C ₂₈ : triglyceride of montanic acid),
Trimellicin (C ₃₀ : triglyceride of melisic acid),
Triluxerone (C ₃₂ : triglyceride of lacceronic acid), trigeda (C ₃₄ : triglyceride of gedamic acid)
Etc. can be given.

These fatty acids may be not only a single kind of triglyceride but also a mixed fatty acid triglyceride in an arbitrary ratio, and the single kind of fatty acid triglyceride may be mixed in an arbitrary ratio. Further, each of hydrogenated products (hardened fats) of fish oils, animal fats and vegetable fats and oils, the main components of the constituent fatty acids are the above-mentioned fatty acids,
It can be used as is in the present invention. An example of this is 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 products such as sesame oil, rapeseed oil, rice bran oil, peanut oil, olive oil, camellia oil, teaseed oil, castor oil and palm oil. In the present invention, triglycerides of the above-mentioned linear saturated fatty acids are 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 oil and animal and vegetable oils and fats are preferable, and tristearin, tribehen, soybean extremely hardened fat and rapeseed extremely hardened oil and fat are preferable. More preferred are tribehen and rapeseed extremely hardened fats and oils. In addition, triglycerides of fatty acids having less than 16 carbon atoms are not preferred because the target product cannot be efficiently separated in the purification step, and fatty acids having more than 34 carbon atoms are difficult to obtain industrially.

Specific examples of the monoester of c) type fatty acid and lower alcohol include stearic acid, isostearic acid (such as 2-heptylundecanoic acid, isostearic acid manufactured by Emery), arachidic acid, behenic acid, lignoceric acid, and the like. Cerotic acid, montanic acid, melicic acid, laccelonic acid, gedic acid, and the like, and mixed fatty acids in any ratio thereof, for example, the above-mentioned fish oil, hydrolyzed fatty acid of each hydrogenated animal fat and vegetable fat, or of the above fats and oils Each hydrolyzed fatty acid hydrogenated methyl, ethyl,
Each ester of n-propyl and isopropyl can be mentioned, and among them, each lower monohydric alcohol of the linear saturated fatty acid having preferably 18 to 30, more preferably 20 to 28, and most preferably 22 to 28 carbon atoms. Monoesters are preferred. In the case of fatty acids having less than 18 carbon atoms, it is difficult to separate the target product in the purification step. Conversely, fatty acids having more than 34 carbon atoms are difficult to obtain industrially.

In the present invention, a) type diester>
Monoesters of type c)> triglycerides of type b) can be used in this order. In addition, the esters that can be used in the present invention include various waxes that 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.

In the first step of the present invention, the raw materials are subjected to a transesterification reaction using lipase as a catalyst. Known lipases can be used, such as porcine pancreatic lipase and Pseudomonas fluorescens.
ens), Pseudomonas sp.
), Candida cylindora
cea), Aspergillus niger
), Mucor miehei, Mucor
Javanicus (Mucor javanicus), Rhizopus delemar (Rhizopus delemar), Rhizopus niveus (Rhizop)
us niveus), Rhizopus jav
anicus), Humicola lanugin
osa), Chromobacterium biscosum (Chromobact)
erium viscosum), Geotricum Candy Dam (Ge
otrichum candidum) and lipases derived from microorganisms such as Penicillium cyclopium. Also, Alcaligenes sp. Described in JP-B-58-36953.
lipase PL-266 produced by P.PL-266) (Microtechnical Laboratory No. 3187), Alcaligenes described in JP-B-60-15312.
lipase PL-679 produced by S. sp. PL-679) (Microtechnical Laboratories No. 3783), JP-A-59-156282.
Publication No. Rhizopus chine
lipase originating from nsis) is thermostable, especially the former two are 81 ° C or higher, more preferably 91 to 130 ° C,
Most preferably, the reaction can be catalyzed even at a high temperature of 101 to 120 ° C. Such a lipase can be used in a powder state or immobilized on a known carrier such as activated carbon, celite, an adsorptive resin, an ion exchange resin, glass, and ceramics.

In the transesterification reaction, the 2-alk
The phenol and the phenol 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 2-alkanol, and the solvent of the raw material, for example, hexane, cyclohexane, heptane, octane, isooctane , Without adding or using a non-aqueous organic solvent such as carbon tetrachloride, diethyl ether, diisopropyl ether, petroleum ether and substantially free of water (that is, about 0.1%, which is the equilibrium water content of the raw material). The lipase powder is dispersed in a reaction system (preferably 0.01% by weight or less, preferably 0.01% by weight or less), and the reaction is carried out with stirring. At this time, it is desirable to carry out the transesterification reaction by controlling 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. Means for uniformizing the particle size include dispersing the lipase powder in the heated and dissolved raw material as necessary, followed by ultrasonic treatment, filtration of the dispersion with a precision membrane or ultrafiltration membrane, centrifugal sedimentation. The treatment may be carried out, but is preferably performed at a reaction temperature of 20 to 150 kHz or lower.
It is convenient to irradiate the ultrasonic wave under the condition of 0 to 250 W for 1 to 30 minutes.

The reaction temperature is set in the range of 20 to 130 ° C. in consideration of the heat resistance of the 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 is carried out for a predetermined time, preferably several hours to 100 hours. When the reaction temperature is lower than 20 ° C., the progress of the reaction is slow,
Conversely, if the temperature exceeds 130 ° C., lipase is inactivated.

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

As described above, the residue obtained by separating the unreacted optically active alcohol from the transesterification product obtained in the first step is 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 2-alkanol is added to the residue under the same conditions as in the first step (in the presence or absence of a solvent using lipase as a catalyst and a solvent). In the presence of an optically active alcohol enriched in either the R-form or the S-form which was not separated in the first step, the transesterification reaction was carried out under reaction conditions substantially free of water). In the free state, which is separated in the same manner as in the first step.

Here, the non-optically active non-racemic alcohol is not particularly limited as long as its boiling point is different from that of the racemic alcohol used as a raw material in the first step and contains no enantiomer. However, general-purpose monohydric alcohols as industrial raw materials are simple. 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 may contain one or more kinds of different boiling points from those of the racemic alcohols.
The ester in the residue obtained in the step is mixed at a molar ratio of 1: 1 or less, preferably 1: 0.5 to 0.25, based on the ester in the residue, and the transesterification reaction is carried out using lipase as in the first step. Then, an optically active alcohol rich in either the R-form or the S-form (enantiomer not separated in the first step), which has been released, is separated from the reaction product.

[0023]

The substance purity of the compounds obtained in the following Examples and Comparative Examples was determined by gas chromatography (GC-14A, manufactured by Shimadzu Corporation), and the optical purity was determined by measuring the specific rotation using a polarimeter. (D1P-37, manufactured by JASCO Corporation)
0), and calculated by comparing the measured value with the value of a standard sample.

[0024]

[0025]

[0026]

Example 2 4.5 g of lipase QL (manufactured by Meito Sangyo Co., Ltd.) derived from Aicaligenes sp.
S) 90 g of 2-octanol and 134 g of dimethyl tetradecadicarboxylate were placed in a 300 ml separable flask, and irradiated with ultrasonic waves at 45 kHz for 1 minute at room temperature using an ultrasonic generator at room temperature in the same manner as in Example 1. Then 1
The transesterification reaction was carried out for 25 hours while methanol produced by stirring at a stirring speed of 350 rpm at 05 ° C. was evaporated. Water content in the 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 -2-octanol had been converted to tetradecadicarboxylic acid ester. After removing lipase by filtration using a membrane filter of 0.5 μm (manufactured by Advantech), simple distillation was performed at 95 ° C. and 3 mmHg to obtain unreacted (S)-(+)-2-octanol (yield). 95%, substance purity 100.2%, optical purity 95
% Ee).

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

Comparative Example 2 A transesterification reaction was carried out at 80 ° C. for 25 hours under the same conditions as in Example 2 except that 140 g of dimethyl didecanedicarboxylate was used instead of dimethyl tetradecadicarboxylate. Water content: 0.
04% by weight, lipase particle size: 95% is 20-6
0 μm). When the reaction product was measured by gas chromatography, 58 mol% of (R, S) -2-octanol was converted to decamethylene dicarboxylic acid ester.
This reaction product was treated in the same manner as in Example 2 to remove lipase, and simple distillation was performed at 95 ° C. and 3 mmHg. As a result, there was co-distillation of other components, and (S)-(−)-2 -It was not possible to separate octanol to 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 a transesterification reaction was similarly performed at 80 ° C. for 48 hours. After treating the reaction product, the reaction product was heated at 95 ° C. and 3 mmHg. (R)-
Although (+)-2-octanol was recovered, the purity of the substance was as low as 61%, and the optical purity was 78% ee.

[0030]

[0031]

Example 4 1 g of lipase PL derived from Alcaligenes sp. (Manufactured by Meito Sangyo Co., Ltd.), (R, S)-
40 g of 2-decanol was placed in a 300 ml separable flask, and irradiated with ultrasonic waves at room temperature for 1 minute at 90 kHz using an ultrasonic generator (same as in Example 1). Thereafter, 60 g of isopropyl stearate was added, and the mixture was stirred at 85 ° C. at a stirring speed of 2
The mixture was stirred at 50 rpm to carry out a transesterification reaction for 30 hours. The water content 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, it was found that (R, S)
57 mol% of -2-decanol had been converted to 2-decanoyl slate. The lipase was separated by filtration in the same manner as in Example 1 and subjected to simple distillation at 70 ° C. and 5 mmHg to obtain unreacted (S)-(+)-2-decanol (yield 73.5).
%, A substance purity of 99.9%, and an optical purity of 93% ee).

On the other hand, a mixture of (R)-(-)-2-decanol stearate and unreacted isopropyl stearate, which is the residue after the simple distillation treatment, is mixed with 90 g of stearyl alcohol and lipase PL (supra).
After adding 3 g, the particle diameter of the enzyme was adjusted by sonication in the same manner as described above, a transesterification reaction was performed at 85 ° C. for 48 hours. The reaction product was subjected to simple distillation under the conditions of 90 ° C. and 3 mmHg to give high-purity (R)-(−)-2-decanol (yield 72%, substance purity 99.6%, optical purity 84%).
ee).

[0034]

According to the present invention, since the transesterification of 2-alkanol is carried out twice, each of the optically active alcohols of the R-form and the S-form can be easily separated with high purity with good yield. it can. That is, in the first step, either an unreacted R-form or S-form optically active alcohol in the racemic form is subjected to a transesterification reaction between a 2-alkanol and an ester by a simple means such as a simple distillation treatment. Thereby, both the substance purity and the optical purity can be increased and can be separated. Further, in the subsequent second step, either the R-form or the S-form optically active alcohol, which cannot be obtained in the first step, is obtained by a transesterification reaction between the residue of the above step and the non-optically active non-racemic alcohol. It can be released, and it can be separated by a simple means similar to the above-mentioned step, in which both the substance purity and the optical purity are increased. Further, if a thermostable lipase is used in the transesterification reaction, a solvent as a raw material becomes unnecessary, and the reaction time can be shortened.

Continuation of the front page (56) References JP-A-3-204837 (JP, A) JP-A-63-273499 (JP, A) CHEMISTRY EXPRESS S, VOL. 4, NO. 11 (1989) P. 721-724 (58) Fields investigated (Int. Cl. ⁶ , DB name) C12P 41/00 BIOSIS (DIALOG) CA (STN) REGISTRY (STN) WPI (DIALOG)

Claims (2)

(57) [Claims] 1. A method for resolving an optically active alcohol, comprising the following first step and second step. First step: 2-alkanol containing no phenyl group , a) lower monohydric alcohol diester of saturated dicarboxylic acid having 14 or more carbon atoms, b) triglyceride composed of saturated fatty acid having 16 or more carbon atoms, and c) carbon One ester selected from the group consisting of lower monohydric alcohol monoesters of a saturated fatty acid having a number of 18 or more is used as a raw material, and 90% of the particles are used.
Using a powdered lipase having a particle size of 1 to 100 μm as a catalyst, a transesterification reaction is carried out in the presence or absence of a solvent as the raw material under conditions substantially free of water, and the R-isomer is obtained from the reaction product. Or a step of separating unreacted optically active alcohol rich in one of the S-isomer. Second
Step: optically active unreacted alcohol obtained residue was separated in a first step, the addition of non-optically active non-racemic alcohol having a boiling point different from the 2-alkanol <br/>, before
The transesterification reaction is carried out in the presence or absence of the solvent of the raw material using the lipase as a catalyst and under conditions substantially free of water, and the R-isomer or the R-isomer not separated in the first step from the reaction product A step of separating an optically active alcohol rich in any one of the S-isomer. 2. The method according to claim 1, wherein the saturated dicarboxylic acid and the saturated fatty acid are linear.