JP2798895B2 - Production method of aliphatic 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 process for producing optically active alcohols which are important as synthetic intermediates in the field of fine chemicals such as liquid crystals, etc.

[0002]

2. Description of the Related Art Optically active alcohols are used as raw materials and synthetic intermediates for pharmaceuticals, agricultural chemicals, fine chemical products such as ferroelectric liquid crystals, etc. In recent years, various compounds have been developed with increasing demand. For example, many useful aliphatic optically active alcohols are 2-octanol, 2-methyl-1-butanol, 1,1,1-trifluoro-2-heptanol and the like. In addition, optically active alcohols are required to have not only high purity as a substance but also high optical purity in order to exhibit sufficient functions.

[0003] In order to increase the substance purity of the optically active alcohol, known means such as solvent extraction, fractionation, recrystallization, simple distillation, azeotropic distillation, molecular distillation and column chromatography are used. On the other hand, in order to increase the optical purity, it is effective to split the enantiomer (enantiomer) of the optically active alcohol from the racemic alcohol using enzymes (lipase, lipoprotein lipase, esterase, protease, etc.). is there. That is, it is difficult to separate an enantiomer from a racemic alcohol in a normal chemical reaction involving a high temperature, but it is possible to distinguish it in a reaction using the enzyme. For this reason, a method for producing an optically active alcohol utilizing such an enzymatic reaction has been intensively studied.

[0004] As a method for resolving an optically active alcohol from a racemic alcohol by using the above-mentioned enzyme, (i) hydrolysis of an ester of the racemic alcohol (Japanese Patent Laid-Open Publication No.
137996, JP-A-1-257484, etc.), (ii) transesterification of racemic alcohol with triglyceride (JP-A-62-166898, JP-B-6-34752), (iii) racemic Transesterification of an alcohol ester with an alcohol (JP-A-63-173597) has been proposed.

[0005] Among them, the method (i) is a reaction using a large amount of water. Therefore, a desired optical activity is obtained by using an ester of an aliphatic racemic alcohol having a high affinity for water such as a lower 2-alkanol as a raw material. In order to obtain alcohol with high purity (meaning that both substance purity and optical purity are high. The same applies hereinafter), a large amount of a solvent having selective solubility for the target substance is used for extraction, fractionation, etc. And / or a purification means such as azeotropic distillation, molecular distillation or preparative liquid chromatography, which requires complicated operations and high production cost, must be used. In addition, in this method, the enzyme is easily deactivated by being an aqueous reaction, for example, carboxylic acid is generated as a reaction by-product, and it is practically difficult to recover and reuse the reaction product by using a powdery enzyme. is there.

In the methods (ii) and (iii), the amount of water in the reaction system is very small, and a substance which causes the deactivation of the enzyme by the reaction is not produced as a by-product. There is no need to extract and separate the target substance from the object,
In addition, the enzyme can be recovered and reused. However, when lipase is used in such an enzymatic reaction, the conventional reaction temperature is usually about 20 to 70 ° C., substantially 20 to 50 ° C.
Since the temperature is ° C, the raw material must be limited to a liquid in this temperature range, or must be dissolved in an organic solvent and reacted. In addition, the reaction time required for the low-temperature reaction as described above requires a long period of several days or more.

[0007] When the ester exchange reaction (ii) and (iii) is carried out in a solvent-free system according to the conventional method, the raw materials (racemic alcohol, its ester, triglyceride, alcohol, etc.) which can be actually used are as described above. It is necessary that the melting point be equal to or lower than the enzyme reaction temperature. Therefore, it is necessary to employ materials whose physical properties such as the melting point, boiling point, and solubility in a solvent are close to each other. Also, when the reaction (iii) is carried out in an organic solvent system (for example, JP-A-63-173597), the alcohol as one of the raw materials has 1 to 10 carbon atoms, and the alcohol as one of the raw materials is racemic. Melting point is similar to ester of body alcohol. When a raw material having almost similar physical properties is used as described above, usually, the optically active alcohol is efficiently separated and recovered from the transesterification reaction product in which the raw material component and the reaction component have a complicated equilibrium composition, and the physical As a purification means for increasing the purity and the optical purity, it is difficult to utilize the difference in the physical properties of each component, and eventually (i.
Also in the methods (i) and (iii), there is a problem that, similarly to the method (i), a complicated and expensive purification method and means must be used.

[0008]

In view of such circumstances, the present invention provides a method for producing an optically active alcohol in which an enzymatic reaction can be carried out in a short time and the target substance can be separated and purified with high purity by a simple operation. The aim was to develop the method.

[0009]

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, specific
By using a diester obtained by esterifying a racemic alcohol with a specific dibasic acid and a specific alcohol as raw materials and subjecting this to a transesterification reaction under reduced pressure and high temperature using a thermostable lipase, the reaction can be performed in a short time. Completed,
In addition, the inventors have found that a high-purity optically active alcohol can be easily isolated from the reaction product in a high yield, and have completed the present invention.

That is, the gist of the present invention is to provide a) 2-alka
Diester and b) a non-optically active and non-racemic alcohol having 16 or more carbon atoms between Knoll and 14 or more straight chain saturated dibasic acid carbon as raw materials, using a heat-resistant lipase,
Without using the solvent of the raw material, under substantially water-free conditions, the optically active alcohol produced while performing a transesterification reaction under reduced pressure and at 81 ° C. or higher is separated by distillation under reduced pressure. This is a method for producing an optically active alcohol.

Hereinafter, the present invention will be described in detail. First, in the present invention, a) a 2-alkanol and a straight chain having 14 or more carbon atoms are used.
The starting materials are a diester with a linear saturated dibasic acid and b) a non-optically active and non-racemic alcohol having 16 or more carbon atoms. Chemical ester synthesis of diesters of 2-alkanol and the dibasic acids known a), such as sulfuric acid, hydrochloric acid, inorganic acids such as paratoluenesulfonic acid, zinc, tin,
Using a metal such as nickel, an oxide or a chloride of the metal as a catalyst, 2-alkanol and a dibasic acid at 100 to 250 ° C
The water produced as a by-product from the reaction system is removed while heating the mixture to effect esterification. If necessary, the esterification reaction product is deoxidized with an alkali (sodium hydroxide, sodium carbonate, etc.), and adsorbent (activated carbon, activated carbon) White clay, etc.) and deodorizing treatment under reduced pressure by inhaling water vapor or nitrogen gas.

Here, 2-alkanol means a racemic linear saturated halogen (chlorine, bromine, fluorine),
An aliphatic primary or secondary alcohol which may be substituted with an atom such as oxygen, nitrogen, phosphorus, and sulfur. Such 2
-As the alkanol , for example, 2-butanol, 2-
Pentanol, 2-hexanol, 2-heptanol,
2-octanol, 2-nonanol, 2-decanol,
1-chloro- wherein the carbon at the 1-position of each 2-alkanol from 2-butanol to 2-decanol is substituted with chlorine.
2-alkanols, 1,1-dichloro-2-alkanols and 1,1,1-trichloro-2-alkanols,
1-chloro-2-propanol, 1,1-dichloro-2
-Propanol, 1,1,1-trichloro-2-propanol, 1-carbon wherein the carbon at the 1-position of each 2-alkanol from 2-butanol to 2-decanol is substituted with bromine.
Bromo-2-alkanol, 1,1-dibromo-2-alkanol and 1,1,1-tribromo-2-alkanol, 1-bromo-2-propanol, 1,1-dibromo-2-propanol, 1,1, 1-tribromo-2
-Propanol, 1-fluoro-2-alkanol in which the 1-position carbon of each 2-alkanol from 2-butanol to 2-decanol is substituted with fluorine, 1,1-difluoro-2-alkanol and 1,1,1,1 -Trifluoro-2-alkanol, 1-fluoro-2-propanol, 1,1-difluoro-2-propanol, 1,
Secondary alcohols such as 1,1-trifluoro-2-propanol can be mentioned. In the present invention, among 2-alkanols, 2-octanol, 1,1-difluoro-
2-octanol, 1,1,1-trifluoro-2-octanol are more preferred.

On the other hand, as the dibasic acid, a linear saturated one can be used arbitrarily, and specifically, dodecamethylene dicarboxylic acid, tetradecamethylene dicarboxylic acid, hexadecamethylene dicarboxylic acid, heptadecamethylene dicarboxylic acid, Examples include octadecamethylene dicarboxylic acid, nonadecamethylene dicarboxylic acid, eicosamethylene dicarboxylic acid, docosamethylene dicarboxylic acid, tetracosamethylene dicarboxylic acid, hexacosamethylene dicarboxylic acid, and octacosamethylene dicarboxylic acid. These dibasic acids may be used alone or as a mixture. In addition to the above, wood wax, a long-chain dibasic acid separated from a sesame crude oil precipitate, or the like may be used.

[0014] In the present invention, since the transesterification reaction temperature as will be described later, the upper limit 130 ° C., and the 2
-It is important that the alkanol and the dibasic acid are combined such that the diester is liquid at the temperature. In addition, from the viewpoint of simplicity in the purification step of separating the desired optically active alcohol from the transesterification reaction product, the dibasic acid has 14 or more carbon atoms, preferably 16 to 30, more preferably 18 to 28, among the above. Most preferably, it is 20 to 28 linear saturated dibasic acids. In the case of dibasic acids or unsaturated dibasic acids having less than 14 carbon atoms, the strictness is required for purification conditions for isolating optically active alcohols with high purity and high yield. Dibasic acids having more than 45 carbon atoms are difficult to obtain as industrial raw materials. The dibasic acid diester used in the present invention has a high melting point (preferably 60 ° C. or higher, more preferably 70 ° C. or higher).
C. or higher).

Specific examples of b) a non-optically active and non-racemic alcohol having 16 or more carbon atoms, which is the other raw material of the present invention, include 1-hexadecanol (cetanol) and 1-hexadecanol.
Heptadecanol, 1-octadecanol (stearyl alcohol), oleyl alcohol, 1-eicosanol, 1-docosanol (behenyl alcohol), 1-tetracosanol, 1-hexacosanol, 1-octacosanol, 1-nonacosanol, myricyl Alcohol (30 carbon atoms), merisyl alcohol (31 carbon atoms),
Lasserol (C32).
Among these, a linear saturated alcohol having preferably 16 to 30, more preferably 18 to 28 carbon atoms is desirable. If the number of carbon atoms is less than 16, it is difficult to separate the desired optically active alcohol in the purification step, and the alcohol having more than 34 carbon atoms is difficult to obtain industrially.

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

The thermostable lipase of the present invention refers to a lipase having transesterification activity even at 81 ° C. or higher. For example, Alcaligenes sp. No. 3187), and lipase PL-679 produced by Alcaligenes sp. PL-679 described in Japanese Patent Publication No. 60-15312 (Microtechnical Laboratory No. 3783). And lipase derived from Rhizopus chinensis described in JP-B-59-156282, and the former two are preferred. In the practice of the present invention, it is convenient to use lipase QL and lipase PL (both trade names) manufactured by Meito Sangyo Co., Ltd. as the lipase derived from Alcaligenes sp, and lipase QL is particularly desirable. Such a thermostable lipase may be used by immobilizing it on a known carrier such as activated carbon, celite, an adsorbent resin, an ion exchange resin, glass beads, and ceramics. Is desirable.

In the transesterification reaction, the diester of the above-mentioned a) with the racemic alcohol and the alcohol of b) are a)
And mixed as a raw material in a molar ratio of 1: 5 or less, preferably 1: 5 to 3 based on the above, without using an organic solvent for dissolving the raw material and containing substantially no water ( That is, the equilibrium water content of the raw material is about 0.1.
Wt% or less, desirably 0.05 wt% or less) of the thermostable lipase powder in a reaction system,
The reaction is performed while stirring or shaking. At this time, 90% or more of the particles of the heat-resistant lipase powder are 1 to 100 μm,
It is desirable to carry out the transesterification reaction while controlling the size to preferably 20 to 50 μm. As a means for adjusting the particle size, if necessary, after dispersing the heat-resistant lipase powder in the heated and dissolved raw material, sonication, filtration of the dispersion with a precision membrane or ultrafiltration membrane, centrifugal sedimentation The treatment may be performed, but is preferably performed at a reaction temperature of 20 to 150 kHz, 100 to 250 W or lower.
It is convenient to irradiate with ultrasonic waves for 1 to 30 minutes under the above conditions.

The reaction temperature is 81 ° C. or higher, more preferably 9 ° C.
The reaction rate is set at 1-130 ° C., most preferably 101-120 ° C., and the reaction rate is checked by, for example, gas chromatography while gently stirring or shaking under reduced pressure, preferably 5-1 mmHg. The transesterification reaction is carried out for a predetermined period of time, preferably several hours to 100 hours, while distilling the optically active alcohol enriched in either the R-form or the S-form which is produced as the process proceeds under reduced pressure.
When the reaction temperature is lower than 81 ° C., the progress of the reaction is slowed and a long time is required. Conversely, when the temperature exceeds 130 ° C., even a thermostable lipase tends to be deactivated. In the present invention, it is particularly important that the transesterification is carried out under reduced pressure, and the transesterification is carried out while the optically active alcohol generated and released in the reaction product is distilled off under reduced pressure. According to this method, the transesterification proceeds rapidly.

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

Embedded image [However, (a): dibasic acid diester of 2 -alkanol , (b): non-optically active and non-racemic alcohol,
(C): a dibasic acid diester of an optically active alcohol,
(D): a dibasic acid diester of a non-optically active and non-racemic alcohol; and (e): an optically active alcohol. ]
As shown, the diester of the 2-alkanol as a raw material is so-called alcoholysis by a non-optically active and non-racemic alcohol, so that either the R- or S-form optically active alcohol is liberated to form and the non-optically active alcohol. An active and non-racemic alcohol dibasic acid diester is newly formed, and an unreacted R-form or S-form optically active dibasic acid diester also coexists. The composition is composed of various components including In addition, in the conventional method, since the physical properties of each component in such a reaction product are similar, a complicated purification step was required to recover the optically active alcohol.
The present invention is characterized in that a non-optically active and non-racemic alcohol having 16 or more carbon atoms is used as a raw material, and its physical properties (melting point, boiling point, solubility in a solvent, and the like) are significantly different from the racemic alcohol. In addition, the isolation of the optically active alcohol becomes easy.

That is, the desired optically active alcohol of either the R-form or the S-form can be sufficiently separated from the other components in the reaction system under reduced pressure and easily distilled off to be separated. Since the reaction equilibrium shifts to the right (product side) in the above reaction formula, the transesterification reaction is further promoted, and as a result, a highly pure optically active alcohol can be isolated in a high yield. In the method of the present invention, the unreacted enantiomer remaining as a monoester or a diester is separated from the reaction product by a known method such as column chromatography, and is separated from an acid (hydrochloric acid, sulfuric acid, etc.) or an alkali (sodium hydroxide). , Potassium hydroxide, etc.) can be similarly isolated with high purity. After the heat-resistant lipase used in the reaction is recovered, it can be used in a new similar transesterification reaction.

[0022]

The substance purity of the compounds obtained in the following Examples and Comparative Examples was measured by gas chromatography (GC-14A, manufactured by Shimadzu Corporation), and the optical purity was measured by a polarimeter (JASCO Corporation). And DIP-370), respectively, and calculated by comparing the measured value with the value of a standard sample.

Example 1 Lipase QL derived from Alcaligenes sp. (Manufactured by Meito Sangyo Co., Ltd.), 10 g, (R, S)
100 g of 1,20-eicosadicarboxylic acid (octadecamethylene dicarboxylic acid) diester of -1-chloro-2-octanol and 300 g of stearyl alcohol are put into a 500 ml separable flask, and an ultrasonic generator (Shimadzu Corporation) is used at 90 ° C. Ultrasonic waves were applied at 45 kHz for 1 minute using SUS-103 manufactured by Seisakusho. Then 105
Stirring at 350 ° C. under a reduced pressure of 5 mmHg at a stirring speed of 350 rpm,
The transesterification reaction was performed for 16 hours. The water content of the reaction system (Karl Fischer method): 0.03% by weight, the size of lipase particles (measured with a Coulter Electronics Co., Ltd. particle size distribution analyzer: Multisizer), and 95% or more was 30 to 60 μm. When the distillate distilled under reduced pressure while reacting was measured by gas chromatography, it was found that (R, S) -1-chloro-2-octanol contained 1,1.
49 mol% of 20-eicosadicarboxylic acid diester is transesterified, and (R) -1-chloro-2-octanol (yield: 85%, material purity: 99% or more, optical purity: 99% ee) I got On the other hand, after completion of the reaction, the lipase was removed from the reaction product by filtration using a membrane filter 0.5 μm (manufactured by Advantech), and the remaining 1,20-eicosadicarboxylic acid diester of 1-chloro-2-octanol was removed. Separation by silica gel column chromatography, alkali hydrolysis and (S)-
1-chloro-2-octanol (yield: 87%, substance purity: 99% or more, optical purity: 98% ee) was obtained.

Example 2 10 g of lipase QL described in Example 1, (R, S) -2
100 g of 1,14-tetradecadicarboxylic acid (dodecamethylenedicarboxylic acid) diester of nonanol and 300 g of oleyl alcohol were placed in a 500 ml separable flask, subjected to ultrasonic treatment in the same manner as in Example 1, and
The mixture was stirred at a stirring speed of 350 rpm under a reduced pressure of 2 mmHg at 95 ° C., and a transesterification reaction was performed for 12 hours. Water content of the reaction system measured by the method described in Example 1: 0.04% by weight,
Lipase particle size: 95% was 20-70 μm. When the distillate distilled under reduced pressure while reacting was measured by gas chromatography, 50 mol% of 1,14-tetradecadicarboxylic acid diester of (R, S) -2-nonanol was transesterified. ) -2-Nonanol (yield: 90%, substance purity: 99% or more, optical purity: 99% ee or more) was obtained. On the other hand, after completion of the reaction, lipase was removed from the reaction product in the same manner as in Example 1, and the remaining 1,14-tetradecadicarboxylic acid diester of 2-nonanol was separated by silica gel column chromatography, and alkali hydrolysis was performed. (S) -2-nonanol (yield: 91%, substance purity: 99% or more, optical purity: 9
9% ee or more).

Example 3 15 g of lipase QL described in Example 1, (R, S) -2
70 g of 1,28-octacosadicarboxylic acid (hexacosamethylenedicarboxylic acid) diester of octanol
Then, 330 g of behenyl alcohol was placed in a 500 ml separable flask, subjected to ultrasonic treatment in the same manner as in Example 1, and then stirred at 110 ° C. under a reduced pressure of 5 mmHg at a speed of 300 rp.
The mixture was stirred for 12 hours to carry out transesterification. The water content of the reaction system measured by the method described in Example 1 was 0.02% by weight, and the size of lipase particles: 95% was 20 to 50 μm.
Met. When the distillate distilled under reduced pressure while reacting was measured by gas chromatography, it was found that (R, S) -2-
50 mol% of 1,28-octacosadicarboxylic acid diester of octanol is transesterified, and (R)
-(-)-2-octanol (yield: 85%, substance purity: 99% or more, optical purity: 99% ee or more) was obtained. On the other hand, after completion of the reaction, lipase was removed from the reaction product in the same manner as in Example 1, and the remaining 2-octanol 1,28
-Octocosadicarboxylic acid diester is separated by silica gel column chromatography, and subjected to alkali hydrolysis to give (S)-(+)-2-octanol (yield: 85%, substance purity: 99% or more, optical purity: 99%) ee).

Comparative Example 1 In Example 2, when the same treatment was carried out using 300 g of lauryl alcohol instead of oleyl alcohol under the same conditions, 1,14-tetradecadicarboxylic acid diester of (R, S) -2-nonanol was obtained. 50 mol% had been transesterified. Distillation was carried out while reacting at 95 ° C. and 2 mmHg. The yield of (R) -2-nonanol was:
The purity was 92%, the substance purity was 84%, and the optical purity was 77% ee. On the other hand, 1,1-
The 4-tetradecadicarboxylic acid diester is similarly separated by silica gel column chromatography, and subjected to alkali hydrolysis to give (S) -2-nonanol (yield: 63%, substance purity: 88%, optical purity: 71% ee). I got

[0027]

According to the present invention, in separating an optically active alcohol from an ester of a 2-alkanol, a high melting point raw material can be used without using a raw material solvent by using a thermostable lipase. A high-temperature transesterification reaction that is not possible can be performed, and the reaction time can be shortened. Further, since a high-melting point, high-boiling long-chain alcohol can be used as a raw material, the optically active alcohol of either the R-form or the S-form is converted from the reaction product by utilizing the difference in physical properties in the transesterification reaction product. , High purity, good yield,
It can be separated by simple purification means. In the present invention, inter alia, the transesterification reaction and the separation and purification of the optically active alcohol can be performed simultaneously. Further, either the R-form or the S-form of the enantiomer of the optically active alcohol can be easily isolated with high purity.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C12P 41/00 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A) 2-alkanol and C14 or more
A diester with a linear saturated dibasic acid and b) a non-optically active and non-racemic alcohol having 16 or more carbon atoms as a raw material, using a heat-resistant lipase, substantially without using a solvent for the raw material. A method for producing an aliphatic optically active alcohol, comprising separating an optically active alcohol produced by performing a transesterification reaction under reduced pressure and at a temperature of 81 ° C. or more under a condition free of moisture by distillation under reduced pressure. 2. The production method according to claim 1, wherein the thermostable lipase is obtained from a microorganism belonging to the genus Alcaligenes. 3. A heat-resistant lipase in powder form, or claim 1 or 90% of the particles are 1~100μm
3. The production method according to any one of 2 . 4. A production method according to any one of claims 1-3 transesterification temperature using heat lipase is 101 to 120 ° C..