JPH08149991A - Production of optically active aliphatic alcohol - Google Patents

Abstract

PURPOSE: To efficiently obtain an optically active aliphatic alcohol which is useful as a starting compound for medicines and agrochemicals and an intermediate for liquid crystals by subjecting a racemic alcohol fatty acid monoester and a higher alcohol to transesterification reaction in the presence of a heat- resistant enzyme under specific conditions and distilling the product under reduced pressure. CONSTITUTION: (A) a monoester from an aliphatic racemic alcohol such as (R,S)-2-octanol and a fatty acid such as stearic acid and (B) not-optically active and not-racemic 16 or more C alcohol such as stearyl alcohol are subjected to anhydrous transesterification reaction in the presence of a heat-resistant lipase originating from a microorganism in Alcaligenes in no solvent over 81 deg.C under normal pressure, while the optically active alcohol formed is separated by distillation under reduced pressure to give this optically active aliphatic alcohol which is useful as an intermediate or starting substance for medicines and agrochemicals and as a synthetic intermediate in the speciality chemical field, for example, for liquid crystals.

Description

Detailed Description of the Invention

[0001]

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

[0002]

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

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

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

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

In the methods (ii) and (iii), the amount of water in the reaction system is very small, and a substance that causes the inactivation of the enzyme is not by-produced by the reaction. There is no need to extract and separate the target product from the product,
It is also possible to recover and reuse the enzyme. However, when a lipase is used in such an enzymatic reaction, the conventional reaction temperature is usually about 20 to 70 ° C, substantially 20 to 50 ° C.
Since the temperature is 0 ° C., the raw materials are limited to those that become liquid in this temperature range, or it is necessary to dissolve the raw materials in an organic solvent to cause a reaction. Moreover, the reaction time required a long period of several days or longer in the above-mentioned low temperature reaction.

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

[0008]

In view of the above situation, in the present invention, in the method for producing an optically active alcohol, the enzymatic reaction can be carried out in a short time and the desired product can be separated and purified with high purity by a simple operation. The aim was to develop said method.

[0009]

[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, by using a monoester obtained by esterifying a specific racemic alcohol with a fatty acid and a specific alcohol as a raw material, and subjecting this to a transesterification reaction under reduced pressure and high temperature using a heat-resistant lipase, the reaction can be performed for a short time. The present invention was completed by finding that the optically active alcohol of high purity can be easily isolated from the reaction product in high yield.

That is, the gist of the present invention is to use a) a monoester of an aliphatic racemic alcohol and a fatty acid and b) a non-optically active non-racemic alcohol having 16 or more carbon atoms as a raw material and using a heat-resistant lipase, It is characterized in that the optically active alcohol produced by the transesterification reaction under reduced pressure and at 81 ° C. or higher is distilled under reduced pressure under the condition of substantially free of water without using a solvent as a raw material. It is a method for producing an optically active alcohol.

The present invention will be described in detail below. First, in the present invention, a) a monoester of an aliphatic racemic alcohol and a fatty acid and b) a non-optically active non-racemic alcohol having 16 or more carbon atoms are used as raw materials. The monoester of a) is a known chemical ester synthesis method using an aliphatic racemic alcohol and a fatty acid, for example, inorganic acids such as sulfuric acid, hydrochloric acid and paratoluenesulfonic acid, metals such as zinc, tin and nickel,
Using the metal oxides, chlorides, etc. as catalysts, the aliphatic racemic alcohol and the fatty acid are heated to 100 to 250 ° C. to remove the by-produced water from the reaction system for esterification,
If necessary, the esterification reaction product may be deoxidized with an alkali (sodium hydroxide, sodium carbonate, etc.), decolorized with an adsorbent (activated carbon, activated clay, etc.), and deodorized with suction of steam or nitrogen gas under reduced pressure. You can get it.

The term "aliphatic racemic alcohol" as used herein refers to a racemic straight-chain or side-chain, saturated or unsaturated halogen (chlorine, bromine, fluorine), oxygen, nitrogen, phosphorus, sulfur atom or the like. It means an aliphatic primary or secondary alcohol which may be substituted. Examples of such an aliphatic racemic alcohol include 2-butanol, 2-pentanol, 2-hexanol, 2-heptanol, 2-octanol, 2-nonanol, 2-decanol, 1-pentyn-3-ol, and the above 2- 1-Chloro-2-alkanol, 1,1-dichloro-2-alkanol and 1,1,1-trichloro-2-alkanol in which the 1-position carbon of each 2-alkanol from butanol to 2-decanol is substituted with chlorine , 1-chloro-2-propanol,
1,1-dichloro-2-propanol, 1,1,1-trichloro-2-propanol, 1-bromo- in which the 1-position carbon of each 2-alkanol from 2-butanol to 2-decanol is substituted with bromine. 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-trifluoro-2-alkanol, 1-
Fluoro-2-propanol, 1,1-difluoro-2
-Propanol, secondary alcohol such as 1,1,1-trifluoro-2-propanol, 2,3-dichloro-1-
Propanol, 2,3-dibromo-1-propanol,
2,3-difluoro-1-propanol, 3,4-dichloro-1-butanol, 3,4-dibromo-1-butanol, 3,4-difluoro-1-butanol, 4,5-
Dichloro-1-pentanol, 4,5-dibromo-1-
Pentanol, 4,5-difluoro-1-pentanol, 5,6-dichloro-1-hexanol, 5,6-dibromo-1-hexanol, 5,6-difluoro-1-
Hexanol, 6,7-dichloro-1-heptanol,
6,7-dibromo-1-heptanol, 6,7-difluoro-1-heptanol, 7,8-dichloro-1-octanol, 7,8-dibromo-1-octanol, 7,
8-difluoro-1-octanol, 8,9-dichloro-1-nonanol, 8,9-dibromo-1-nonanol, 8,9-difluoro-1-nonanol, 9,10-
Dichloro-1-decanol, 9,10-dibromo-1-
Primary alcohols such as decanol and 9,10-difluoro-1-decanol can be mentioned. In the present invention, 2
-Alkanol is preferable, and among 2-alkanols, 2-octanol, 1,1-difluoro-2-octanol, and 1,1,1-trifluoro-2-octanol are more preferable.

On the other hand, as the fatty acid, a linear and saturated or unsaturated fatty acid can be arbitrarily used. Specifically, specific examples thereof include n-nonanoic acid, capric acid, lauric acid, n-tridecanoic acid, myristic acid, and n-pentadecane. Acid, palmitic acid, n-
Heptadecanoic acid, palmitooleic acid, stearic acid,
Oleic acid, elaidic acid, linoleic acid, arachidic acid (20: 0), behenic acid (22: 0), erucic acid (2
2: 1), lignoceric acid (24: 0), cerotic acid (26: 0), montanic acid (28: 0), melissic acid (30: 0), laccelonic acid (32: 0), geta acid (34 :). 0) etc. can be illustrated. The number in parentheses indicates the total carbon number of each fatty acid: the number of carbon-carbon double bonds.
These fatty acids may be used alone or as a mixture, and in addition to the above, vegetable oils, animal oils, fish oils, hydrolyzed fatty acids of these hydrogenated products or hydrogenated products of hydrolyzed fatty acids of the aforementioned oils and fats, montan Wax, carnauba wax, rice wax, candelilla wax, sunflower wax, beeswax, whale wax, shellac wax, insect white wax, sugarcane wax, poppy wax, cotton wax, etc. Fatty acids and the like may be used.

In the present invention, the transesterification temperature is 130 ° C as an upper limit as will be described later. Therefore, the above-mentioned aliphatic racemic alcohol and fatty acid are combined so that the monoester thereof becomes liquid at that temperature. This is very important. From the viewpoint of simplicity in the purification step of separating the target optically active alcohol from the transesterification reaction product, the fatty acid has 16 or more carbon atoms among the above-mentioned ones,
It is preferably 18 to 30, more preferably 20 to 28, and most preferably 22 to 28 linear saturated fatty acid. In the case of a fatty acid having less than 16 carbon atoms, a side chain fatty acid, or the like, strictness is required in the purification conditions for isolating the optically active alcohol with high purity and high yield. Fatty acids having more than 34 carbon atoms are difficult to obtain as industrial raw materials. The fatty acid monoester used in the present invention preferably has a high melting point (preferably 60 ° C or higher, more preferably 70 ° C or higher).

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

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

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

In the transesterification reaction, the racemic alcohol monoester of a) and the alcohol of b) are a).
On the basis of 1: 5 or less, preferably 1: 5 to 3 or less in a molar ratio as a raw material, without using an organic solvent for dissolving the raw material, and substantially free of water (That is, the equilibrium water content in the raw material is about 0.1% by weight or less, preferably 0.05% by weight or less)
The heat-resistant lipase powder is preferably dispersed in the reaction system, and the reaction is carried out while stirring or shaking. At this time, 90% or more of the particles of the heat-resistant lipase powder are 1-100.
It is desirable to conduct the transesterification reaction while controlling the size to be μm, preferably 20 to 50 μm. This particle size can be adjusted by dispersing the heat-resistant lipase powder in the raw material that has been heated and dissolved, if necessary, and then sonicated, filtered with a precision membrane or ultrafiltration membrane of the dispersion, and subjected to centrifugal sedimentation. It may be subjected to a treatment or the like, but preferably below the reaction temperature, 20 to 150 kHz, 100 to 25
Irradiation with ultrasonic waves for 1 to 30 minutes under the condition of 0 W is convenient.

The reaction temperature is 81 ° C or higher, more preferably 9 ° C.
The reaction rate is set to 1 to 130 ° C, most preferably 101 to 120 ° C, and the reaction rate is checked by, for example, gas chromatography while gently stirring or shaking under a reduced pressure condition, preferably a reduced pressure of 5 to 1 mmHg. The transesterification reaction is carried out for a predetermined time, preferably several hours to 100 hours while distilling the optically active alcohol enriched in either the R-form or the S-form that is produced along with the progress under reduced pressure.
If the reaction temperature is lower than 81 ° C., the reaction proceeds slowly and requires a long time. On the contrary, if the reaction temperature exceeds 130 ° C., even thermostable lipase tends to be inactivated. In the present invention, it is particularly important to carry out the transesterification reaction under reduced pressure, while distilling off the optically active alcohol produced and liberated in the reaction product under reduced pressure. This method allows the transesterification reaction to proceed rapidly.

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

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

That is, the optically active alcohol of either the R-form or the S-form of interest can be easily distilled off and separated under the above-mentioned reduced pressure sufficiently distinguishing from other components in the reaction system. Since the reaction equilibrium shifts to the right side (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 which remains as a monoester is separated from the reaction product by a known method such as column chromatography, and the acid (hydrochloric acid, sulfuric acid, etc.) or alkali (sodium hydroxide, water) is used. Similarly, it can be isolated with high purity by hydrolysis with potassium oxide or the like. Further, the thermostable lipase used in the reaction can be used in a new similar transesterification reaction after recovery.

[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 polarimeter (JASCO ( Co., Ltd., DIP-370), and the calculated values were calculated by comparing the measured values with those of standard samples.

Example 1 10 g of lipase QL (manufactured by Meito Sangyo Co., Ltd.) derived from Alcaligenes sp., (R, S)
2-Octanol stearic acid monoester 150
45 g of stearyl alcohol and 300 g of stearyl alcohol were placed in a 500 ml separable flask at 45 ° C. using an ultrasonic wave generator (SUS-103, manufactured by Shimadzu Corporation).
Ultrasonic waves were applied for 1 minute at kHz. Then, at 95 ℃ 3
Stirring was carried out at a stirring speed of 350 rpm under reduced pressure of mmHg, and transesterification reaction was carried out for 15 hours. Water content of reaction system (Karl Fischer method): 0.04% by weight, size of lipase particles (particle size distribution measuring device manufactured by Coulter Electronics Co .: measured by Multisizer): 95% or more is 30 to
It was 70 μm. The distillate distilled under reduced pressure while reacting was measured by gas chromatography to find that (R,
49 mol% of the stearic acid monoester of (S) -2-octanol is transesterified, and (R)-(−)
-2-octanol (yield: 90%, material purity: 99%
Above, optical purity: 98% ee. ) Got. On the other hand, after completion of the reaction, remove the lipase from the reaction product with a membrane filter 0.5.
After removal by filtration using μm (manufactured by Advantech), the remaining stearic acid monoester of 2-octanol is separated by silica gel column chromatography and alkali-hydrolyzed to give (S)-(+)-2-octanol. (Yield: 90%, substance purity: 99% or more, optical purity: 99% ee).

Example 2 10 g of lipase PL (manufactured by Meito Sangyo Co., Ltd.) derived from Alcaligenes sp., (R, S)
-2-decanol palmitate monoester 130g
And 320 g of n-hexadecanol were placed in a 500 ml separable flask, subjected to ultrasonic treatment in the same manner as in Example 1, and then stirred at 85 ° C. under a reduced pressure of 1 mmHg and a stirring speed of 350 rp.
The mixture was stirred at m and a transesterification reaction was carried out for 24 hours. Water content of reaction system measured by the method described in Example 1: 0.03
% By weight, size of lipase particles: 90% is 20-50 μ
It was m. When the distillate obtained by distillation under reduced pressure while reacting was measured by gas chromatography, (R, S) -2
50 mol% of palmitic acid monoester of decanol
Are transesterified with (R) -2-decanol (yield: 90%, material purity: 99% or more, optical purity: 9
9% ee) was obtained. On the other hand, after completion of the reaction, the lipase was removed from the reaction product in the same manner as in Example 1, and the remaining palmitic acid monoester of 2-decanol was separated by silica gel column chromatography and subjected to alkaline hydrolysis to (S) -2. -Decanol (yield: 90%, material purity: 9
9% or more, optical purity: 98% ee) was obtained.

Example 3 Lipase QL5g, (R, S) -1-as described in Example 1
Chloro-2-octanol montanic acid monoester 1
00 g and behenyl alcohol 300 g were 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 stirring speed of 2
The mixture was stirred at 50 rpm and transesterification was performed for 34 hours. Water content of the reaction system measured by the method described in Example 1:
0.01% by weight, particle size of lipase: 93% is 2
It was 0 to 60 μm. When the distillate distilled under reduced pressure while reacting was measured by gas chromatography,
50 mol% of montanic acid monoester of (R, S) -1-chloro-2-octanol is transesterified, and (R) -1-chloro-2-octanol (yield: 8
1%, substance purity: 99% or more, optical purity: 99% ee) were obtained. On the other hand, after completion of the reaction, the lipase was removed from the reaction product in the same manner as in Example 1, and the remaining montanic acid monoester of 1-chloro-2-octanol was separated by silica gel column chromatography and subjected to alkali hydrolysis ( S) -1-chloro-2-octanol (yield: 84
%, Material purity: 99% or more, optical purity: 99% ee).

Comparative Example 1 In Example 2, when 300 g of myristyl alcohol was used in place of n-hexadecanol and treated under the same conditions, 48 mol of palmitic acid monoester of (R, S) -2-decanol was obtained. % Was transesterified. Distillation was carried out while reacting at 85 ° C. and 1 mmHg, and the yield of (R) -2-decanol was 95%, the material purity was 89%, and the optical purity was 76% ee. On the other hand, the palmitic acid monoester of 2-decanol remaining in the reaction product was similarly separated by silica gel column chromatography and alkali-hydrolyzed to give (S) -2-decanol (yield: 60%, material purity: 93 %, Optical purity: 98%
ee).

[0027]

According to the present invention, when optically active alcohol is resolved from the racemic alcohol ester,
By using a thermostable lipase, a high melting point raw material can be used without using a raw material solvent, a transesterification reaction at a high temperature which has never been possible can be performed, and the reaction time can be shortened. Furthermore, since a long-chain alcohol having a high melting point and a high boiling point can be used as a raw material, an optically active alcohol of either the R isomer or the S isomer can be obtained from the reaction product by utilizing the difference in the physical properties in the transesterification reaction product. It can be separated with high purity, high yield, and simple purification means. In the present invention, the transesterification reaction and the separation and purification of the optically active alcohol can be carried out simultaneously. Further, the optically active alcohol in either the R form or the S form which is an antipode to the optically active alcohol can be easily isolated with high purity.

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Claims (6)

[Claims] 1. A) a) a monoester of an aliphatic racemic alcohol and a fatty acid and b) a non-optically active non-racemic alcohol having 16 or more carbon atoms as a raw material, a heat resistant lipase, and a solvent of the raw material. Of the aliphatic optically active alcohol, wherein the optically active alcohol produced by the transesterification reaction under reduced pressure and at 81 ° C. or higher is distilled under reduced pressure under conditions substantially free of water without separation. Production method. 2. The method according to claim 1, wherein the aliphatic racemic alcohol is a 2-alkanol. 3. The method according to claim 1, wherein the fatty acid is a linear saturated fatty acid having 16 or more carbon atoms. 4. The method according to claim 1, wherein the thermostable lipase is obtained from a microorganism belonging to the genus Alcaligenes. 5. The method according to claim 1, wherein the thermostable lipase is in powder form, and 90% or more of the particles have a size of 1 to 100 μm. 6. The method according to claim 1, wherein the temperature of the transesterification reaction using thermostable lipase is 101 to 120 ° C.