JP2005095155A - Method for producing alcohols and esters - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for easily and efficiently producing alcohols and esters in which a ratio of a specified stereoisomer (geometric isomer) is increased, by using an enzyme derived from a microorganism, without using enzymes derived from animals difficult to be massively supplied, nor enzymes derived from plants having problems in handling. <P>SOLUTION: This method for obtaining the alcohol having a high steric purity of the specified geometric isomer comprises subjecting a geometrically isomeric alcohol mixture to half esterification with an acid anhydride in the presence of a hydrolase, or subjecting the mixture to transesterification reaction with a carboxylic acid ester used as a substitute for the acid anhydride, so as to obtain a half ester or an ester in which the ratio of the specified geometric isomer is increased, and then subjecting the half ester or the ester thus obtained to a hydrolyzing operation, etc., according to ordinary procedures. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing alcohols and esters. More specifically, the present invention relates to a method for producing alcohols and esters having an improved specific stereoisomerism (geometric isomerism) ratio using an enzyme.

  Reactions using enzymes and microorganisms are known to perform unique reactions that are different from chemical methods due to their unique selectivity, etc., and it is known that optical resolution of racemates and isomerization into one of geometric isomer mixtures. It has been reported that the conversion can proceed under a mild condition and with high selectivity. For example, in Non-Patent Document 1, a ratio of specific geometric isomers was improved by performing a transesterification reaction with a mixture of primary allylic geometric isomers and butyric acid trifluoroethyl ester using porcine pancreatic lipase. A process for the production of allyl alcohol butyrate is described. In addition, many examples are known in which similar reactions are performed using plant-derived enzymes as enzymes other than animals. However, animal-derived enzymes such as pigs are difficult to supply in large quantities, and plant-derived enzymes require special knowledge for handling, and therefore there are many problems in implementation on a large scale such as industrial level.

Tetrahedron: Asymmetry Vol. 4, No. 5,907-910, 1993

  The present invention has been made in view of the current situation as described above, and does not use an animal-derived enzyme that is difficult to supply in large quantities or a plant-derived enzyme that has a problem in handling. It is an object of the present invention to provide a method for easily and efficiently producing alcohols and esters having an improved (geometric isomerism) ratio.

  In order to achieve the above object, the present inventors conducted a transesterification reaction between a stereoisomeric (geometric isomer) alcohol mixture and an acylating agent such as a carboxylic acid anhydride or a carboxylic acid ester using a microorganism-derived enzyme. The present inventors have found that a carboxylic acid ester having an improved specific stereoisomeric (geometric isomerism) ratio can be efficiently produced, and that the resulting ester is hydrolyzed according to a conventional method to obtain a specific stereoisomeric (geometric isomerism) ratio. It has been found that improved alcohols are produced, and furthermore, a specific stereoisomeric (geometric isomerism) ratio can be obtained by allowing a microbial-derived hydrolase to act on the carboxylic acid ester of the stereoisomeric (geometric isomer) alcohol mixture. The inventors have also found that improved alcohols are efficiently produced, and have completed the present invention.

That is, the present invention provides the following general formula [1]
ROH [1]
(In the formula, R represents an alkenyl group which may have a substituent.)
An isomer mixture of alcohols represented by
(1) General formula [2] in the presence of hydrolase

(In the formula, A ¹ represents a divalent hydrocarbon group which may have a substituent.)
Is reacted with an acid anhydride represented by the following general formula [3]

(In the formula, R ′ represents an alkenyl group optionally having a substituent, represented by R, rich in one geometric isomer, and A ¹ is the same as above.)
Or esters represented by
(2) General formula [4] in the presence of hydrolase

(In the formula, R ¹ represents a hydrogen atom, an alkyl group, a halogenated alkyl group, or an aryl group, R ² represents a hydrocarbon group, and A ² represents a divalent group or a bond.)
Is reacted with a carboxylic acid ester represented by the following general formula [5]

(In the formula, R ′, R ¹ and A ² are the same as above.)
The ester represented by the following general formula [6] is characterized by hydrolyzing the ester rich in one of these geometric isomers.
R'OH [6]
(In the formula, R ′ is the same as described above.)
It is related with the manufacturing method of alcohol with high steric purity of a geometric isomer shown by these.

The present invention also provides a general formula [1].
ROH [1]
(In the formula, R represents an alkenyl group which may have a substituent.)
In the presence of hydrolase, an alcohol isomer mixture represented by general formula [2]

(In the formula, A ¹ represents a divalent hydrocarbon group which may have a substituent.)
It is made to react with the acid anhydride shown by General formula [3]

(In the formula, R ′ represents an alkenyl group optionally having a substituent, represented by R, rich in one geometric isomer, and A ¹ is the same as above.)
It is related with the manufacturing method of ester with high stereo purity of the geometric isomer shown by these.

Furthermore, the present invention provides a compound of the general formula [1]
ROH [1]
(In the formula, R represents an alkenyl group which may have a substituent.)
In the presence of hydrolase, an alcohol isomer mixture represented by the general formula [4]

(In the formula, R ¹ represents a hydrogen atom, an alkyl group, a halogenated alkyl group, or an aryl group, R ² represents a hydrocarbon group, and A ² represents a divalent group or a bond.)
The following general formula [5], characterized by reacting with a carboxylic acid ester represented by

（式中、Ｒ’、Ｒ^１及びＡ^２は前記と同じ。）
で示される幾何異性体の立体純度の高いエステル類の製造法に関する。

(In the formula, R ′, R ¹ and A ² are the same as above.)
It is related with the manufacturing method of ester with high stereo purity of the geometric isomer shown by these.

  Furthermore, the present invention provides the following general formula [9]

(In the formula, R ¹ represents a hydrogen atom, an alkyl group, a halogenated alkyl group or an aryl group, A ² represents a divalent group or a bond, and R ³ and R ⁴ each independently represent a chain-like saturated group. Alternatively, it represents an unsaturated hydrocarbon group, and the wavy line represents a mixture of a cis isomer and a trans isomer.)
The ester represented by the following general formula [10], wherein the ester is hydrolyzed in the presence of a hydrolase:

(In the formula, R ³ and R ⁴ are the same as above. One of the cis and trans isomers is 80% or more in the configuration of the double bond.)
It is related with the manufacturing method of alcohol with high steric purity of the geometric isomer represented by these.

  According to the present invention, alcohols and esters having high steric purity of geometric isomers that are useful as fragrances, pharmaceuticals, agricultural chemicals, or intermediates thereof can be easily and extremely efficiently produced.

  One of the production methods of the present invention is a method in which a geometrical alcohol mixture represented by the above general formula [1] and an acid anhydride represented by the above general formula [2] are half-esterified in the presence of a hydrolase to produce In the above general formula [3], the ratio of the specific geometric isomer is increased by separating the half ester of the product from the unreacted alcohol and acid anhydride, preferably by an industrially advantageous method. Further, by subjecting the obtained half ester to an operation such as hydrolysis according to a conventional method, an alcohol represented by the above general formula [6] having a high steric purity of a specific geometric isomer is obtained. It is what you say.

  In addition, another one of the production methods of the present invention is the transesterification reaction using the carboxylic acid ester represented by the general formula [4] instead of the acid anhydride represented by the general formula [2]. To obtain an ester represented by the above general formula [5] in which the ratio of a specific geometric isomer is increased, and further subjecting the obtained ester to an operation such as hydrolysis according to a conventional method. This is to obtain an alcohol represented by the general formula [6] having high steric purity of the isomer.

  In the geometrically isomeric alcohol mixture represented by the general formula [1], the alkenyl group which may have a substituent represented by R is preferably a linear or branched group which may have a substituent. And monoalkenyl groups, alkanepolyenyl groups, and the like. The alkanepolyenyl group here is an aliphatic hydrocarbon group having two or more double bonds.

  An alkenyl group and an alkanepolyenyl group (hereinafter, these two groups may be collectively referred to as an unsaturated aliphatic group) include an unsaturated aliphatic group having at least one double bond capable of taking a cis or trans configuration. Group, preferably a branched or monocyclic or bicyclic unsaturated aliphatic group having 5 to 20 carbon atoms. Specific examples of the group include 2-butenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 2,4-hexadienyl group, 2,6-octadienyl group, 6-nonel group, 2, Examples include 6-nonadienyl group and 2,6,10-dodecatrienyl group.

  Examples of the substituent that can be substituted with the unsaturated aliphatic group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. A linear or branched alkyl group having 1 to 4 carbon atoms; for example, a cyclic alkyl group having 5 to 8 carbon atoms such as cyclopentyl group, cyclopentenyl group, trimethylcyclopentenyl group, cyclohexyl group, cyclohexenyl group, and cyclooctyl group Group or cyclic alkenyl group; for example, alkoxy group having 1 to 4 carbon atoms such as methoxy group, ethoxy group, isopropoxy group, tert-butoxy group; for example, aromatic hydrocarbon group such as phenyl group, naphthyl group; Aralkyl groups such as benzyl group and phenethyl group; for example, heterocyclic groups such as pyridyl group and tetrahydrofuryl group It is below.

  As a more preferable example of the alkenyl group which may have a substituent represented by R, for example, the following general formula [7]

(In the formula, R ³ and R ⁴ each independently represent a chain-like saturated or unsaturated hydrocarbon group, and the wavy line represents a mixture of a cis isomer and a trans isomer.)
The group shown by these is mentioned.

Here, examples of the chain saturated or unsaturated hydrocarbon group represented by R ³ and R ⁴ include an alkyl group, an alkenyl group, and an alkynyl group.
Examples of the alkyl group include those similar to the alkyl group represented by R ¹ above.
Examples of the alkenyl group include linear or branched alkenyl groups having 2 to 10 carbon atoms, and specific examples include a vinyl group, an allyl group, and a 2-butenyl group.
Moreover, as an alkynyl group, a C2-C6 alkynyl group is mentioned, for example, Specifically, an ethynyl group, 2-propynyl group, etc. are mentioned, for example.

  Among these groups represented by the general formula [7], particularly preferred are, for example, 3,7-dimethyl-2,6-octadien-1-yl group, 3,7,11-trimethyl-2,6,10. -Dodecatrien-1-yl group etc. are mentioned.

In the acid anhydride represented by the general formula [2] used in this method, the divalent hydrocarbon group optionally having a substituent represented by A ¹ is, for example, substituted with an alkyl group. A good alkylene group, the same alkenylene group, the same phenylene group and the like. Specific examples of the alkylene group include, for example, a methylene group, ethylene group, trimethylene group, tetramethylene group, and propylene group. Specific examples of the alkenylene group include, for example, vinylene group, propenylene group, 1,3- Examples thereof include a butadiene-1,4-diyl group. Among these, an ethylene group and a trimethylene group are particularly preferable.

In the carboxylic acid ester represented by the general formula [4], the alkyl group represented by R ¹ may be linear, branched or cyclic, for example, an alkyl group having 1 to 10 carbon atoms, specifically Are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, tert-pentyl, cyclopentyl and cyclohexyl. Groups and the like.
Examples of the halogenated alkyl group include C1-C10 halogenated alkyl groups in which at least one hydrogen atom of the alkyl group is substituted with a halogen atom (chlorine, bromine, fluorine, etc.), specifically Examples include chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, perfluoroisopropyl group and the like.
Moreover, as an aryl group, a C6-C14 aryl group is mentioned, for example, A phenyl group, a tolyl group, a xylyl group, a naphthyl group, a methyl naphthyl group, an anthryl group, a biphenyl group etc. are mentioned specifically ,.

In the carboxylic acid ester represented by the general formula [4], examples of the hydrocarbon group represented by R ² include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and an aralkyl group.
Here, examples of the alkyl group and aryl group include the same groups as the alkyl group and aryl group represented by R ¹ .
Examples of the alkenyl group may be linear or branched, for example, an alkenyl group having 2 to 10 carbon atoms. Specific examples include a vinyl group, an allyl group, a 2-butenyl group, and an isopropenyl group. Can be mentioned.
Examples of the alkynyl group include alkynyl groups having 2 to 6 carbon atoms, and specific examples include an ethynyl group and a 2-propynyl group.
Examples of the aralkyl group include groups in which at least one hydrogen atom of the alkyl group is substituted with the aryl group. For example, an aralkyl group having 7 to 12 carbon atoms is preferable, and specifically, for example, a benzyl group, A phenethyl group etc. are mentioned.

As the divalent group represented by ^{A 2,} for ^{_{example, - [(CH 2) m}} -A 3 - (CH 2) n] q - group ^{(A 3} is an oxygen atom, - (C = O) -Group or-(C = O) -NH- group, m, n and q represent an integer of 1-6), an alkylene group, a (hetero) arylene group, and the like. The alkylene group may be linear, branched or cyclic, for example, an alkylene group having 1 to 6 carbon atoms. Specific examples include methylene group, ethylene group, trimethylene group, propylene group, tetramethylene. Group and cyclohexylene group.
Examples of the (hetero) arylene group include a (hetero) arylene group having 6 to 12 carbon atoms, and specifically include a phenylene group, a biphenyldiyl group, a binaphthalenediyl group, a bis (methylene) phenylene group, and a pyridinediyl group. Etc.

  The half-ester having high stereo purity of the geometric isomer represented by the general formula [3], the ester having high stereo purity of the geometric isomer represented by the general formula [5], and the geometric isomer represented by general formula [6] In an alcohol with high steric purity, the alkenyl group optionally having a substituent represented by R and rich in one geometric isomer represented by R ′ is usually one of cis and trans isomers. Is an alkenyl group which may be substituted, represented by R, wherein is 80% or more. Preferred examples of such R ′ include, for example, the following general formula [8]

(In the formula, R ³ and R ⁴ are the same as above. One of the cis and trans isomers is 80% or more in the configuration of the double bond.)
The group shown by these is mentioned.

  Among these groups represented by the general formula [8], particularly preferable examples include (2E, 6E) -3,7,11-trimethyl-2,6,10-dodecatrien-1-yl group. It is done.

Examples of the hydrolase used in the half esterification step and the esterification step include lipase and acylase as preferable enzymes.
These enzymes are usually commercially available.
Specific examples of suitable enzymes for use in the method of the present invention, Aspergillus niger, Mucor javanicus, Pseudomonas aeruginosa, Pseudomonas cepasia, Pseudomonas fluorescence, Rhizopus delemar, Rhizopus niveus, Rhizomucor miehei, Candida antarctica, Candida rugosa, Geotrichum candidum Lipase and acylase originating from Penicillium cyclopium, Penicillium roqueforti, and the like.

Examples of particularly preferred hydrolases for use in the method of the present invention include lipases derived from bacteria such as Pseudomonas spp., Alcaligenes spp., And lipases originating from Candida antarctica.
The hydrolase used in the present invention may be in a free state or a state supported on an insoluble carrier.
The hydrolase used in the present invention must be capable of discriminating one of the geometric isomers in order to largely esterify only one geometric isomer.

In the half esterification step according to the present invention, the reaction is usually performed in an inert organic solvent.
Specific examples of the solvent used in the half esterification step include aliphatic hydrocarbons such as pentane, hexane, heptane, octane and cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, for example, Halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, o-dichlorobenzene, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, ethylene glycol diethyl ether, tetrahydrofuran, Ethers such as 1,4-dioxane, for example, ketones such as acetone and methyl ethyl ketone, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, such as di Sulfoxides such as sulfoxide, for example, acetonitrile, although nitriles such as propionitrile and the like, but is not limited thereto. These solvents may be used alone or in combination of two or more.
Among these solvents, more preferable solvents include tetrahydrofuran, acetone, and the like.
Although the usage-amount of an organic solvent is arbitrary and is not specifically limited, Usually 0.5-10 times capacity is used with respect to alcohol of general formula [1].

The amount of the acid anhydride used in the half esterification step is preferably equivalent (theoretical amount) to more than the amount of the alcohol of the general formula [1]. More preferably, it is 0.5 to 10 times, more preferably 0.5 to 2 times the theoretical amount.
The amount of hydrolase used is 0.1 to 100% by weight, preferably 0.5 to 50% by weight of the geometrically isomeric alcohol mixture.
The reaction temperature must be compatible with the activity of the enzyme. Preferably it is 80 degrees C or less, More preferably, it is 0 to 50 degreeC.
The reaction is preferably carried out at atmospheric pressure, but lower or higher pressures are not a problem and can also be carried out in an inert gas.
The reaction time is determined according to the conversion rate of the alcohol to be esterified. Needless to say, if the selectivity of the enzyme is not high, a technique known to those skilled in the art to limit the conversion rate, such as stopping the reaction at a stage where the conversion rate is low, should be used.
At the end of the reaction, most of one of the geometric isomers exists as a half ester and the other geometric isomer remains as an unreacted alcohol.

The esterification step according to the present invention is also usually performed in an inert organic solvent.
Specific examples of the solvent used in the esterification step include aliphatic hydrocarbons such as pentane, hexane, heptane, octane and cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, for example dichloromethane. 1,2-dichloroethane, chloroform, carbon tetrachloride, o-dichlorobenzene and the like, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, ethylene glycol diethyl ether, tetrahydrofuran, 1 Ethers such as 1,4-dioxane, for example, alcohols such as methanol, ethanol, 2-propanol, n-butanol, 2-ethoxyethanol, benzyl alcohol, such as ethylene glycol, propylene group Polyhydric alcohols such as chol, 1,2-propanediol and glycerin, for example, ketones such as acetone and methyl ethyl ketone, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone Examples thereof include, but are not limited to, sulfoxides such as dimethyl sulfoxide, and cyano-containing organic compounds such as acetonitrile and propionitrile. Moreover, the carboxylic acid ester etc. which are represented by the said General formula [4] can also be used as a solvent. These solvents may be used alone or in combination of two or more.
Among these solvents, more preferable solvents include hexane, heptane, toluene, tetrahydrofuran, dichloromethane and the like.
The amount of the organic solvent used is arbitrary and is not particularly limited, but is usually 0 to 100 times, preferably 0.5 to 30 times the volume of the alcohol of the general formula [1]. Selected.

The amount of the carboxylic acid ester used in the esterification step is preferably equivalent (theoretical amount) to more than the amount of the alcohol of the general formula [1]. More preferably, it is 0.5 to 10 times, more preferably 0.5 to 2 times the theoretical amount.
The amount of the hydrolase used is 0.1 to 100% by weight, preferably 0.5 to 50% by weight, of the stereoisomeric (geometric isomer) alcohol mixture of the general formula [1].
The reaction temperature must be compatible with the activity of the enzyme. Preferably it is 100 degrees C or less, More preferably, it is 0 to 60 degreeC.
The reaction is preferably carried out at atmospheric pressure, but lower or higher pressures are not a problem and can also be carried out in an inert gas.
The reaction time is determined according to the conversion rate of the alcohol to be esterified. Needless to say, if the selectivity of the enzyme is not high, a technique known to those skilled in the art to limit the conversion rate, such as stopping the reaction at a stage where the conversion rate is low, should be used.
At the end of the reaction, one of the geometric isomers exists as an ester of general formula [5] and the other geometric isomer remains as an unreacted alcohol.

  The enzyme used in the reaction can be removed by performing a treatment such as filtration before performing the hydrolysis step in both cases of half esterification and esterification, and can be any enzyme supported on an insoluble carrier. The filtered material can be reused multiple times.

The half ester or ester produced by each reaction described above is preferably separated from unreacted alcohols by an industrially advantageous operation. The half ester is separated from unreacted alcohols by an industrially advantageous operation. As a method, distillation, extraction, treatment with an ion exchange resin or the like is preferable.
For example, in the case of extraction, when the solvent used in the reaction is a solvent that does not mix with water, an alkaline aqueous solution that can contain the half ester in the aqueous layer is added, or the solvent used in the reaction is mixed with water. If the solvent is a solvent that does not mix with water, and after adding a solvent that can dissolve unreacted alcohol, oil-water separation is performed, the alkali salt of the half ester is dissolved in the water layer, and the oil layer is not yet mixed. The reaction can be separated by dissolving the alcohol.
In addition, as a method for separating the ester from unreacted alcohols by an industrially advantageous operation, separation may be performed by using commonly used operations such as distillation, crystallization, and various chromatography alone or in combination. Although possible, distillation is more preferred.

  Thus, the half ester represented by the general formula [3] or the ester represented by the general formula [5] separated from unreacted alcohols by an industrially advantageous operation is obtained by a conventional method, for example, a 10% aqueous sodium hydroxide solution. Hydrolysis in the presence of a strong alkali can efficiently produce the alcohol represented by the general formula [6] in which the desired specific geometric isomer has high steric purity.

One of the production methods of the present invention is to selectively hydrolyze a carboxylic acid allyl derivative ester represented by the general formula [9] having a geometric isomer configuration in the cis or trans form in the presence of a hydrolase. Thus, a cis or trans-allyl alcohol represented by the above general formula [10] having a high steric purity is obtained.
The definitions and specific examples of R ¹ , R ³ , R ⁴ and A ^{2 in} the carboxylic acid allyl derivative ester represented by the general formula [9] are the same as described above. .
The hydrolase used here is the same as the hydrolase used in the production methods described so far, but lipases derived from microorganisms are more preferable.

In this production method, the reaction can be performed using water and an inert organic solvent in the hydrolysis reaction.
Specific examples of the solvent used in the hydrolysis reaction include water, a buffer solution such as a phosphate buffer, for example, aliphatic hydrocarbons such as pentane, hexane, heptane, octane, and cyclohexane, such as benzene and toluene. Aromatic hydrocarbons such as xylene, for example, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, o-dichlorobenzene, such as diethyl ether, diisopropyl ether, tert-butylmethyl Ethers such as ether, dimethoxyethane, ethylene glycol diethyl ether, tetrahydrofuran, 1,4-dioxane, for example, alcohols such as methanol, ethanol, 2-propanol, n-butanol, 2-ethoxyethanol, benzyl alcohol, For example, polyhydric alcohols such as ethylene glycol, propylene glycol, 1,2-propanediol and glycerin, for example, ketones such as acetone and methyl ethyl ketone, such as N, N-dimethylformamide, N, N-dimethylacetamide, N -Amides such as methylpyrrolidone, sulfoxides such as dimethyl sulfoxide, and nitriles such as acetonitrile and propionitrile, but are not limited thereto. These solvents may be used alone or in combination of two or more.
Among these solvents, more preferred solvents include tetrahydrofuran-water mixed solvent, methanol-heptane mixed solvent, methanol-tetrahydrofuran mixed solvent, and the like.
The amount of the organic solvent used is arbitrary and is not particularly limited, but is usually appropriately selected from the range of 0 to 100 times, preferably 1 to 30 times the volume of the ester of the general formula [9]. The

The usage-amount of the hydrolase used in this hydrolysis reaction is 0.1 to 100% by weight, preferably 1 to 50% by weight of the ester of the general formula [9].
The reaction temperature must be compatible with the activity of the enzyme. Preferably it is 100 degrees C or less, More preferably, it is 0 to 60 degreeC.
The reaction is advantageously carried out at atmospheric pressure, but lower or higher pressures are not a problem and can also be carried out in an inert gas.
The reaction time is determined according to the conversion rate of the ester of the general formula [9] to be hydrolyzed. Needless to say, if the selectivity of the enzyme is not large, a technique known to those skilled in the art to limit the conversion rate, such as stopping the reaction at a stage where the conversion rate is low, should be used.
At the end of the reaction, most of one of the geometric isomers exists as an alcohol of general formula [10] and the other isomer remains as an unreacted ester. These products and unreacted products can be separated by one or a combination of commonly used operations such as distillation, crystallization, and various chromatography, but distillation is more preferred.

The process of the present invention is suitable for the selective separation of a number of geometric isomeric alcohol mixtures, in particular mixtures consisting of two geometric isomers distinguished by either the trans or cis configuration of terpene-based allyl alcohols, in particular farnesol. Very suitable. Farnesol is composed of four isomers as apparent from its molecular structure, but there are mainly two isomers (2E, 6E) and (2Z, 6E).
In one preferred embodiment, a cyclic ester anhydride was used to perform a half esterification reaction of a mixture of geometrically allylic alcohols, and an unreacted alcohol and a product half ester were separated by oil-water separation. By hydrolyzing the half ester under alkaline conditions, allyl alcohols having a desired configuration are obtained.
In another preferred embodiment, a transesterification reaction of a mixture of geometrically allylic alcohols is performed using a carboxylic acid ester, and an unreacted alcohol and a product ester are separated by distillation or chromatography. The product ester is separated by separation, and the resulting ester is hydrolyzed under alkaline conditions to obtain allyl alcohols having the desired configuration.
Further, as a further preferred embodiment, allyl alcohol having a desired configuration is obtained by selectively hydrolyzing a carboxylic acid ester of a mixture of geometrically isomeric allyl alcohols.

The process of the present invention can thus be used to separate allyl alcohol isomers having a cis or trans configuration at the allyl position with an increased specific geometric isomer ratio.
A preferred compound obtained by the method of the present invention includes (2E, 6E) -farnesol.
(2E, 6E) -farnesol is used in various fields as a fragrance, a pharmaceutical, or an intermediate thereof.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these Examples. In the following examples, the instrument used in the GLC analysis is GC6890 (column used: Neutrabond-1, 0.25 mm × 30 m) manufactured by Hewlett Packard.

Farnesol (435 mg, 1.96 mmol, (2Z, 6E): (2E, 6E) = 43: 57) and succinic anhydride (100 mg, 1 mmol) were dissolved in acetone (4 ml), and Lipase PS-C (10 mg, Amano Enzyme). (2.3% by weight with respect to farnesol, manufactured by the company) at 4 ° C. for 10 hours. After the enzyme was filtered off, 2 ml of hexane and 2 ml (1 mmol) of 0.5N NaOH solution were added and vigorously stirred. Oil and water could be easily separated by standing. The organic layer contained unreacted farnesol, and the aqueous layer contained succinic acid half ester of farnesol as a reaction product.
A strong alkali (10% NaOH solution 1 ml) was separately added to the aqueous layer and stirred to obtain (2Z, 6E) :( 2E, 6E) = 8.5: 91.5 farnesol.

Farnesol (10.0 g, 45.0 mmol, (2Z, 6E): (2E, 6E) = 36: 64), Novozym 435 (Nipozymes lipase, 30 wt% with respect to farnesol) and ethyl propionate (5.15 ml) , 1.0 equivalent to farnesol) was stirred in toluene (100 ml) at 30 ° C. for 16 hours. According to GLC analysis, farnesyl propionate was obtained with an isomer ratio of (2Z, 6E) :( 2E, 6E) = 7.3: 92.7 with a conversion of farnesol to farnesyl propionate of 43.5%. It was confirmed that
Farnesol and farnesyl propionate were easily separated by distillation, and farnesol was distilled at 106 ° C./50 Pa and had a GC purity of 96%. The GC purity of farnesyl propionate remaining as a distillation residue was 96%.

Farnesyl propionate (5.0 g, 22.5 mmol, (2Z, 6E): (2E, 6E) = 30: 70) in 10% aqueous THF (50 ml), Lipase PS-C (0.5 g, manufactured by Amano Enzyme) , 10 wt% with respect to farnesyl propionate) and treated at 30 ° C. for 16 hours. According to GLC analysis, farnesol propionate to farnesol was converted to 46.8%, and (2Z, 6E) :( 2E, 6E) = 6.3: 93.7 farnesol was obtained.
Farnesol and farnesyl propionate were easily separated by distillation, and farnesol was distilled at 106 ° C./50 Pa and had a GC purity of 96%. The GC purity of farnesyl propionate remaining as a distillation residue was 96%.

  Farnesyl acetate (5.0 g, 22.5 mmol, (2Z, 6E): (2E, 6E) = 22: 78) in 10% aqueous THF (100 ml) in Lipase PS-C (2.5 g, manufactured by Amano Enzyme, 50 wt% with respect to farnesyl acetate) and treated at 30 ° C. for 16 hours. According to GLC analysis, farnesol of (2Z, 6E) :( 2E, 6E) = 5.2: 94.8 was obtained with a conversion rate of farnesyl acetate to farnesol of 73.5%.

  Farnesol (10.0 g, 45.0 mmol, (2Z, 6E): (2E, 6E) = 27: 73), Lipase PS-C (3.0 g, Amano Enzyme, 30 wt% with respect to farnesol) and pivalic acid Vinyl (20.0 ml, 3.0 equivalents to farnesol) was stirred in toluene (200 ml) at 30 ° C. for 16 hours. According to GLC analysis, the conversion rate of farnesyl to farnesyl pivalate was 49.3%, and farnesyl pivalate was obtained in an isomer ratio of (2Z, 6E) :( 2E, 6E) = 10.0: 90.0. It was confirmed that

  Farnesol (1.0 g, 4.50 mmol, (2Z, 6E): (2E, 6E) = 27: 73), Lipase QLC (0.30 g, manufactured by Meisei Sangyo Co., Ltd., 30 wt% with respect to farnesol) and ethyl acetate ( 0.44 ml, 1.0 equivalent to farnesol) was stirred in toluene (20 ml) at 30 ° C. for 16 hours. According to GLC analysis, the conversion rate of farnesol to farnesyl acetate was 13.6%, and farnesyl acetate was obtained in an isomer ratio of (2Z, 6E) :( 2E, 6E) = 3.5: 96.5. Was confirmed.

Farnesyl butanoate (30.0 g, 135 mmol, (2Z, 6E): (2E, 6E) = 35: 65) in 10% aqueous THF (300 ml) in Lipase PS-C (9.0 g, Amano Enzyme, Butane) 30 wt% with respect to farnesyl acid) and treated at 4 ° C. for 16 hours. As a result of GLC analysis, farnesol of (2Z, 6E) :( 2E, 6E) = 6.0: 94.0 was obtained with a conversion rate of farnesyl butanoate to farnesol of 55.8%.
Farnesol and farnesyl butanoate can be easily separated by distillation. Farnesol was distilled at 111 ° C./60 Pa and had a GC purity of 99.2%. The GC purity of farnesyl butanoate remaining as a distillation residue was 98.9%.

Enzyme recycling experiment was conducted.
Farnesyl butanoate (0.05 g, (2Z, 6E) :( 2E, 6E) = 35: 65) in 10% aqueous THF (0.5 mL), LipasePS-C (0.015 g, Amano Enzyme, Butane) 30 wt% with respect to farnesyl acid) and treated at 4 ° C. for 16 hours. After completion of the reaction, the enzyme LipasePS-C was filtered and the filtrate was subjected to GLC analysis. As a result, the conversion rate of farnesyl butanoate to farnesol was 47.0%, and (2Z, 6E) :( 2E, 6E) = 9. 3: 90.7 farnesol was obtained. Subsequently, a recycling experiment was performed using the filtered enzyme. The reaction was carried out in the same manner as described above, and the reaction was carried out up to the 50th time, but no enzyme deactivation was observed. The recycling results are shown in the table.

  Alcohols and esters having high steric purity of geometric isomers that can be easily and efficiently produced by the production method of the present invention are widely used in various fields of industry, for example, as perfumes and intermediates thereof. obtain.

Claims (22)

The following general formula [1]
ROH [1]
(In the formula, R represents an alkenyl group which may have a substituent.)
An isomer mixture of alcohols represented by
(1) General formula [2] in the presence of hydrolase

(In the formula, A ¹ represents a divalent hydrocarbon group which may have a substituent.)
Is reacted with an acid anhydride represented by the following general formula [3]

(In the formula, R ′ represents an alkenyl group optionally having a substituent, represented by R, rich in one geometric isomer, and A ¹ is the same as above.)
Or esters represented by
(2) General formula [4] in the presence of hydrolase

(In the formula, R ¹ represents a hydrogen atom, an alkyl group, a halogenated alkyl group, or an aryl group, R ² represents a hydrocarbon group, and A ² represents a divalent group or a bond.)
Is reacted with a carboxylic acid ester represented by the following general formula [5]

(In the formula, R ′, R ¹ and A ² are the same as above.)
The ester represented by the following general formula [6] is characterized by hydrolyzing the ester rich in one of these geometric isomers.
R'OH [6]
(In the formula, R ′ is the same as described above.)
A process for producing alcohols having a high steric purity of geometrical isomers represented by   After reacting an isomer mixture of alcohol represented by the general formula [1] with an acid anhydride represented by the general formula [2] in the presence of a hydrolase, an ester represented by the general formula [3] is obtained. The manufacturing method of Claim 1 which isolates and hydrolyzes this. Process according to claim 1 or 2 A ¹ is an ethylene group or a trimethylene group.   After reacting the isomer mixture of alcohol represented by the general formula [1] with the carboxylic acid ester represented by the general formula [4] in the presence of a hydrolase, the ester represented by the general formula [5] is obtained. The manufacturing method of Claim 1 which isolates and hydrolyzes this.   The method according to claim 1, wherein the hydrolase is lipase or acylase.   The method according to any one of claims 1 to 4, wherein the hydrolase is a lipase derived from a microorganism. R in the general formula [1] is represented by the following general formula [7]

(In the formula, R ³ and R ⁴ each independently represent a chain-like saturated or unsaturated hydrocarbon group, and the wavy line represents a mixture of a cis isomer and a trans isomer.)
In the formula [3], formula [5] and formula [6], R ′ is a group represented by the following general formula [8]:

(In the formula, R ³ and R ⁴ are the same as above. One of the cis and trans isomers is 80% or more in the configuration of the double bond.)
The manufacturing method in any one of Claims 1-6 which is group shown by these.   The production method according to any one of claims 1 to 7, wherein R is a (6E) -3,7,11-trimethyl-2,6,10-dodecatrien-1-yl group.   The process according to any one of claims 1 to 8, wherein R 'is a (2E, 6E) -3,7,11-trimethyl-2,6,10-dodecatrien-1-yl group. General formula [1]
ROH [1]
(In the formula, R represents an alkenyl group which may have a substituent.)
In the presence of hydrolase, an alcohol isomer mixture represented by general formula [2]

(In the formula, A ¹ represents a divalent hydrocarbon group which may have a substituent.)
It is made to react with the acid anhydride shown by General formula [3]

(In the formula, R ′ represents an alkenyl group optionally having a substituent, represented by R, rich in one geometric isomer, and A ¹ is the same as above.)
A method for producing esters having high steric purity of geometric isomers represented by Process according to claim 10 A ¹ is an ethylene group or a trimethylene group. General formula [1]
ROH [1]
(In the formula, R represents an alkenyl group which may have a substituent.)
In the presence of hydrolase, an alcohol isomer mixture represented by the general formula [4]

(In the formula, R ¹ represents a hydrogen atom, an alkyl group, a halogenated alkyl group, or an aryl group, R ² represents a hydrocarbon group, and A ² represents a divalent group or a bond.)
The following general formula [5], characterized by reacting with a carboxylic acid ester represented by

(In the formula, R ′, R ¹ and A ² are the same as above.)
A method for producing esters having high steric purity of geometric isomers represented by   The method according to any one of claims 10 to 12, wherein the hydrolase is lipase or acylase.   The method according to any one of claims 10 to 12, wherein the hydrolase is a microorganism-derived lipase. R in the general formula [1] is represented by the following general formula [7]

(In the formula, R ³ and R ⁴ each independently represent a chain-like saturated or unsaturated hydrocarbon group, and the wavy line represents a mixture of a cis isomer and a trans isomer.)
In the formula [3], R ′ is a group represented by the following general formula [8]:

(In the formula, R ³ and R ⁴ are the same as above. One of the cis and trans isomers is 80% or more in the configuration of the double bond.)
The production method according to claim 10, claim 11, claim 13, or claim 14, which is a group represented by: R in the general formula [1] is represented by the following general formula [7]

(In the formula, R ³ and R ⁴ each independently represent a chain-like saturated or unsaturated hydrocarbon group, and the wavy line represents a mixture of a cis isomer and a trans isomer.)
In the formula [4], R ′ is a group represented by the following general formula [8]:

(In the formula, R ³ and R ⁴ are the same as above. One of the cis and trans isomers is 80% or more in the configuration of the double bond.)
The production method according to any one of claims 12 to 14, which is a group represented by:   The process according to any one of claims 10 to 16, wherein R is a (6E) -3,7,11-trimethyl-2,6,10-dodecatrienyl group.   The production method according to any one of claims 10 to 17, wherein R 'is a (2E, 6E) -3,7,11-trimethyl-2,6,10-dodecatrienyl group. The following general formula [9]

(In the formula, R ¹ represents a hydrogen atom, an alkyl group, a halogenated alkyl group or an aryl group, A ² represents a divalent group or a bond, and R ³ and R ⁴ each independently represent a chain-like saturated group. Alternatively, it represents an unsaturated hydrocarbon group, and the wavy line represents a mixture of a cis isomer and a trans isomer.)
The ester represented by the following general formula [10], wherein the ester is hydrolyzed in the presence of a hydrolase:

(In the formula, R ³ and R ⁴ are the same as above. One of the cis and trans isomers is 80% or more in the configuration of the double bond.)
A process for producing alcohols having a high steric purity of the geometric isomer represented by   The production method according to claim 19, wherein the hydrolase is a lipase derived from a microorganism. The production method according to claim 19 or 20, wherein R ³ is an (E) -4,8-dimethyl-3,7-nonadienyl group and R ⁴ is a methyl group. The method according to any one of claims 19 to 21, wherein the alcohol is (2E, 6E) -farnesol.