JP2006223233A - Method for producing capsinoid, method for stabilizing the same, and capsinoid composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a capsinoid, capable of simply producing the capsinoid in a short time with a high yield, without using a scavenger of water or an alcohol which is formed according to condensation, when the capsinoid is produced by esterification for which an enzyme is used, and to provide a method for stably preserving the produced capcinoid, by conducting purification of the obtained capsinoid under a stable condition. <P>SOLUTION: This method for producing an ester compound comprises condensing a vinyl ester expressed by general formula (1) (R1 is a 5-25C alkyl or a 5-25C alkenyl of which the each may be substituted) with a hydroxymethylphnenol expressed by general formula (2) (R2 to R6 are each hydrogen, hydroxy, a 1-25C alkyl, a 2-25C alkenyl, a 2-25C alkynyl, a 1-25C alkoxy, a 2-25C alkenyloxy or a 2-25C alkynyloxy, provided that at least one of R2 to R6 is hydroxy) in the presence of an enzyme, so as to produce the ester compound expressed by general formula (3). Further, a method for stabilizing the ester compound comprises adding a fatty acid expressed by general formula (4) (R1' is a 5-25C alkyl or a 5-25C alkenyl of which the each may be substituted) to the ester compound expressed by general formula (3). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a novel method for synthesizing and stabilizing capsinoids and a capsinoid composition.

  Capsaicum capsicum ((E) -N-[(4-hydroxy-3-methoxybenzyl] -8-methyl-6-nonenamide) of capsicum annuum L. has a physiological effect such as obesity-inhibiting action and energy metabolism enhancement. Although it has activity, it has a very strong pungent taste, so the amount of use is limited, and its use as a food additive or pharmaceutical product has been hindered.

In recent years, Yazawa et al. Have developed and reported a spicy varieties chili pepper CH-19 sweet in which a spicy fruit selected from a strong spicy cultivar CH-19 native to Thailand has been fixed for many years (see, for example, Non-Patent Document 1). ).
CH-19 sweet contains a large amount of capsinoids having no pungent taste, and the capsinoids are capsiate, dihydrocapsiate and nordihydrocapsiate in descending order of content, and they have the following chemical formula.

  Although these capsinoids have the same physiological activity as capsaicin, they do not have a pungent taste and may be used as food additives or pharmaceuticals. However, there is a limit in obtaining a large amount of high-purity capsinoid from nature, and a new synthesis method for easily producing a large amount of capsinoid is required.

In order to form capsinoid esters, condensation of vanillyl alcohol and a fatty acid derivative is common.
However, there are two reactive sites of vanillyl alcohol, a primary hydroxyl group and a phenolic hydroxyl group, and a general esterification method, for example, condensing vanillyl alcohol and an acid chloride of a fatty acid in the presence of a base. In the method (for example, refer nonpatent literature 2), since the acid chloride reacts with both a primary hydroxyl group and a phenolic hydroxyl group, the yield of the target capsinoid will become low.
Therefore, in order to synthesize capsinoids by a general esterification method, it may be possible to selectively protect the phenolic hydroxyl group of vanillyl alcohol, but it is necessary to protect and deprotect before and after esterification. This is not preferable because it causes a multi-step process. Further, since capsinoids are unstable, there is a problem that they are easily decomposed during deprotection.

Methods for selectively reacting only the primary hydroxyl group include a Mitsunobu reaction method (for example, see Non-Patent Document 3) and a method using LiClO ₄ (for example, see Non-Patent Document 4). Since a reduced product of phenylphosphine oxide and diethyl azodicarboxylate is produced as a co-product, there is a problem that purification is difficult, and the latter has faithfully reproduced the experiment described in the literature by the inventors, but as described. It is difficult to achieve the yield of either, and neither is suitable for industrial practice.

  On the other hand, it is possible to selectively react only the primary hydroxyl group by an esterification method using an enzyme, and this method is suitable for industrial implementation from the viewpoint of easy availability of reagents and simple process. It is thought that. As a specific example of a method using an enzyme, a method of condensing vanillyl alcohol with a side chain fatty acid or a methyl ester thereof using lipase (Novozyme 435, manufactured by Novozymes) as an enzyme (see, for example, Patent Document 1) There is. However, since the reaction using this enzyme is an equilibrium reaction with water or alcohol generated with esterification, there are problems that the reaction takes a long time and the yield is as low as about 60%. Although the yield can be improved by adding water or alcohol trapping agents such as molecular sieves, the trapping agent must be removed by filtration. There is a problem that the enzyme and the trapping agent must be separated from the filtrate.

  By the way, the reaction of acetylating a hydroxyl group using vinyl acetate and an enzyme is widely known, and the reaction of condensing vanillyl alcohol and vinyl acetate by an enzyme to form an acetate ester (for example, see Non-Patent Document 5) is also known. It is. However, there is no known reaction for synthesizing capsinoids by performing esterification selectively on primary hydroxyl groups by condensation of general fatty acid vinyl esters, particularly long-chain fatty acid vinyl esters and vanillyl alcohol.

In addition, capsinoids are unstable, and it is known that decomposition proceeds only by dissolving in a certain organic solvent (see, for example, Non-Patent Document 6). Therefore, in order to manufacture capsinoids industrially, a technique for stably purifying and storing capsinoids is also required.
JP 2000-31598 A Yazawa, S .; Suetome, N .; Okamoto, K .; Namiki, TJ Japan Soc. Hort. Sci. 1989, 58, 601-607. Kobata, K .; Todo, T .; Yazawa, S .; Iwai, K .; Watanabe, TJ Agric. Food Chem. 1998, 46, 1695-1697. Appendino, G .; Minassi, A .; Daddario, N .; Bianchi, F .; Tron, GC Organic Letters 2002, 4, 3839-3841. Bandgar, BP; Kamble, VT; Sadavarte, VS; Uppalla, LS Synlett 2002, 735-738. Allevi, P .; Ciuffreda, P .; Longo, A .; Anastasia, M. Tetrahedron: Asymmetry 1998, 9, 2915-2924. Sutoh, K .; Kobata, K .; Watanabe, TJ Agric. Food Chem. 2001, 49, 4026-4030.

  The problem to be solved by the present invention is that in a method for producing capsinoids by esterification using an enzyme, capsinoids can be easily produced in a short time and in a high yield without using a water or alcohol scavenger produced by condensation. It is also intended to provide an intermediate compound useful for the production thereof. It is another object of the present invention to provide a method for stably storing the produced capsinoid by purifying the obtained capsinoid under stable conditions.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have carried out a simple, short time and high yield by performing a condensation reaction using a vinyl ester of fatty acid and vanillyl alcohol in an enzymatic condensation reaction. And found that capsinoids can be obtained. Furthermore, when several percent of fatty acid was allowed to coexist in the capsinoid, it was found that the capsinoid could be stably isolated and could be stored for a long time, and the present invention was completed.

  As described below, the present invention provides a method of using a vinyl ester as a fatty acid component in synthesizing a capsinoid, a vinyl ester as a capsinoid synthesis raw material, and a capsinoid by coexisting a fatty acid corresponding to the obtained capsinoid. The present invention relates to a method for stably purifying and storing.

That is, the present invention is as follows.
[1] General formula (1)

(In the formula, R 1 represents an alkyl group having 5 to 25 carbon atoms or an alkenyl group having 5 to 25 carbon atoms, and may have a substituent.)
A vinyl ester (hereinafter also referred to as vinyl ester (1)), and a general formula (2)

(Wherein R2 to R6 each independently represent hydrogen, a hydroxyl group, an alkyl group having 1 to 25 carbon atoms, an alkenyl group having 2 to 25 carbon atoms, an alkynyl group having 2 to 25 carbon atoms, or an alkyl group having 1 to 25 carbon atoms. An alkoxy group, an alkenyloxy group having 2 to 25 carbon atoms, or an alkynyloxy group having 2 to 25 carbon atoms, at least one of which is a hydroxyl group.)
And the following general formula (3), wherein the hydroxymethylphenol represented by the formula (hereinafter also referred to as hydroxymethylphenol (2)) is condensed in the presence of an enzyme:

(In the formula, R1 to R6 have the same meanings as described above.)
The manufacturing method of the ester compound (henceforth ester compound (3)) represented by these.
[2] The production method of the above-mentioned [1], wherein the hydroxymethylphenol (2) is vanillyl alcohol.
[3] Before or after condensation of vinyl ester (1) and hydroxymethylphenol (2), general formula (4)

(Wherein R1 ′ represents an alkyl group having 5 to 25 carbon atoms or an alkenyl group having 5 to 25 carbon atoms, and may have a substituent.)
The production method according to [1] or [2], wherein a fatty acid represented by the formula (hereinafter also referred to as fatty acid (4)) is added.
[4] The above-mentioned [1], further comprising a purification step in which the ester compound (3) obtained after the condensation and the fatty acid corresponding to the vinyl ester (1) by-produced during the condensation are fractionated simultaneously. ] Or the production method of [2].
[5] The production method according to the above (3), further comprising a purification step of fractionating the ester compound (3) and the fatty acid (4) obtained after the condensation.
[6] R1 is hexyl group, 5-methylhexyl group, trans-5-methyl-3-hexenyl group, heptyl group, 6-methylheptyl group, 5-methylheptyl group, trans-6-methyl-4-heptenyl Group, octyl group, 7-methyloctyl group, trans-7-methyl-5-octenyl group, nonyl group, 8-methylnonyl group, 7-methylnonyl group, trans-8-methyl-6-nonenyl group, trans-8- Methyl-5-nonenyl group, trans-7-methyl-5-nonenyl group, decyl group, 9-methyldecyl group, trans-9-methyl-7-decenyl group, trans-9-methyl-6-decenyl group, undecyl group And the production method according to any one of the above [1] to [5], which is a group selected from the group consisting of and a dodecyl group.
[7] The production method according to any one of [1] to [6], wherein the enzyme is lipase.
[8] Condensation is one or two or more solvents selected from the group consisting of acetone, 4-methyl-2-pentanone, 2-butanone, dimethoxyethane, tetrahydrofuran, toluene, pentane, hexane, heptane, or no solvent The production method according to any one of [1] to [7], which is performed below.
[9] The production method according to any one of [1] to [8], wherein the condensation is performed at 15 ° C. to 90 ° C.
[10] The vinyl ester (1) is represented by the general formula (11)

(Wherein R1 is as defined above, and Rc represents a methyl group, an ethyl group, an isopropyl group, a t-butyl group, an allyl group, or a benzyl group.)
The general formula (12) obtained by hydrolyzing an ester compound represented by the formula (hereinafter also referred to as ester compound (11)) and reacting with a base to form a salt crystal.

(Wherein R1 has the same meaning as above).
The manufacturing method in any one of said [1] thru | or [9] which is obtained by vinyl-esterifying the fatty acid represented by these (henceforth a fatty acid (12)).
[11] The ester compound (11) is represented by the general formula (8)

(In the formula, Ra represents an optionally substituted alkyl group having 1 to 24 carbon atoms or an optionally substituted alkenyl group having 2 to 24 carbon atoms, and X represents a halogen atom. Show.)
A compound represented by general formula (9) below (hereinafter also referred to as compound (8))

(In the formula, Ra and X are as defined above.)
Is converted to a Grineer reagent (hereinafter also referred to as Grineer reagent (9)),

(In the formula, Rb represents an alkyl group having 1 to 24 carbon atoms which may have a substituent or an alkenyl group having 2 to 24 carbon atoms which may have a substituent, provided that the carbon of Rb Regarding the number, the sum of the carbon number of Ra and Rb is 5 to 25, Rc is as defined above, and Y represents a halogen atom, a methanesulfonyloxy group, a paratoluenesulfonyloxy group or a trifluoromethanesulfonyloxy group. )
The manufacturing method of said [10] description obtained by attaching | subjecting to a cross-coupling reaction with the compound (henceforth a compound (10)) represented by these.
[12] The vinyl ester (1) is represented by the general formula (13)

(In the formula, Rd and Re each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, m is 0 or 1, and n is an integer of 1 to 5.)
Based on the difference in crystallinity or solubility of the formed salt, a salt is formed by reacting the mixture with a base from a mixture of a fatty acid represented by (hereinafter also referred to as fatty acid (13)) and its cis isomer. The production method according to any one of the above [1] to [9], wherein the fatty acid (13) is obtained by purification and is obtained by vinyl esterification of the obtained fatty acid (13).
[13] General formula (5)

8-methylnonanoic acid vinyl ester represented by
[14] General formula (6)

Trans-8-methyl-6-nonenoic acid vinyl ester represented by
[15] Ester compound (3) and general formula (7)

(Wherein R1 ″ represents an alkyl group having 5 to 25 carbon atoms or an alkenyl group having 5 to 25 carbon atoms, and may have a substituent.)
A composition comprising a fatty acid represented by the formula (hereinafter also referred to as fatty acid (7)) (excluding an oil or fat extract from a plant).
[16] The composition according to [15] above, wherein the fatty acid (7) is contained in an amount of 0.1 to 30% by weight based on the ester compound (3).
[17] The above [15] or [16], further comprising one or more additives selected from the group consisting of an oil and fat composition, an emulsifier, a preservative, and an antioxidant as a bulking agent or carrier. The composition as described.
[18] A method for stabilizing an ester compound (3), wherein the fatty acid (4) is added to the ester compound (3) to maintain or improve the purity of the ester compound (3).
[19] The stabilization method according to the above [18], wherein the fatty acid (4) is added in an amount of 0.1 to 30% by weight based on the ester compound (3).

According to the present invention, capsinoid can be easily mass-produced in a short time with a high yield using an enzyme. In addition, since no trapping agent such as molecular sieves is required, the enzyme can be reused simply by collecting it by filtration. Moreover, the produced capsinoid can be obtained stably and with high purity by separation in the presence of fatty acids. Thus, according to the present invention, capsinoid can be produced industrially advantageously.
Furthermore, according to the stabilization method of the present invention, it is possible to stably store the capsinoid by allowing the capsinoid to coexist with a fatty acid.

Embodiments of the present invention will be described below.
First, definitions of terms used in the present invention will be described.
The alkyl group having 5 to 25 carbon atoms represented by R1 may be linear or branched, and examples thereof include an n-pentyl group, a sec-pentyl group, a tert-pentyl group, an isopentyl group, n-hexyl group, isohexyl group, 6-methylhexyl group, heptyl group, 4,4-dimethylpentyl group, octyl group, 2,2,4-trimethylpentyl group, 7-methyloctyl group, nonyl group, 8-methylnonyl Group, decyl group, 9-methyldecyl group, dodecyl group, tetradecyl group, hexadecyl group, octadecyl group, icosyl group, docosyl group, pentacosyl group and the like. In addition, these various branched chain isomers are included.

  The alkenyl group having 5 to 25 carbon atoms represented by R1 may be linear or branched, and the number of double bonds may be one or two. Is a pentenyl group (eg, 4-pentenyl group, 3-pentenyl group, etc.), hexenyl group (eg, 2-hexenyl group, 4-hexenyl group, etc.), 6-methyl-4-hexenyl group, peptenyl group (eg, 2-heptenyl group, 3-heptenyl group, 5-heptenyl group, etc.), octenyl group (eg, 3-octenyl group, 6-octenyl group, etc.), 7-methyl-5-octenyl group, nonenyl group (eg, 3-enyl group) Nonenyl group, 7-nonenyl group, etc.), 8-methyl-6-nonenyl group, decenyl group (eg, 8-decenyl group, etc.), 9-methyl-7-decenyl group, and undecenyl group (eg, 9-andenyl group, etc.) ), Dodecenyl group (eg, 10 Dodecenyl group, etc.), tetradecenyl group, 4,8,12-tetradecatrienyl group, pentadecenyl group (eg, 13-pentadecenyl group, etc.), hexadecenyl group, heptadecenyl group (eg, 15-heptadecenyl group, etc.), octadecenyl group ( Examples, 16-octadecenyl group etc.), nonadecenyl group (eg, 17-nonadecenyl group), icocenyl group (eg, 18-icocenyl group etc.), henicocenyl group (eg, 19-henicosenyl group etc.), dococenyl group (eg, 20 -Docosenyl group etc.), pentacocenyl group etc. are mentioned. In addition, these various branched chain isomers are included. The steric structure of the double bond portion may be either trans or cis, but is preferably trans.

  The alkyl group having 5 to 25 carbon atoms and the alkenyl group having 5 to 25 carbon atoms represented by R1 may be optionally substituted with 1 to 4 substituents. Examples of the substituent include an alkyl group and a halogen atom. Haloalkyl group, amino group, hydroxyl group, acyl group, nitro group, cyano group, thiol group and the like. Among these, a C1-C4 alkyl group is preferable. Examples of the alkyl having 1 to 4 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, and isobutyl group.

  R1 is a hexyl group, a 5-methylhexyl group, a trans-5-methyl-3-hexenyl group, a heptyl group, a 6-methylheptyl group, 5- Methylheptyl group, trans-6-methyl-4-heptenyl group, octyl group, 7-methyloctyl group, trans-7-methyl-5-octenyl group, nonyl group, 8-methylnonyl group, 7-methylnonyl group, trans- 8-methyl-6-nonenyl group, trans-8-methyl-5-nonenyl group, trans-7-methyl-5-nonenyl group, decyl group, 9-methyldecyl group, trans-9-methyl-7-decenyl group, A trans-9-methyl-6-decenyl group, an undecyl group, a dodecyl group and the like are preferable.

  The vinyl ester (1) may be a single compound or a mixture of two or more compounds in which R1 is different within the above definition, but is preferably a single compound. However, when a capsinoid is synthesized by condensation with vanillyl alcohol using a fatty acid isolated from natural capsaicinoid, vinyl ester (1) is trans-8-methyl-6-nonenoic acid vinyl ester, 8-methylnonanoic acid. It is a mixture of vinyl ester and 7-methyloctanoic acid vinyl ester. In addition, when it is desired to reproduce a capsinoid composition, which is a natural abundance ratio, with a synthetic product, a capsinoid synthesized separately by this method may be mixed. However, by using a mixture of corresponding compounds as vinyl ester (1). The purpose can also be achieved by applying this method.

  The alkyl group having 1 to 25 carbon atoms represented by R2 to R6 may be linear or branched, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, and n-butyl. Group, t-butyl group and the like and the same alkyl group having 5 to 25 carbon atoms represented by R1.

  The alkenyl group having 2 to 25 carbon atoms represented by R2 to R6 may be linear or branched, and the number of double bonds may be one or more. Examples thereof include a vinyl group, an allyl group, a propenyl group, an isopropenyl group, a butenyl group, and the like and the same alkenyl groups having 5 to 25 carbon atoms represented by R1.

  The alkynyl group having 2 to 25 carbon atoms represented by R2 to R6 may be linear or branched, and the number of triple bonds may be one or two. Specific examples include Ethynyl group, propynyl group, pentynyl group, hexynyl group, octynyl group, noninyl group and the like.

  The alkoxy group having 1 to 25 carbon atoms represented by R2 to R6 may be linear or branched, and the alkyl portion is an alkyl group having 1 to 25 carbon atoms represented by R2 to R6. The alkoxy group which is the same can be illustrated.

  The alkenyloxy group having 2 to 25 carbon atoms represented by R2 to R6 may be linear or branched, and the number of double bonds may be one or two or more. And an alkenyloxy group having the same alkenyl moiety as the alkenyl group having 2 to 25 carbon atoms represented by R2 to R6.

  The alkynyloxy group having 2 to 25 carbon atoms represented by R2 to R6 may be linear or branched, and the number of triple bonds may be one or two, An alkynyloxy group in which the alkynyl moiety is the same as the alkynyl group having 2 to 25 carbon atoms represented by R2 to R6 can be exemplified.

  At least one of R2 to R6 is preferably a hydroxyl group, and R4 is preferably a hydroxyl group. Moreover, it is preferable that only one of R2 to R6 is a hydroxyl group.

  R2 to R6 are preferably hydrogen, methoxy group, ethoxy group, allyl group, vinyl group, or vinyloxy group.

  As a preferable combination of R2 to R6, R2, R5 and R6 are hydrogen, R3 is a methoxy group, an ethoxy group, an allyl group, a vinyl group or a vinyloxy group, and R4 is a hydroxyl group. Among these, R3 is most preferably a methoxy group (that is, hydroxymethylphenol (2) is vanillyl alcohol) from the viewpoint of the usefulness of the target compound, the ester compound (3), as a capsinoid.

  Hydroxymethylphenol (2) may be a single compound or a mixture of two or more compounds in which R2 to R6 are within the above definition, but is preferably a single compound.

The alkyl group having 5 to 25 carbon atoms represented by R1 ′ may be linear or branched, and examples thereof are the same as the alkyl group having 5 to 25 carbon atoms represented by R1.
The alkenyl group having 5 to 25 carbon atoms represented by R1 ′ may be linear or branched, and the number of double bonds may be one or two, and R1 The same thing as the C5-C25 alkenyl group represented by these can be illustrated.

  The substituent that the alkyl group having 5 to 25 carbon atoms and the alkenyl group having 5 to 25 carbon atoms represented by R1 ′ may have is an alkyl group having 5 to 25 carbon atoms and carbon number represented by R1. It is the same as the substituent which 5 to 25 alkenyl group may have.

  R1 ′ is a hexyl group, 5-methylhexyl group, trans-5-methyl-3-hexenyl group, heptyl group, 6-methylheptyl group, 5-methylheptyl group, trans-6-methyl-4-heptenyl group, Octyl group, 7-methyloctyl group, trans-7-methyl-5-octenyl group, nonyl group, 8-methylnonyl group, 7-methylnonyl group, trans-8-methyl-6-nonenyl group, trans-8-methyl- 5-nonenyl group, trans-7-methyl-5-nonenyl group, decyl group, 9-methyldecyl group, trans-9-methyl-7-decenyl group, trans-9-methyl-6-decenyl group, undecyl group, dodecyl It is preferably a group or the like, and most preferably a group selected as R1. That is, R1 of the vinyl ester (1) and R1 'of the fatty acid (4) are preferably the same group.

The alkyl group having 5 to 25 carbon atoms represented by R1 ″ may be linear or branched, and examples thereof are the same as the alkyl group having 5 to 25 carbon atoms represented by R1.
The alkenyl group having 5 to 25 carbon atoms represented by R1 ″ may be linear or branched, and the number of double bonds may be one or two, Examples thereof are the same as the alkenyl group having 5 to 25 carbon atoms represented by R1.

  The substituent that the alkyl group having 5 to 25 carbon atoms and the alkenyl group having 5 to 25 carbon atoms represented by R1 ″ may have is an alkyl group having 5 to 25 carbon atoms and carbon represented by R1. This is the same as the substituent which the alkenyl group of formula 5 to 25 may have.

  R1 ″ is a hexyl group, 5-methylhexyl group, trans-5-methyl-3-hexenyl group, heptyl group, 6-methylheptyl group, 5-methylheptyl group, trans-6-methyl-4-heptenyl group Octyl group, 7-methyloctyl group, trans-7-methyl-5-octenyl group, nonyl group, 8-methylnonyl group, 7-methylnonyl group, trans-8-methyl-6-nonenyl group, trans-8-methyl It is preferably -5-nonenyl group, decyl group, 9-methyldecyl group, trans-9-methyl-7-decenyl group, trans-9-methyl-6-decenyl group, undecyl group, dodecyl group, etc. Most preferably, it is a selected group. That is, R1 of the vinyl ester (1) and R1 ″ of the fatty acid (7) are preferably the same group.

  The present invention is a method for producing an ester compound (3), characterized in that a vinyl ester (1) and a hydroxymethylphenol (2) are condensed in the presence of an enzyme.

In the conventional method using carboxylic acid or methyl ester, since esterification is an equilibrium reaction with water or methanol to be eliminated, the yield does not increase and the problem of prolonged reaction time and residual raw materials has occurred. When ester (1) is used, the compound to be eliminated is vinyl alcohol, and this vinyl alcohol is isomerized to form a low-boiling acetaldehyde that is released from the reaction system. It becomes. As a result, it is also possible to produce the ester compound (3) in a short time with a high yield of 90% or more and with a high purity of 99 area% or more by HPLC analysis.
In addition, in the conventional method using carboxylic acid or methyl ester, an improvement in yield is expected if molecular sieves or the like is added as a supplement for water or methanol to be eliminated. However, if the enzyme is to be reused after filtration, And supplements need to be separated. On the other hand, when vinyl ester (1) is used, only a low-boiling acetaldehyde is generated, and the acetaldehyde is distilled off together with the solvent when the reaction solution is concentrated. Can be reused.

  The vinyl ester (1) used in the present invention is obtained by vinyl esterifying a corresponding fatty acid according to a known method (for example, see JP-A-53-127410, Synthesis 1994, 375-377, etc.) It can be easily manufactured and obtained in one step. Moreover, regarding the synthesis | combination of a corresponding fatty acid, the cross-coupling method shown by the following reaction scheme is suitable.

(In the formula, X represents a halogen atom, and Ra and Rb are each independently an optionally substituted alkyl group having 1 to 24 carbon atoms or an optionally substituted carbon number. Represents an alkenyl group having 2 to 24, provided that the sum of the carbon number of Ra and Rb is 5 to 25 (if the substituent includes carbon, the carbon number of the substituent is excluded), and Rc is a methyl group , Ethyl group, isopropyl group, t-butyl group, allyl group, or benzyl group, and Y represents a halogen atom, a methanesulfonyloxy group, a paratoluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group.)

Ra and Rb are each an optionally substituted alkyl group having 1 to 24 carbon atoms or an optionally substituted alkenyl group having 2 to 24 carbon atoms, and each of Ra and Rb carbons. A group in which the sum of the numbers is 5 to 25, the group represented by Ra and the group represented by Rb are bonded by a cross-coupling reaction to form a group represented by R1 (that is, An alkyl group having 5 to 25 carbon atoms or an alkenyl group having 5 to 25 carbon atoms, which may have a substituent. Therefore, specifically, Ra and Rb are appropriately determined depending on the structure of R1.
Examples of the halogen atom represented by X and Y include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a bromine atom.

  In the cross-coupling method, first, the compound (8) is converted into a Grineer reagent (9), the Grineer reagent (9) is subjected to a cross-coupling reaction with the compound (10), and the ester compound (11). And the ester compound (11) is hydrolyzed.

  Compound (8) and compound (10) can be obtained by synthesis by a known method, and commercially available products can be used as they are for commercially available products.

  Conversion of compound (8) to Grineer reagent (9) can be carried out by reacting compound (8) with magnesium according to a conventional method.

For example, the cross-coupling reaction between the Grineer reagent (9) and the compound (10) may be carried out by adding 1 to 3 equivalents of the compound (10) with respect to the Grineer reagent (9) and copper in a solvent. The reaction can be carried out in the presence of a catalyst at a low temperature (preferably -5 ° C to 10 ° C, more preferably -3 ° C to 5 ° C) for 15 minutes to 3 hours.
Solvents include ethers such as tetrahydrofuran (THF), diethyl ether, t-butyl methyl ether, dimethoxyethane, N-methylpyrrolidone (NMP), 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidine (DMPU) or the like, or a mixed solvent thereof or the like can be used.
Examples of the copper catalyst include Li ₂ CuCl ₄ , CuI, CuBr, CuCl, CuBr · Me ₂ S, etc., and the copper catalyst is 0.5 to 20 mol%, preferably 1 to 3 with respect to the compound (10). Used in mole percent.
Moreover, in order to advance reaction smoothly, you may use additives, such as a trimethylchlorosilane, 0.5-4 equivalent (preferably 1-2 equivalent) with respect to a compound (10).

  Hydrolysis of the ester compound (11) obtained by the coupling reaction can be performed by a known method (eg, a method using an acid, a method using an alkali, etc.).

The fatty acid represented by the formula (12) obtained by hydrolysis (hereinafter also referred to as fatty acid (12)) can remove impurities by forming a salt crystal with a base.
The salt crystal can be formed, for example, by stirring the fatty acid (12) and the base in a solvent.

  Examples of the base include inorganic bases (eg, lithium, sodium, potassium, calcium, magnesium, barium etc.), organic amines (eg, ethylenediamine, 1,3-diaminopropane, 1,3-diamino-2-propanol, cyclohexylamine, 4-methoxybenzylamine, ethanolamine, (S)-or (R) -phenylglycinol, (S)-or (R) -phenylalaninol, cis-2-aminocyclohexanol, trans-4-aminocyclohexanol (1S, 2R) -cis-1-amino-2-indanol, L-lysine, L-arginine, etc.), ammonia and the like. As a usage-amount of a base, it is 0.8-1.2 equivalent with respect to a fatty acid (12), Preferably it is 0.9-1.1 equivalent.

  Examples of the solvent include water; alcohols such as methanol, ethanol and isopropanol; acetates such as ethyl acetate and isopropyl acetate; ethers such as diethyl ether, t-butyl methyl ether and THF; carbonization such as hexane and heptane. Hydrogens; ketones such as acetone; halogen solvents such as chloroform; and mixed solvents thereof can be used.

By forming a salt crystal of the fatty acid (12) and the base as described above and then recrystallizing as necessary, reaction by-products other than the fatty acid (12), such as alcohol and ketone, can be easily obtained. It can be removed efficiently.
Next, the obtained salt crystal is added to an acidic aqueous solution (for example, aqueous hydrochloric acid solution), extracted with hexane and the like, and then the target fatty acid (12) can be regenerated with high purity by distilling off the hexane and the like.
The purification of fatty acids by forming salt crystals with a base is not limited to the fatty acids obtained by the above-described cross-coupling method, and can be applied as a purification method for various fatty acids obtained by known methods. The purified fatty acid can be converted to a vinyl ester (1) by vinyl esterification, and thus becomes a suitable material for the vinyl ester (1).

  The fatty acid (12) used for the material of the vinyl ester (1) is represented by the formula (13)

(In the formula, Rd and Re each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, m is 0 or 1, and n is an integer of 1 to 5.)

A compound having a structure represented by the following (hereinafter also referred to as fatty acid (13)), and the available material is a mixture of fatty acid (13) and its cis isomer, and only fatty acid (13) is separated. The mixture is reacted with a base to form a salt, and the salt of fatty acid (13) is separated from the salt with its cis isomer based on the crystallinity or solubility of the salt formed. be able to.

Examples of the alkyl group having 1 to 6 carbon atoms represented by Rd and Re include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t-butyl group, and pentyl group. , Isopentyl group, neopentyl group, t-pentyl group, hexyl group, and the like. Preferably, both Rd and Re are methyl groups.
m is 0 or 1, preferably 0. n is an integer of 1 to 5, preferably 3 or 4, and more preferably 4.

In the separation of the fatty acid (13) and its cis isomer, the salt can be formed in the same manner as the salt crystals of the fatty acid (12) and the base described above.
Examples of the method for separating the salt of the fatty acid (13) from the salt with the cis isomer based on the difference in crystallinity or solubility of the formed salt include crystallization, slurry washing, recrystallization and the like.

  An example of separation of fatty acid (13) and its cis isomer is shown as a mixture of trans-8-methyl-6-nonenoic acid and its cis isomer (cis-8-methyl-6-nonenoic acid) (trans 88%, cis isomer 12%), cis-2-aminocyclohexanol was used as a base, and cis isomers were separated by crystallization a few times to obtain trans-8-methyl-6-nonenoic acid. Can be increased to 97% or more.

  The obtained salt crystals are added to an acidic aqueous solution (for example, aqueous hydrochloric acid solution), extracted with hexane and the like, and then hexane and the like are distilled off to obtain a free form of fatty acid (13).

  As a result of literature search, 8-methylnonanoic acid vinyl ester and 8-methyl-6-nonenoic acid vinyl ester which are vinyl esters of 8-methylnonanoic acid and 8-methyl-6-nonenoic acid, which are constituents of main natural capsinoids, CAS registration number is not attached, it is a novel substance as a fatty acid vinyl ester, and constitutes a part of the present invention.

  Hydroxymethylphenol (2) used in the present invention is a known compound and can be obtained by synthesis by a known method. About what has a commercial item, a commercial item can be used.

  The operation for the condensation is not particularly limited as long as the condensation reaction of vinyl ester (1) and hydroxymethylphenol (2) proceeds. For example, vinyl ester (1) is dissolved in a solvent, and hydroxy For example, methylphenol (2) and an enzyme may be added.

The enzyme used in the present invention can be used without particular limitation as long as it can mediate the condensation reaction of vinyl ester (1) and hydroxymethylphenol (2), and typically esterase is used. As the esterase, lipase is usually used, and it may be of microbial origin, or of animal origin or plant origin.
Examples of the lipase include lipase PS “Amano”, lipase AK “Amano”, lipase AS “Amano”, lipase AYS “Amano” (hereinafter, manufactured by Amano Enzyme Co., Ltd.) and the like.
Moreover, the form of the enzyme may be used in any form as long as it can be added to the reaction solution. However, it is preferable to use the immobilized enzyme because subsequent enzyme recovery or the like becomes easy. As the immobilized enzyme, lipase PS-C “Amano” I (ceramic fixation), lipase PS-C “Amano” II (ceramic fixation), lipase PS-D “Amano” I (diatomaceous earth fixation) (above, Amano) Enzyme), Novozyme 435 (Novozymes) and other immobilized lipase enzymes can be used, but lipase PS “Amano” is desirable in terms of low cost and lipase PS- Lipase immobilized enzymes such as C “Amano” are desirable. Further, when lipase PS-C “Amano” or lipase PS-D “Amano” I is used, the reaction solution may be slightly colored. However, when Novozyme 435 is used, Novozyme 435 is desirable.
The amount of the enzyme added depends on the activity of the enzyme, but can be selected from the range of 0.01 to 60% by weight, preferably 0.1 to 30% by weight of the vinyl ester (1). Further, an enzyme may be further added during the reaction and used in excess.

As the solvent, organic solvents such as acetone, 4-methyl-2-pentanone, 2-butanone, dimethoxyethane, tetrahydrofuran, toluene, pentane, hexane, heptane, and mixed solvents thereof can be used as appropriate, but they are inexpensive. It is preferable to use 1 type (s) or 2 or more types selected from the group which consists of acetone, 4-methyl-2-pentanone, tetrahydrofuran, and toluene from the point of having a certain or high reaction yield. The amount of the solvent to be used is generally 1 to 70 ml, preferably 5 to 15 ml, with respect to 1 g of vinyl ester.
Furthermore, the reaction can be carried out in the absence of a solvent. When the reaction is carried out in the absence of a solvent, there is an advantage that the operation of removing the solvent is unnecessary and the reaction proceeds with good yield even if the amount of hydroxymethylphenol (2) used is reduced.

  The vinyl ester (1) and hydroxymethylphenol (2) used in the reaction may be used in a molar ratio that produces the ester compound (3) in the highest yield. The ratio of vinyl ester (1) and hydroxymethylphenol (2) corresponding to the side chain of compound (3) can be determined by simple preliminary experiments. For example, the ratio of vinyl ester (1): vanillyl alcohol is appropriately selected from a molar ratio of 0.8: 1 to 1: 6, and more preferably 0.9: 1 to 1: 3. can do. When lipase PS “Amano” is used as the enzyme, it is sufficient to use vanillyl alcohol in a small excess of 1.2 to 1.4 equivalents. When about 3 equivalents of vanillyl alcohol is used, or when a total of about 3 equivalents is added, the reaction rate further increases. The vanillyl alcohol used in excess can be removed or collected together with the enzyme by filtration because vanillyl alcohol precipitates when hexane or heptane is added to the reaction solution in the post-treatment after completion of the reaction.

  The reaction temperature should just select the temperature which the enzyme to use reacts most efficiently, and those skilled in the art can set easily by a simple preliminary experiment. Since the optimum temperature differs depending on the enzyme used, it cannot be generally stated, but generally 15 ° C. to 90 ° C., more preferably 35 ° C. to 65 ° C. can be selected. For example, when lipase PS “Amano” is selected as the enzyme, the reaction is promoted when heated to about 50 ° C.

  The reaction time is appropriately selected from the viewpoint of yield and the like taking into account the activity of the enzyme used, the concentration of each reagent, etc., but is usually 1 hour to 72 hours, preferably 3 hours to 48 hours. is there.

  After completion of the reaction, the ester compound (3) can be recovered according to a conventional method. For example, a solvent in which hydroxymethylphenol (2) is insoluble (for example, hexane or heptane when hydroxymethylphenol (2) is vanillyl alcohol) is added to precipitate unreacted hydroxymethylphenol (2). The hydroxymethylphenol (2) and the enzyme are filtered off. After distilling off the solvent from the filtrate, the ester compound (3) can be obtained by separation and purification using silica gel column chromatography. In addition, after completion of the reaction, hexane or heptane is added to the reaction solution, followed by filtration. Then, the filtrate is subjected to a liquid separation operation with, for example, a 10% aqueous citric acid solution, and the organic layer is simply concentrated under reduced pressure. 3) is obtained and is convenient. If it is desired to reuse the enzyme, only the enzyme needs to be filtered first. At that time, if hydroxymethylphenol is mixed in the enzyme, it can be used in the next reaction as a mixture, or after removing only hydroxymethylphenol by dissolving it in an organic solvent, only the enzyme is used in the next reaction. You can also

  The obtained ester compound (3) can be stabilized by coexisting with the fatty acid (4).

  When the ester compound (3) is separated and purified by silica gel column chromatography, it is produced in a very small amount in the reaction system (perhaps due to hydrolysis by a very small amount of water present in the reaction system). The fatty acid (ie, the fatty acid represented by R1COOH) has a similar Rf value to that of the ester compound (3), but the present inventors completely separated and purified them by silica gel column chromatography. However, it was found that the obtained pure ester compound (3) was easily decomposed. For example, after synthesizing vanillyl decanoate from decanoic acid and vanillyl alcohol, decanoic acid decanoate was separated and purified by silica gel column chromatography, and pure vanillyl decanoate was dissolved in acetonitrile and subjected to HPLC analysis. The purity of vanillyl was 95.6 area%. However, when the sample was analyzed again after 62 hours, the purity decreased to 82.0 area%, and the decomposition of vanillyl decanoate was observed.

Capsinoids obtained by extraction from plants containing capsinoids have been known to be relatively stable in the oily base material used during extraction, but methods for stabilizing capsinoids obtained through synthesis have been developed so far. unknown.
The inventors have found that the ester compound (3) obtained by elution with a fatty acid having a close Rf value is stable, that is, the fatty acid contributes to the stabilization of the ester compound (3). The stabilization method has been completed. For example, after synthesizing dihydrocapsiate, HPLC analysis was performed on dihydrocapsiate purified by fractionating together with about 2% by weight of fatty acid generated during the reaction. It was found that it can be stably stored at 5 ° C. without decomposition for at least 30 days.

Therefore, the ester compound (3) can be purified from the condensation reaction mixture by simultaneously separating and purifying the ester compound (3) and the fatty acid corresponding to the vinyl ester (1) as a by-product during the reaction. It can be obtained stably in purity.
Further, before or after condensation of vinyl ester (1) and hydroxymethylphenol (2), fatty acid (4) is added, and ester compound (3) and fatty acid (4) are fractionated simultaneously. By purifying in this manner, the ester compound (3) can be stably obtained with high purity.
As a method for obtaining the fatty acid (4), the synthesis method by the cross coupling method described above and the purification method by salt crystallization of the fatty acid are suitable.

  As long as the fractionation can be obtained by simultaneously separating the ester compound (3) and the fatty acid from other components, the method is not particularly limited. For example, silica gel chromatography using silica gel as the stationary phase. Can be performed.

  When fractionation is performed by silica gel chromatography, the ester compound (3) is obtained by using a column packed with 10 g of silica gel per 1 g of the crude product and flowing a mixed solvent of diethyl ether: hexane = 15: 85. ) And fatty acids elute almost simultaneously. The eluted fractions are collected and concentrated under reduced pressure to obtain a mixture of the purified ester compound (3) and a small amount of fatty acid.

  Thus, if the ester compound (3) and the fatty acid are separated at the same time, the amount of silica gel used for purification may be small compared to the case where only the ester compound (3) is isolated, and the resulting ester compound (3 ) Stability can be increased.

Further, when the ester compound (3) is isolated alone or recovered together with an amount of fatty acid that is insufficient for stabilization (in these cases, the ester compound (3) is different from the present invention). Even if it may be obtained by a production method), the ester compound (3) can be stabilized by adding the fatty acid (4) to the ester compound (3).
For example, when 9.1% by weight of decanoic acid in acetonitrile was added to pure vanillyl decanoate separated from decanoic acid, it was maintained at a high purity of 97.6 area% even after 19.5 hours.
As described above, the present inventors have found that the ester compound (3) is extremely stable if a small excess of fatty acid is allowed to coexist, whereas the ester compound (3) is separated from the fatty acid. As a result, the purity decreases over time. As a result of analysis of this phenomenon by the present inventors, when a small excess amount of the fatty acid (4) is newly added to the ester compound (3) which has once been reduced in purity by separation from the fatty acid, the ester compound ( It was discovered that the purity of 3) can be improved (recovered). In other words, the ester compound (3) can be purified by adding the fatty acid (4) to the ester compound (3).

  The fatty acid (4) to be added is appropriately selected according to the use of the composition containing the ester compound (3) and the fatty acid (4). R1 ′ in the general formula (4) is an ester compound (3). The fatty acid (4) which is the same group as R1 in the general formula (3), particularly a side chain fatty acid is most preferable.

  The fatty acid may be present in the range of 0.1 wt% to 30 wt% with respect to the ester compound (3), and more preferably in the range of 1 wt% to 5 wt%. Therefore, when the fatty acid (4) is added for stabilization after the isolation of the ester compound (3), it is preferably added so as to be within the above range.

  In the case where the ester compound (3) is obtained by, for example, the above production method and contains a fatty acid corresponding to the vinyl ester (1) by-produced during the reaction, a fatty acid (4) is further added as necessary. It is preferable to adjust so as to be within the above range as a whole.

The composition of the present invention is a composition comprising an ester compound (3) and a fatty acid (7). The composition is not extracted as an oil or fat extract from a plant body, but is artificially obtained, for example, by the method as described above, and has physiological activities such as an obesity suppressing action and energy metabolism enhancement. Therefore, it can be used for food additives and pharmaceuticals.
The fatty acid (7) is a component mixed in the ester compound (3). For example, the fatty acid corresponding to the vinyl ester (1) by-produced during the reaction by the above production method, the fatty acid (4) added separately. Etc.

In the composition, the fatty acid (7) is preferably contained in the range of 0.1% by weight to 30% by weight, more preferably in the range of 1% by weight to 5% by weight with respect to the ester compound (3). Contained.
The composition may contain one or more additives selected from the group consisting of an oil and fat composition, an emulsifier, a preservative, and an antioxidant. Even when these additives are included, it goes without saying that the coexistence of the fatty acid (7) is effective in stabilizing the ester compound (3).

  The composition comprising the ester compound (3) and the fatty acid (7) of the present invention can be stably stored without being decomposed for a long period of time. When preparing a preparation, it is extremely useful because it can be stably stored for a long time as a high-concentration active ingredient.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not limited to these Examples. In the following examples, the structure of the synthesized compound was identified by nuclear magnetic resonance spectrum (Bruker AVANCE400 (400 MHz)). GC-MS was measured using HEWLETT PACKARD 5890 SERIES II, 5972 SERIES, 7673 CONTROLLER. The free fatty acid content was calculated from the peak integral value of the nuclear magnetic resonance spectrum or analyzed using a YMC fatty acid analysis kit.
The HPLC measurement conditions for capsinoids are as follows.
HPLC conditions:
Column: Inertsil C8 3um (Diameter 4.0mm x 100mm)
Eluent: A mixed solvent of eluent-A, B and buffer shown below was eluted by a gradient elution method.
Buffer: 30 mM KH ₂ PO ₄ (pH = 2.0, H ₃ PO ₄ )
Eluent-A: CH ₃ CN: Buffer = 80: 20
Eluent-B: CH ₃ CN: Buffer = 0: 100
Gradient condition: 0 min: A / B = (20/80); 15 min: A / B = (70/30); 30 min: A / B = (100/0); 45 min: A / B = (100/0); 45.1 min: A / B = (20/80); 50 min: A / B = (20/80)
Detection: UV210 nm
Temperature: room temperature

Example 1 Synthesis of 8-methylnonanoic acid (example of cross-coupling method)
In an argon atmosphere, Mg cut pieces (6.12 g, 252 mmol) were suspended in THF (10 ml). 200 mg of isoamyl bromide (34.6 g, 229 mmol) was added at room temperature, and heat generation and foaming were confirmed. THF (50 ml) was added, and a THF (65 ml) solution of the entire remaining amount of isoamyl bromide was slowly added dropwise at room temperature over 1 hour, followed by further stirring for 2 hours. At this time, it was in a gentle reflux state. The reaction solution was washed with THF and filtered with a cotton plug to prepare a solution of isoamyl magnesium bromide in THF (total amount 180 ml).
Under an argon atmosphere, copper (I) chloride (426 mg, 4.30 mmol) was dissolved in NMP (55.2 ml, 575 mmol). The reaction vessel was cooled to 0 ° C. (ice bath), and a solution of 5-bromovaleric acid ethyl ester (30.0 g, 144 mmol) in THF (35 ml) was added dropwise over 10 minutes. Subsequently, the THF solution of isoamyl magnesium bromide prepared above was slowly added dropwise at 0 ° C. (ice bath) over 1.5 hours. After further stirring at the same temperature for 45 minutes, the reaction was carefully quenched with saturated aqueous ammonium chloride solution (200 ml) and extracted twice with heptane (200 ml). The combined heptane layers were washed with saturated aqueous ammonium chloride solution (100 ml), water (100 ml), saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a pale yellow An oily substance (30.8 g) was obtained. Of these, 29.6 g was distilled under reduced pressure (1.2 mmHg, 69-71 ° C.) to obtain 8-methylnonanoic acid ethyl ester (20.6 g, yield 74.7%) as a colorless transparent oily substance.
¹ H-NMR (CDCl ₃ , δ): 0.860 (d, 6H, J = 6.63Hz), 1.13-1.33 (m, 11H), 1.48-1.64 (m, 3H), 2.28 (t, 2H, J = 7.55 Hz), 4.12 (q, 2H, J = 7.13Hz).
¹³ C-NMR (CDCl ₃ , δ): 14.60, 22.98, 25.36, 27.56, 28.30, 29.54, 29.89, 34.75, 39.31, 60.47, 174.2
Among the obtained 8-methylnonanoic acid ethyl ester, 19.20 g was dissolved in ethanol (72.0 ml), and 2M NaOH aqueous solution (72.0 ml) was slowly added at 0 ° C. (ice bath). Subsequently, the mixture was heated and stirred for 1 hour using a 60 ° C. oil bath, the reaction vessel was returned to room temperature, and ethanol was distilled off under reduced pressure. 2M NaOH (30 ml), water (30 ml) and t-butyl methyl ether (100 ml) were added to carry out a liquid separation operation, and then t-butyl methyl ether (100 ml) was further added to the aqueous layer. The layers were separated. The aqueous layer was acidified by careful addition of 2M aqueous HCl (150 ml) and extracted twice with heptane (150 ml). The combined heptane layers were washed with water (100 ml), then saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 8-methylnonanoic acid (15.9 g, crude (96.6% yield) was obtained as a pale yellow oily crude product. GCMS analysis revealed unstructured impurities A (0.01%), B (0.03%), C (0.04%), D (0.07%), and the purity of 8-methylnonanoic acid was 99.6%.
¹ H-NMR (CDCl ₃ , δ): 0.862 (d, 6H, J = 6.64Hz), 1.14-1.17 (m, 2H), 1.26-1.35 (m, 6H), 1.48-1.65 (m, 3H), 2.35 (t, 2H, J = 7.52Hz).
¹³ C-NMR (CDCl ₃ , δ): 22.95, 25.04, 27.55, 28.12, 29.47, 29.88, 34.51, 39.31, 181.0.
GC-MS: M = 172.

[Example 2] Purification by cyclohexylamine salt formation of 8-methylnonanoic acid (Example of purification by fatty acid salt crystals)
Of the 8-methylnonanoic acid crude product obtained in Example 1, 8.00 g was dissolved in heptane (30 ml). Cyclohexylamine (6.91 ml, 60.4 mmol) was slowly added dropwise at 0 ° C. (ice bath), followed by stirring at room temperature for 20 minutes. The reaction solution was filtered to obtain 8-methylnonanoic acid cyclohexylamine salt (15.7 g).
¹ H-NMR (CDCl ₃ , δ): 0.81-0.85 (m, 6H), 1.11-1.20 (m, 3H), 1.24-1.35 (m, 10H), 1.46-1.68 (m, 4H), 1.73-1.81 (m, 2H), 1.96-2.02 (m, 2H), 2.15-2.19 (t, 2H), 2.77-2.88 (m, 1H).
Melting point: 70.1-70.6 ℃
Among these, 10% aqueous citric acid solution (50 ml) and heptane (50 ml) were added to 15.6 g of the salt for liquid separation operation. Further, the aqueous layer was extracted with heptane (50 ml), and the combined heptane layer was washed with 10% aqueous citric acid solution (50 ml), water (50 ml) and saturated brine (50 ml). The heptane layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 8-methylnonanoic acid (7.69 g) as a colorless transparent oily substance.
Among these, 7.18 g was distilled under reduced pressure (1.1 mmHg, 103 ° C.) to obtain 8-methylnonanoic acid distillate (6.80 g, 91.0% yield from 8-methylnonanoic acid crude product). When GCMS analysis was performed, the impurities A, B, C, and D were below the detection limit, and the purity of 8-methylnonanoic acid was 99.7%.

[Example 3] Resolution of trans form and cis form of 8-methyl-6-nonenoic acid with cis-2-aminocyclohexanol salt (example of purification method by fatty acid salt crystal formation)
8-Methyl-6-nonenoic acid (isomer ratio trans: cis = 88: 12, 800 mg, 4.70 mmol) obtained by a known method (J. Org. Chem. 1989, 54, 3477-3478) was mixed with chloroform. (10 ml), and a solution of cis-2-aminocyclohexanol (460 mg, 4.00 mmol) dissolved in chloroform (5 ml) was added dropwise at room temperature. The reaction solution was concentrated under reduced pressure, the residue was dissolved again in chloroform (4 ml), and hexane (12 ml) was added dropwise. The reaction solution was stirred at room temperature for 3 days, and the precipitated crystals were collected by filtration. Hexane (10 ml) was added to the obtained crystals, washed 3 times with 10% aqueous citric acid solution (8 ml) and once with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 8-methyl-6-nonenoic acid (isomer ratio trans: cis = 29: 1, 408 mg, 2.40 mmol).
The obtained 8-methyl-6-nonenoic acid was dissolved again in chloroform (10 ml), and a solution of cis-2-aminocyclohexanol (249 mg, 2.16 mmol) in chloroform (5 ml) was dissolved at room temperature. It was dripped. The reaction solution was concentrated under reduced pressure, the residue was dissolved again in chloroform (3 ml), and hexane (12 ml) was added dropwise. The reaction solution was stirred overnight at room temperature, and the precipitated crystals were collected by filtration. Hexane (15 ml) was added to the obtained crystals, washed 3 times with 10% aqueous citric acid solution (10 ml) and once with saturated brine (10 ml), and then dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain trans-8-methyl-6-nonenoic acid (250 mg, 1.47 mmol, purity 98.8%, yield 35.1%).
¹ H-NMR (CDCl ₃ , δ): 0.96 (d, 6H, J = 6.8Hz), 1.38-1.46 (m, 2H), 1.60-1.70 (m, 2H), 1.95-2.05 (m, 2H), 2.18-2.38 (m, 1H), 2.35 (t, 2H, J = 7.4Hz), 5.28-5.42 (m, 2H).

Example 4 Synthesis of 8-methylnonanoic acid vinyl ester (1)
8-Methylnonanoic acid (1.00 g; 5.80 mmol), vinyl acetate (4.0 ml; 43.4 mmol), potassium carbonate (160 mg; 1.15 mmol) and palladium acetate (39.0 mg; 0.173 mmol) were sequentially added at room temperature. Subsequently, the mixture was heated and stirred overnight (17 hours) using an oil bath at 50 ° C., and then returned to room temperature. Hexane (8 ml) was added at room temperature, the resulting precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a pale yellow oil. Purification by silica gel column chromatography (eluent of ether: hexane = 3: 97) gave 1.03 g (yield 89%) of 8-methylnonanoic acid vinyl ester.
¹ H-NMR (CDCl ₃ , δ): 0.86 (d, 6H, J = 6.64Hz), 1.15-1.35 (m, 8H), 1.48-1.55 (m, 1H), 1.61-1.69 (m, 2H), 2.37 (t, 2H, J = 7.52Hz), 4.47-4.59 (m, 1H), 4.82-4.92 (m, 1H), 7.21-7.36 (m, 1H)
¹³ C-NMR (CDCl ₃ , δ): 22.93, 24.94, 27.52, 28.28, 29.42, 29.83, 34.23, 39.28, 97.54, 141.57, 170.98

Example 5 Synthesis of 8-methylnonanoic acid vinyl ester (2)
To 8-methylnonanoic acid (7.30 g; 42.4 mmol), vinyl acetate (11.7 ml; 126 mmol), potassium carbonate (585 mg; 4.23 mmol) and palladium acetate (476 mg; 2.12 mmol) were added at room temperature, and 60 ° C. And stirred overnight using an oil bath (15 hours). Since the residual of the raw material was confirmed by TLC, potassium carbonate (292 mg; 2.11 mmol) and palladium acetate (190 mg; 0.84 mmol) were added, and the mixture was further heated and stirred at 60 ° C. for 4 hours. After returning to room temperature, hexane (10 ml) was added, and the resulting precipitate was filtered through Celite. The filtrate was concentrated under reduced pressure using an evaporator to obtain a brown oily substance. This was purified by distillation (2.9 mmHg; 60 ° C.) to give 8-methylnonanoic acid vinyl ester (5.11 g; 25.8 mmol; 61% yield) as a colorless transparent oil.

[Example 6] Synthesis of 8-methyl-6-nonenoic acid vinyl ester 8-methyl-6-nonenoic acid (1.00 g; 5.88 mmol), vinyl acetate (4.0 ml; 43.4 mmol), potassium carbonate (162 mg; 1.17 mmol) and palladium acetate (39.5 mg; 0.176 mmol) were added sequentially at room temperature. Subsequently, the mixture was heated and stirred overnight (17 hours) using an oil bath at 50 ° C., and then returned to room temperature. Hexane (8 ml) was added at room temperature, the resulting precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a pale yellow oil. Purification by silica gel column chromatography (eluent of ether: hexane = 3: 97) gave 1.01 g (yield 88%) of 8-methyl-6-nonenoic acid vinyl ester.
¹ H-NMR (CDCl ₃ , δ): 0.95 (d, 6H, J = 6.80Hz), 1.36-1.43 (m, 2H), 1.61-1.69 (m, 2H), 1.97-2.02 (m, 2H), 2.18-2.26 (m, 1H), 2.37 (t, 2H, J = 7.48Hz), 4.58 (d, 1H, J = 6.32Hz), 4.82-4.87 (m, 1H), 5.28-5.46 (m, 2H) , 7.20-7.36 (m, 1H)
¹³ C-NMR (CDCl ₃ , δ): 22.97, 24.19, 24.38, 29.31, 31.33, 32.40, 34.07, 97.59, 126.68, 138.51, 141.56, 170.90

[Example 7] Synthesis of capsiate To a solution of 8-methyl-6-nonenoic acid vinyl ester (450 mg) in acetone (4 ml), vanillyl alcohol (530 mg) and lipase PS “Amano” (287 mg) were added at room temperature. And stirred with heating in an oil bath at 50 ° C. After 4 hours, lipase PS “Amano” (353 mg) was additionally added, and after 3.5 hours, lipase PS “Amano” (287 mg) was added, followed by heating and stirring for 19 hours. 10 ml of hexane was added to the reaction solution at room temperature, the precipitated vanillyl alcohol and enzyme were filtered through Celite, and the filtrate was concentrated under reduced pressure. As a result of HPLC analysis of the obtained oily substance, the produced capsiate was as high as 92.2 area%. This was purified by silica gel column chromatography (eluent of ether: hexane = 15: 85) to obtain a mixture (609 mg) of capsiate and 8-methyl-6-nonenoic acid. As a result of the analysis, the yield of capsiate was 83%, and the purity by HPLC was 97.8% by area. The mixture contained 3.32% by weight of 8-methyl-6-nonenoic acid based on the capsiate.
¹ H-NMR (CDCl ₃ , δ): 0.95 (d, 6H, J = 6.74Hz), 1.33-1.40 (m, 2H), 1.59-1.67 (m, 2H), 1.94-1.99 (m, 2H), 2.18-2.23 (m, 1H), 2.33 (t, 2H, J = 7.52Hz), 3.89 (s, 3H), 5.02 (s, 2H), 5.26-5.39 (m, 2H), 5.63 (br, 1H) , 6.83-6.90 (m, 3H)

[Example 8] Synthesis of dihydrocapsiate (1)
Vanillyl alcohol (705 mg) and lipase PS “Amano” (113 mg) were added to a solution of 8-methylnonanoic acid vinyl ester (453 mg) in acetone (4 ml) at room temperature, and in an oil bath at 55 ° C. Stir with heating. After 13 hours, additional vanillyl alcohol (105 mg) was added, and after 3.5 hours, vanillyl alcohol (247 mg) was added and stirred with heating for 1 hour. 10 ml of hexane was added to the reaction solution at room temperature, the precipitated vanillyl alcohol and enzyme were filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained oily substance was analyzed by HPLC. As a result, the produced dihydrocapsiate was 89.0 area%. This was purified by silica gel column chromatography (eluent of ether: hexane = 15: 85) to obtain a mixture (649 mg) of dihydrocapsiate and 8-methylnonanoic acid. As a result of the analysis, the yield of dihydrocapsiate was 90%, and the purity by HPLC was 99.3 area%. The mixture contained 2.63% by weight of 8-methylnonanoic acid based on dihydrocapsiate.
¹ H-NMR (CDCl ₃ , δ): 0.86 (d, 6H, J = 6.60Hz), 1.12-1.37 (m, 8H), 1.46-1.64 (m, 3H), 2.32 (t, 2H, J = 7.56 Hz), 3.89 (s, 3H), 5.02 (s, 2H), 5.63 (br, 1H), 6.83-6.90 (m, 3H)

[Example 9] Synthesis of dihydrocapsiate (2)
Vanillyl alcohol (933 mg) and lipase PS-C “Amano” I (ceramic immobilized enzyme) (100 mg) were added to a solution of 8-methylnonanoic acid vinyl ester (400 mg) in acetone (4 ml) at room temperature. The mixture was heated and stirred in an oil bath at 55 ° C. After 14 hours, 15 ml of hexane was added to the reaction solution at room temperature, the precipitated vanillyl alcohol and enzyme were filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (eluent of ether: hexane = 15: 85) to obtain a mixture (583 mg) of dihydrocapsiate and 8-methylnonanoic acid. As a result of the analysis, the yield of dihydrocapsiate was 90%, and the purity by HPLC analysis was as high as 99.4 area%. The mixture contained 3.61% by weight of 8-methylnonanoic acid based on dihydrocapsiate.

[Example 10] Synthesis of dihydrocapsiate (3)
Vanillyl alcohol (933 mg) and lipase PS-C “Amano” II (ceramic immobilized enzyme) (100 mg) were added to a solution of 8-methylnonanoic acid vinyl ester (400 mg) in acetone (4 ml) at room temperature. The mixture was heated and stirred in an oil bath at 55 ° C. After 18 hours, 15 ml of hexane was added to the reaction solution at room temperature, the precipitated vanillyl alcohol and enzyme were filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (eluent of ether: hexane = 15: 85) to obtain a mixture (586 mg) of dihydrocapsiate and 8-methylnonanoic acid. As a result of the analysis, the yield of dihydrocapsiate was 91%, and the purity by HPLC was 99.6 area%. The mixture contained 3.11% by weight of 8-methylnonanoic acid based on dihydrocapsiate.

[Example 11] Synthesis of dihydrocapsiate (4)
To a solution of 8-methylnonanoic acid vinyl ester (402 mg) in acetone (4 ml), add vanillyl alcohol (938 mg) and lipase PS-D “Amano” I (diatomaceous earth immobilized enzyme) (100 mg) to room temperature. And heated and stirred in a 55 ° C. oil bath. After 21 hours, 15 ml of hexane was added to the reaction solution at room temperature and stirred for 40 minutes. The precipitated vanillyl alcohol and enzyme were filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (eluent of ether: hexane = 15: 85) to obtain dihydrocapsiate and 8 -A mixture of methylnonanoic acid (573 mg) was obtained. As a result of the analysis, the yield of dihydrocapsiate was 90%, and the purity by HPLC was 98.5 area%. The mixture contained 2.23% by weight of 8-methylnonanoic acid based on dihydrocapsiate.

[Example 12] Synthesis of dihydrocapsiate (5)
Vanillyl alcohol (936 mg) and lipase AK “Amano” (100 mg) were added to a solution of 8-methylnonanoic acid vinyl ester (401 mg) in acetone (4 ml) at room temperature, and in an oil bath at 55 ° C. Stir with heating. After 21 hours, 15 ml of hexane was added to the reaction solution at room temperature and stirred for 30 minutes. The precipitated vanillyl alcohol and enzyme were filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (eluent of ether: hexane = 15: 85) to obtain dihydrocapsiate and 8 -A mixture of methylnonanoic acid (599 mg) was obtained. As a result of the analysis, the yield of dihydrocapsiate was 94%, and the purity by HPLC analysis was as high as 99.7 area%. The mixture contained 1.96% by weight of 8-methylnonanoic acid based on dihydrocapsiate.

[Example 13] Synthesis of dihydrocapsiate (6)
Vanillyl alcohol (1.05 g) and lipase PS “Amano” (56.4 mg) were added to a solution of 8-methylnonanoic acid vinyl ester (451 mg) in acetone (4 ml) at room temperature, and in an oil bath at 55 ° C. Stir with heating. After 16.5 hours, 15 ml of hexane was added to the reaction solution at room temperature and stirred for 30 minutes. The precipitated vanillyl alcohol and enzyme were filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (eluent of ether: hexane = 15: 85) to obtain dihydrocapsiate (482 mg, yield 69%). The obtained dihydrocapsiate was analyzed by HPLC and found to be 99.6 area% and high purity.

[Example 14] Synthesis of dihydrocapsiate (7)
Vanillyl alcohol (816 mg) and Novozyme 435 (8.16 mg) were added to 8-methylnonanoic acid vinyl ester (1.00 g) at room temperature, and the mixture was heated and stirred in a 55 ° C. oil bath. After 18 hours, 5 ml of heptane was added to the reaction solution at room temperature, followed by stirring for 30 minutes. The precipitated vanillyl alcohol and enzyme were filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain an oily substance (1.57 g). Of these, 1.51 g was extracted as follows. Liquid separation operation was performed with heptane (15 ml) and 10% aqueous citric acid solution (15 ml), and the aqueous layer was further extracted with heptane (15 ml). The combined heptane layers were washed with water (15 ml) followed by saturated brine (15 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1.49 g of a mixture of dihydrocapsiate and 8-methylnonanoic acid as an oil. As a result of analysis, the yield of dihydrocapsiate was 99.3%, and analysis by HPLC was 96.8 area%. The mixture contained 0.397% by weight of 8-methylnonanoic acid based on dihydrocapsiate.

[Example 15] Synthesis of vanillyl decanoate To decanoic acid vinyl ester (1.00 g), vanillyl alcohol (816 mg) and Novozyme 435 (20.4 mg) were added at room temperature, and in an oil bath at 55 ° C. Stir with heating. After 18 hours, 5 ml of heptane was added to the reaction solution at room temperature, followed by stirring for 30 minutes. The precipitated vanillyl alcohol and enzyme were filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain an oily substance (1.49 g). Of these, 1.44 g was extracted as follows. Liquid separation operation was performed with heptane (15 ml) and 10% aqueous citric acid solution (15 ml), and the aqueous layer was further extracted with heptane (15 ml). The combined heptane layers were washed with water (15 ml) followed by saturated brine (15 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1.43 g of a mixture of vanillyl decanoate and decanoic acid as an oil. As a result of the analysis, the yield of vanillyl decanoate was 94.0%, and the analysis by HPLC was 96.7 area%. The mixture contained 1.29% by weight of decanoic acid relative to vanillyl decanoate.
¹ H-NMR (CDCl ₃ , δ): 0.87 (t, 3H, J = 7.1Hz), 1.18-1.30 (m, 12H), 1.55-1.65 (m, 2H), 2.33 (t, 2H, J = 7.7 Hz), 3.90 (s, 3H), 5.03 (s, 2H), 5.64 (br, 1H), 6.80-6.90 (m, 3H)
¹³ C-NMR (CDCl ₃ , δ): 14.49, 23.05, 25.37, 29.52, 29.65, 29.65, 29.81, 32.25, 34.78, 56.27, 66.70, 111.70, 114.80, 122.38, 128.38, 146.18, 146.92, 174.26

[Reference Example 1] Stability of capsinoid in the absence of fatty acid An ester of vanillyl alcohol and decanoic acid (vanillyl decanoate) was separately synthesized and the stability was examined. A pure product of vanillyl decanoate purified by separating and removing decanoic acid by silica gel column chromatography was dissolved in acetonitrile and subjected to HPLC analysis. The purity was 95.6 area%. Furthermore, when the sample was analyzed again after 62 hours, the purity decreased to 82.0 area%, and it was confirmed that vanillyl decanoate was decomposed.

[Example 16] Stabilization by fatty acid coexistence (1)
Pure vanillyl decanoate purified by separating and removing decanoic acid by silica gel column chromatography was dissolved in acetonitrile and analyzed by HPLC after 9 hours. As a result, it was 90.4 area%. On the other hand, when 9.1 wt% decanoic acid was added to this pure vanillyl decanoate acetonitrile solution and HPLC analysis was performed 19.5 hours later, the purity improved to 97.6 area%. Similarly, when 16.7 wt%, 28.7 wt%, and 44.8 wt% decanoic acid were added to vanillyl decanoate, 98.1 area%, 98.1 area%, and 97.9 area%, respectively, were higher than when no decanoic acid was added.

[Example 17] Example of stabilization by fatty acid coexistence (2)
When the capsiate synthesized by the method of Example 7 and purified with 3.2% by weight of fatty acid was subjected to HPLC analysis, it was as high as 97.8 area%. When this capsiate was stored in hexane solvent at 5 ° C. for 30 days and then subjected to HPLC analysis, it was maintained at a high purity of 97.6 area%.

[Example 18] Example of stabilization by fatty acid coexistence (3)
When HPLC analysis was performed on dihydrocapsiate synthesized by the same method as in Example 8 and purified with 2.0% by weight of fatty acid, it was 99.2% by area and high purity. When this dihydrocapsiate was stored in a hexane solvent at 5 ° C. for 30 days and then subjected to HPLC analysis, it was maintained at a high purity of 99.3 area%.

  The production method of the present invention is useful in that it is easy to operate using an inexpensive enzyme and can produce capsinoids in a high yield and high purity in a shorter time than existing techniques. Furthermore, by allowing an ester compound (capsinoid) to coexist with a fatty acid, it has become possible to stably supply and store capsinoids that have been unstable in the past. Therefore, the composition of the ester compound and fatty acid of the present invention can be used for food additives and pharmaceuticals. Furthermore, 8-methylnonanoic acid vinyl ester and 8-methyl-6-nonenoic acid vinyl ester are novel substances and can be used very advantageously in the production method of the present invention.

Claims (19)

General formula (1)

(In the formula, R 1 represents an alkyl group having 5 to 25 carbon atoms or an alkenyl group having 5 to 25 carbon atoms, and may have a substituent.)
A vinyl ester represented by the general formula (2)

(Wherein R2 to R6 each independently represent hydrogen, a hydroxyl group, an alkyl group having 1 to 25 carbon atoms, an alkenyl group having 2 to 25 carbon atoms, an alkynyl group having 2 to 25 carbon atoms, or an alkyl group having 1 to 25 carbon atoms. An alkoxy group, an alkenyloxy group having 2 to 25 carbon atoms, or an alkynyloxy group having 2 to 25 carbon atoms, at least one of which is a hydroxyl group.)
And a hydroxymethylphenol represented by the general formula (3), characterized in that it is condensed in the presence of an enzyme.

(In the formula, R1 to R6 have the same meanings as described above.)
The manufacturing method of the ester compound represented by these.   The process according to claim 1, wherein the hydroxymethylphenol represented by the general formula (2) is vanillyl alcohol. Before or after the condensation of the vinyl ester represented by the general formula (1) and the hydroxymethylphenol represented by the general formula (2), the general formula (4)

(Wherein R1 ′ represents an alkyl group having 5 to 25 carbon atoms or an alkenyl group having 5 to 25 carbon atoms, and may have a substituent.)
The manufacturing method of Claim 1 or 2 which adds the fatty acid represented by these.   After the condensation, the obtained ester compound represented by the general formula (3) and purification obtained by fractionating the fatty acid corresponding to the vinyl ester represented by the general formula (1) by-produced during the condensation at the same time The manufacturing method of Claim 1 or 2 which further includes a process.   4. The method according to claim 3, further comprising a purification step of fractionating the ester compound represented by the general formula (3) and the fatty acid represented by the general formula (4) obtained after the condensation. Production method.   R1 is hexyl, 5-methylhexyl, trans-5-methyl-3-hexenyl, heptyl, 6-methylheptyl, 5-methylheptyl, trans-6-methyl-4-heptenyl, octyl Group, 7-methyloctyl group, trans-7-methyl-5-octenyl group, nonyl group, 8-methylnonyl group, 7-methylnonyl group, trans-8-methyl-6-nonenyl group, trans-8-methyl-5 -Nonenyl group, trans-7-methyl-5-nonenyl group, decyl group, 9-methyldecyl group, trans-9-methyl-7-decenyl group, trans-9-methyl-6-decenyl group, undecyl group and dodecyl group The production method according to claim 1, which is a group selected from the group consisting of:   The production method according to claim 1, wherein the enzyme is lipase.   Condensation is carried out in one or more solvents selected from the group consisting of acetone, 4-methyl-2-pentanone, 2-butanone, dimethoxyethane, tetrahydrofuran, toluene, pentane, hexane, heptane, or without solvent. The manufacturing method in any one of Claim 1 thru | or 7.   The production method according to any one of claims 1 to 8, wherein the condensation is carried out at 15 to 90 ° C. The vinyl ester represented by the general formula (1) is represented by the general formula (11).

(Wherein R1 is as defined above, and Rc represents a methyl group, an ethyl group, an isopropyl group, a t-butyl group, an allyl group, or a benzyl group.)
The ester compound represented by general formula (12) obtained by hydrolyzing and reacting with a base to form a salt crystal

(Wherein R1 has the same meaning as above).
The manufacturing method in any one of Claims 1 thru | or 9 which is obtained by vinyl-esterifying the fatty acid represented by these. The ester compound represented by the general formula (11) is represented by the general formula (8).

(In the formula, Ra represents an optionally substituted alkyl group having 1 to 24 carbon atoms or an optionally substituted alkenyl group having 2 to 24 carbon atoms, and X represents a halogen atom. Show.)
The compound represented by general formula (9)

(In the formula, Ra and X are as defined above.)
The Grineer reagent represented by the general formula (9) is converted into the Grineer reagent represented by the general formula (10).

(In the formula, Rb represents an alkyl group having 1 to 24 carbon atoms which may have a substituent or an alkenyl group having 2 to 24 carbon atoms which may have a substituent, provided that the carbon of Rb Regarding the number, the sum of the carbon number of Ra and Rb is 5 to 25, Rc is as defined above, and Y represents a halogen atom, a methanesulfonyloxy group, a paratoluenesulfonyloxy group or a trifluoromethanesulfonyloxy group. )
The manufacturing method of Claim 10 obtained by attaching | subjecting to a cross-coupling reaction with the compound represented by these. The vinyl ester represented by the general formula (1) is represented by the general formula (13).

(In the formula, Rd and Re each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, m is 0 or 1, and n is an integer of 1 to 5.)
By reacting the mixture with a base to form a salt from the mixture of the fatty acid represented by formula (1) and its cis isomer, and purifying based on the difference in crystallinity or solubility of the formed salt. The production method according to any one of claims 1 to 9, wherein the fatty acid represented by formula (13) is obtained by vinyl esterification of the fatty acid represented by the general formula (13). General formula (5)

8-methylnonanoic acid vinyl ester represented by General formula (6)

Trans-8-methyl-6-nonenoic acid vinyl ester represented by General formula (3)

(In the formula, R 1 represents an alkyl group having 5 to 25 carbon atoms or an alkenyl group having 5 to 25 carbon atoms, and may have a substituent, and R 2 to R 6 are each represented by hydrogen, hydroxyl group, carbon number 1 to 25 alkyl groups, alkenyl groups having 2 to 25 carbon atoms, alkynyl groups having 2 to 25 carbon atoms, alkoxy groups having 1 to 25 carbon atoms, alkenyloxy groups having 2 to 25 carbon atoms, or alkynyloxy having 2 to 25 carbon atoms A group, at least one of which is a hydroxyl group.)
An ester compound represented by the general formula (7)

(Wherein R1 ″ represents an alkyl group having 5 to 25 carbon atoms or an alkenyl group having 5 to 25 carbon atoms, and may have a substituent.)
A composition comprising a fatty acid represented by the formula (excluding an oil or fat extract from a plant).   The composition according to claim 15, wherein the fatty acid represented by the general formula (7) is contained in an amount of 0.1 to 30% by weight with respect to the ester compound represented by the general formula (3).   The composition according to claim 15 or 16, further comprising one or more additives selected from the group consisting of an oil and fat composition, an emulsifier, a preservative, and an antioxidant as an extender or carrier. General formula (3)

(In the formula, R 1 represents an alkyl group having 5 to 25 carbon atoms or an alkenyl group having 5 to 25 carbon atoms, and may have a substituent, and R 2 to R 6 are each represented by hydrogen, hydroxyl group, carbon number 1 to 25 alkyl groups, alkenyl groups having 2 to 25 carbon atoms, alkynyl groups having 2 to 25 carbon atoms, alkoxy groups having 1 to 25 carbon atoms, alkenyloxy groups having 2 to 25 carbon atoms, or alkynyloxy having 2 to 25 carbon atoms A group, at least one of which is a hydroxyl group.)
In the ester compound represented by general formula (4)

(Wherein R1 ′ represents an alkyl group having 5 to 25 carbon atoms or an alkenyl group having 5 to 25 carbon atoms, and may have a substituent.)
A method for stabilizing an ester compound represented by the general formula (3), wherein the fatty acid represented by general formula (3) is added to maintain or improve the purity of the ester compound represented by the general formula (3).   The stabilization method according to claim 18, wherein the fatty acid represented by the general formula (4) is added in an amount of 0.1 to 30% by weight with respect to the ester compound represented by the general formula (3).