JP2000072761A - Preparation of optically active glycidic acid ester compounds - Google Patents

Abstract

(57) [Summary] (with correction) [Problem] To produce an optically active glycidic acid ester compound with high yield, high optical purity and high selectivity, and to reuse a chiral ketone compound used in the production. To provide a manufacturing method excellent in efficiency and economy. An asymmetric oxidizing agent is allowed to act on a cinnamic acid ester compound (I) to obtain an optically active glycidic acid ester compound (I).
Ia) and an optically active glycidic acid ester compound (IIb), and after obtaining only the ester compound (IIa), the alcohol compound in the presence of an enzyme that stereoselectively transesterifies the ester compound (IIb) to the residue The ester compound (IIb) is transesterified to the ester compound (IIb ¹ ) to obtain only the ester compound (IIa) by crystallization, or, after transesterification, a chiral ketone before transesterification. If the compound is not removed, remove the compound and crystallize the ester compound (IIa) alone to obtain the compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an optically active glycidic acid ester compound. For more information,
A method for producing an optically active glycidic acid ester compound by combining asymmetric oxidation and enzymatic transesterification, and a 1,5-benzothiazepine derivative or a pharmacologically acceptable derivative thereof from the optically active glycidic acid ester compound obtained by the method The present invention relates to a method for producing a salt.

[0002]

2. Description of the Related Art 1,5-Benzothiazepine derivatives are useful compounds for cardiovascular diseases such as angina pectoris, myocardial infarction and arrhythmia, hypertension, coronary vascular infarction and cerebral infarction. is there. In particular, diltiazem hydrochloride [chemical name: (2
S, 3S) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2- (4-methoxyphenyl) -2,
3-dihydro-1,5-benzothiazepine-4 (5H)
-One hydrochloride] is widely used for the treatment of angina pectoris and essential hypertension.

In recent years, various methods have been proposed as methods for producing optically active glycidic acid derivatives useful as intermediates of the 1,5-benzothiazepine derivatives. The main production methods of the glycidic acid derivative include (A) a method by an asymmetric hydrolysis method (Japanese Patent Publication No. 4-501360, Japanese Patent Publication No. 6-78, Japanese Patent Publication No. 7-12231), and (B) Asymmetric transesterification method (JP-A-4-228095, JP-A-5-76389, JP-A-6-78790), (C) a method by a chemical optical resolution method (JP-A-60-13776) JP-A No. 4-28268, JP-A-2-231480), (D) Asymmetric amidation method (WO 95/07359 pamphlet), and the like.

However, in any of the above methods (A) to (D), since a racemic trans-glycidic acid derivative is used as a raw material, the yield of the desired optical isomer is low. There is a disadvantage that it is 50% or less.

Japanese Patent Application Laid-Open No. Sho 59-196881 discloses that trans-3- (4-acetoxyphenyl) cinnamyl alcohol is prepared by using tetraisopropoxytitanium and L
-Oxidation with m-chloroperbenzoic acid in the presence of diethyl tartrate to produce (2S, 3S) -3- (4-acetoxyphenyl) glycidyl alcohol, oxidation with ruthenium dioxide-sodium metaperiodate, A method for obtaining methyl ester of (2R, 3S) -3- (4-acetoxyphenyl) glycidic acid as a methyl ester with dimethyl sulfate has been proposed. However, according to such a method, the reaction steps are very complicated and the yield is not so high.

In recent years, various oxidation reactions using dioxirane compounds have been studied [Chemical Reviews 89, 1187].
1201 (1989)]. For example, the journal
Of Organic Chemistry (J. Org. Ch.)
em. Vol. 50, pages 2847-2853 (1985), added dimethyldioxirane having no chirality to trans-cinnamic acid ethyl ester,
It is reported that epoxidation is caused by reacting for 2 hours.

However, dimethyldioxirane does not have chirality and has a drawback that a phenyloxirane compound having optical activity which is the object of the present invention cannot be obtained.

[0008] Also, Journal of American Chemical Society (J. Am. Chem. So
c. 118, 11311-11132 (1996)
Year) has the formula:

[0009]

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Oxone [manufactured by Du Pont, trade name, composition formula: 2
[KHSO ₅ · KHSO ₄ · K ₂ SO ₄ ], a simple C compound is obtained by using a chiral dioxirane compound obtained by oxidation.
It has been reported that asymmetric epoxidation of trans-stilbene, which is a symmetric compound and has two electron-donating phenyl groups bonded to a double bond, is performed.

However, there is no description or suggestion in the above-mentioned literature regarding the method for producing the optically active glycidic acid ester compound which is the object of the present invention.

[0012]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above prior art, and is intended to convert a cinnamate compound which is a complex compound having no symmetry element and a chiral ketone compound and an oxidizing agent. Asymmetric oxidation (asymmetric epoxidation) using an asymmetric oxidizing agent (for example, a chiral dioxirane compound) generated from, and subjecting the resulting reaction product to an enzymatic transesterification reaction to obtain the desired optical Active glycidic acid ester compounds can be obtained with high yield, high optical purity, and high selectivity, and the chiral ketone compound, which is the raw material of the asymmetric oxidizing agent used in the production, can be reused. It is an object of the present invention to provide a production method which is excellent in productivity and economy.

[0013]

That is, the gist of the present invention is as follows: (1) (A) General formula (I):

[0014]

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(Wherein, ring A represents a substituted or unsubstituted benzene ring, and R represents an ester residue), a cinnamate compound (I) represented by the formula: The main product is a general formula (IIa):

[0016]

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(Wherein rings A and R are the same as above, * indicates an asymmetric carbon atom) and an optically active glycidic acid ester compound (IIa) represented by the general formula (IIb) ):

[0018]

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(Wherein rings A and R are as defined above. **
Represents an asymmetric carbon atom having an absolute configuration opposite to that of the corresponding asymmetric carbon atom of the optically active glycidic acid ester compound (IIa)). And (B
-1) After removing the chiral ketone compound from the reaction mixture and crystallizing only the optically active glycidic acid ester compound (IIa) contained in excess, the optically active glycidic acid contained in the residue is obtained. Acid ester compound (II
In the presence of an enzyme capable of stereoselectively transesterifying an optically active glycidic acid ester compound (IIb) to a mixture of a) and (IIb), a compound of the general formula (III):

[0020]

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(Wherein R ¹ represents a group corresponding to an ester residue different from R), and an optically active glycidic acid ester compound (IIb) is converted to a compound represented by the general formula (IIb ¹ ):

[0022]

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(Wherein rings A, R ¹ and ** are the same as described above) and transesterified to an ester compound (IIb ¹ ) represented by the following formula: From the resulting mixture, crystallize only the optically active glycidic acid ester compound (IIa) Or (B-2) having the ability to stereoselectively transesterify an optically active glycidic acid ester compound (IIb) after removing a chiral ketone compound as required from the reaction mixture. When an alcohol compound (III) is allowed to act in the presence of an enzyme to transesterify the optically active glycidic acid ester compound (IIb) to the ester compound (IIb ¹ ), and the chiral ketone compound is not removed before the transesterification. Is characterized by removing the chiral ketone compound and crystallizing only the optically active glycidic acid ester compound (IIa) from the resulting mixture to obtain Preparation of sexual glycidic acid ester compound (IIa),

(2) After removing the chiral ketone compound from the reaction mixture as necessary, the alcohol compound is removed in the presence of an enzyme capable of stereoselectively transesterifying the optically active glycidic acid ester compound (IIb). (III)
To form an optically active glycidic acid ester compound (II
b) is transesterified to an ester compound (IIb ¹ ) .If the chiral ketone compound was not removed before transesterification, the chiral ketone compound was removed, and the optically active glycidic acid ester compound (IIa ) Is obtained only by crystallization.

(3) After the chiral ketone compound is removed from the reaction mixture, only the optically active glycidic acid ester compound (IIa) contained in excess is crystallized to obtain the optically active glycidic acid ester compound (IIa). A mixture of active glycidic acid ester compounds (IIa) and (IIb) is reacted with an alcohol compound (III) in the presence of an enzyme capable of stereoselectively transesterifying the optically active glycidic acid ester compound (IIb). Transesterifying the optically active glycidic acid ester compound (IIb) into an ester compound (IIb ¹ ),
The process according to the above (1), wherein only the optically active glycidic acid ester compound (IIa) is crystallized and obtained from the resulting mixture,

(4) After transesterification, the optically active glycidic acid ester compound (IIa) is crystallized, and the optically active glycidic acid ester compound (IIa) is crystallized, but the ester compound (IIb ¹ ) is dissolved. The method according to any one of the above (1) to (3), wherein

(5) If the ester compound (IIb ¹ ) does not exist, the optically active glycidic acid ester compound (IIb) precipitates from the mixture formed by the transesterification.
Due to the presence of the ester compound (IIb ¹ ), the optically active glycidic acid ester compound (IIa) crystallizes, but the optically active glycidic acid ester compound (IIb) does not precipitate until the optically active glycidic acid ester compound ( IIa)
The method according to any one of the above (1) to (4), wherein

(6) The chiral ketone compound has the general formula (IV):

[0029]

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[In the formula, ring Ar may have a substituent, 1-3 cyclic aromatic ring, and Y is a general formula: (i) -OQ-Alk ^1- , (ii)- ^{Q-O-Alk 2 -,} (iii) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi) -Q- NR ² -Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ² is a hydrogen atom ,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group.] The above (1) to (5) which are optical isomers of the ketone compound (IV)
Any of the manufacturing methods,

(7) The asymmetric oxidizing agent has the general formula (V):

[0032]

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[Wherein, ring Ar is an optionally substituted 1-3-cyclic aromatic ring, Y is a general formula: (i) -OQ-Alk ^1- , (ii) -Q ^{-O-Alk 2 -, (iii} ) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi) -Q-NR ^2- Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], the production method according to the above (1), which is an optical isomer of the dioxirane compound (V)

(8) The chiral ketone compound has the general formula (VI):

[0035]

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Wherein R ^a and R ^b are hydrogen atoms or substituents, and R ^c and R ^d are groups satisfying the following conditions: (I) R ^c and R ^d are each a hydrogen atom or a substituent Or (II) R ^c and R ^d are bonded to each other to form a general formula:

[0037]

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Wherein R ^e , R ^f , R ^g and R ^h are
Indicates one of the following: (A) two adjacent groups are bonded to each other, form a benzene ring which may have a substituent together with two carbon atoms between them, and whether the other two groups are a hydrogen atom or a substituent. Or (b) each of which is a hydrogen atom or a substituent), or
(III) R ^c and R ^d are bonded to each other to form a general formula:

[0039]

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Wherein R ⁱ , R ^j , R ^k and R ^m each represent a hydrogen atom or a substituent, and Y represents a general formula: (i) —O—Q—Alk ^{1 -, (ii) -Q-} O-Alk 2 -, (iii) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 - (Vi) -Q-NR ² -Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], the production method according to the above (1), which is an optical isomer of the ketone compound (VI)

(9) The asymmetric oxidizing agent has the general formula (VII):

[0042]

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Wherein R ^a and R ^b are each a hydrogen atom or a substituent, and R ^c and R ^d are groups satisfying the following conditions: (I) R ^c and R ^d are each a hydrogen atom or a substituent Or (II) R ^c and R ^d are bonded to each other to form a general formula:

[0044]

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(Where R ^e , R ^f , R ^g and R ^h are
Indicates one of the following: (A) two adjacent groups are bonded to each other, form a benzene ring which may have a substituent together with two carbon atoms between them, and whether the other two groups are a hydrogen atom or a substituent. Or (b) each of which is a hydrogen atom or a substituent), or (III) R ^c and R ^d are bonded to each other to form a general formula:

[0046]

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Wherein R ⁱ , R ^j , R ^k and R ^m each represent a hydrogen atom or a substituent, and Y is a general formula: (i) —O—Q—Alk ^{1 -, (ii) -Q-} O-Alk 2 -, (iii) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 - (Vi) -Q-NR ² -Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], wherein the dioxirane compound (VII) is an optical isomer of (7),

(10) In the chiral ketone compound (VI) represented by the general formula (VI), Y is -CO-O-CH ₂
A group, R ^{a to} R ^d are (a) R ^a and R ^b are a hydrogen atom,
R ^c and R ^d combine with each other

[0049]

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Whether R is^cIs a hydrogen atom, R^d
Is a halogen atom, or R ^cIs a hydrogen atom, R
^dIs a nitro group, or (b) R^aIs a halogen field
Child, R^bIs a hydrogen atom, R^cAnd R^dJoined to each other
hand

[0051]

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The manufacturing method according to the above (8), wherein

(11) In the chiral ketone compound (VI) represented by the general formula (VI), R ^a and R ^b are bonded to a hydrogen atom and R ^c and R ^d are bonded to each other.

[0054]

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The production method according to the above (10), wherein

(12) The reaction between the chiral ketone compound and the oxidizing agent and the reaction of the resulting asymmetric oxidizing agent on the cinnamate compound (I) in the same reaction system as described in (1) to (1). (6), (8), (10) and (11)
The manufacturing method according to any of

(13) Cinnamic acid ester compound (I)
Is a trans form, the optically active glycidic acid ester compound (IIa) is the (2R, 3S) -isomer, and the optically active glycidic acid ester compound (IIb) is (2S, 3
R) -isomer or the optically active glycidic acid ester compound (IIa) is a (2S, 3R) -isomer,
And the optically active glycidic acid ester compound (IIb) is (2
R, 3S) -isomer, the process according to any one of the above (1) to (12),

(14) Cinnamic acid ester compound (I)
Is a trans form, and the chiral ketone compound has the general formula
(VI-a):

[0059]

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Wherein R ^a and R ^b are each a hydrogen atom or a substituent, and R ^c and R ^d are groups satisfying the following conditions: (I) R ^c and R ^d are each a hydrogen atom or a substituent Or (II) R ^c and R ^d are bonded to each other to form a general formula:

[0061]

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Where R ^e , R ^f , R ^g and R ^h are
Indicates one of the following: (A) two adjacent groups are bonded to each other, form a benzene ring which may have a substituent together with two carbon atoms between them, and whether the other two groups are a hydrogen atom or a substituent. Or (b) each of which is a hydrogen atom or a substituent), or (III) R ^c and R ^d are bonded to each other to form a general formula:

[0063]

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Wherein R ⁱ , R ^j , R ^k and R ^m each represent a hydrogen atom or a substituent, and Y represents a general formula: (i) —O—Q—Alk ^{1 -, (ii) -Q-} O-Alk 2 -, (iii) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 - (Vi) -Q-NR ² -Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], wherein the optically active glycidic acid ester compound (IIa) is an (2R, 3S) -isomer and the optically active glycidic acid ester compound (IIb) is (2
The process according to the above (13), which is an (S, 3R) -isomer,

(15) The enzyme having the ability to perform stereoselective transesterification, wherein the E value for transesterification at a conversion of 10% is 20 or more.
(14) The production method according to any of the above,

(16) The method according to the above (15), wherein the enzyme capable of stereoselectively transesterifying is an esterase derived from a microorganism of the genus Serratia.

(17) An enzyme capable of stereoselectively transesterifying is Serratia marcescens (Serr
atia marucescens) The process according to the above (16), which is an esterase derived from a microorganism,

(18) The transesterification of 70% or more of the optically active glycidic acid ester compound (IIb) to give an ester compound (IIb ¹ ) having high solubility in a solvent. Manufacturing method,

(19) In the cinnamate compound (I) represented by the general formula (I), the ring A is a 4-lower alkoxyphenyl group, R is a methyl group or an ethyl group, and R ^{1 of} the ester compound (IIb ¹ ) may have a halogen atom,
A straight-chain or branched-chain alkyl group having more carbon atoms than R; a straight-chain or branched-chain alkoxyalkyl group having more carbon atoms than R which may have a halogen atom; The method according to any one of the above (1) to (18), which is a branched alkyl group, a linear or branched alkoxy group, or an arylalkyl group optionally having a halogen atom.

(20) The above (19) wherein ring A is a 4-methoxyphenyl group, R is a methyl group, and R ^{1 of} the ester compound (IIb ¹ ) formed by transesterification is an n-butyl group. Manufacturing method,

(21) The optically active glycidic acid ester compound (IIa) obtained in any one of the above (1) to (20)
Using the general formula (VIII):

[0072]

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Wherein ring B is a substituted or unsubstituted benzene ring, R ³ is a hydrogen atom or a substituted alkyl group, R ⁴ is a lower alkanoyl group, and rings A and * are as defined above. 1, producing a 5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof.
Method for producing 5-benzothiazepine derivative or pharmaceutically acceptable salt thereof, and

(22) The optically active glycidic acid ester compound (IIa) obtained in any one of the above (1) to (20)
Using the general formula:

[0075]

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(Wherein ring A and ring B are substituted or unsubstituted benzene rings, and * is an asymmetric carbon atom) or a salt thereof. The present invention relates to a method for producing a nitrocarboxylic acid compound or a salt thereof.

[0077]

According to the production method of the present invention, (A) the general formula (I):

[0078]

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(Wherein ring A represents a substituted or unsubstituted benzene ring, and R represents an ester residue), the cinnamate compound (I) represented by the formula The main product is a general formula (IIa):

[0080]

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(Wherein, rings A and R are the same as above, and * indicates an asymmetric carbon atom) and an optically active glycidic acid ester compound (IIa) represented by the general formula (IIb) ):

[0082]

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(Wherein rings A and R are as defined above. **
Represents an asymmetric carbon atom having an absolute configuration opposite to that of the corresponding asymmetric carbon atom of the optically active glycidic acid ester compound (IIa)). And (B
-1) After removing the chiral ketone compound from the reaction mixture and crystallizing only the optically active glycidic acid ester compound (IIa) contained in excess, the optically active glycidic acid contained in the residue is obtained. Acid ester compound (II
In the presence of an enzyme capable of stereoselectively transesterifying an optically active glycidic acid ester compound (IIb) to a mixture of a) and (IIb), a compound of the general formula (III):

[0084]

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(Wherein R ¹ represents a group corresponding to an ester residue different from R), and an optically active glycidic acid ester compound (IIb) is converted to a compound represented by the general formula (IIb ¹ ):

[0086]

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(Wherein rings A, R ¹ and ** are the same as described above), and transesterified to an ester compound (IIb ¹ ) represented by the following formula, and crystallized only the optically active glycidic acid ester compound (IIa) from the resulting mixture. Or (B-2) having the ability to stereoselectively transesterify an optically active glycidic acid ester compound (IIb) after removing a chiral ketone compound as required from the reaction mixture. When an alcohol compound (III) is allowed to act in the presence of an enzyme to transesterify the optically active glycidic acid ester compound (IIb) to the ester compound (IIb ¹ ), and the chiral ketone compound is not removed before the transesterification. In this case, the chiral ketone compound is removed, and only the optically active glycidic acid ester compound (IIa) is crystallized from the resulting mixture. Acid ester compound (I
Ia) can be obtained.

In the process of the present invention, the starting material of the step (A) is represented by the general formula (I):

[0089]

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(Wherein ring A represents a substituted or unsubstituted benzene ring, and R represents an ester residue).

In the cinnamate compound (I) represented by the general formula (I), the ring A is a substituted or unsubstituted benzene ring as described above. Specifically, the ring A includes a phenyl group, a phenyl group having 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a halogen atom. Examples of the lower alkyl group include an alkyl group having 1 to 4 carbon atoms represented by a methyl group, an ethyl group, a propyl group and a t-butyl group. Examples of the lower alkoxy group include an alkoxy group having 1 to 4 carbon atoms represented by a methoxy group, an ethoxy group, a propoxy group and a butoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among the rings A, a phenyl group having 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a halogen atom is preferable, and a 4-lower alkylphenyl group and a 4-lower alkoxyphenyl group are preferable. More preferably, 4-
A methylphenyl group and a 4-methoxyphenyl group are more preferred, and a 4-methoxyphenyl group is particularly preferred.

As R, any conventional ester residue can be used.

Specific examples of R include those having 1 to carbon atoms represented by methyl, ethyl, propyl, butyl and the like.
4 lower alkyl group, cyclopentyl group, 6 carbon atoms represented by cycloalkyl group having 3 to 7 carbon atoms represented by cyclohexyl group, phenyl group, naphthyl group and the like.
And 10 to 10 aryl groups. These lower alkyl group, cycloalkyl group and aryl group may have a substituent. Examples of the substituent for the lower alkyl group and the cycloalkyl group include a substituted or unsubstituted phenyl group, a halogen atom, a lower alkoxy group having 1 to 4 carbon atoms,
C1-C5 lower alkanoyloxy group, C4-C4
8 cycloalkylcarbonyloxy groups, having 7 to 1 carbon atoms
Examples of the arylcarbonyloxy group include a lower alkyl group having 1 to 4 carbon atoms, a halogen atom, and a lower alkoxy group having 1 to 4 carbon atoms. Among these R, a lower alkyl group is preferable, a methyl group and an ethyl group are more preferable, and a methyl group is particularly preferable.

Regarding the geometric isomer of the cinnamate compound (I) represented by the general formula (I), -CHＣＨCH-
Positional relationship between the ring A and the -CO ₂ R which is bonded to the group may be any of cis and trans.

In the cinnamate compound (I), in the general formula (I), the ring A is a methoxyphenyl group or a methylphenyl group, R is a methoxycarbonyl group, and the ring A and —CO ₂ Cinnamic acid ester compound (I) in which R is bonded to trans, in particular, trans-4-methoxycinnamic acid methyl ester can be suitably used.

The asymmetric oxidizing agent formed from the chiral ketone compound and the oxidizing agent can be obtained by causing the oxidizing agent to act on the chiral ketone compound. Or a mixture of a plurality of asymmetric oxidants. Specific examples of such an asymmetric oxidizing agent include a chiral dioxirane compound, but are not limited thereto, and may be a mixture containing a chiral dioxirane compound.

Examples of the chiral ketone compound used for producing the asymmetric oxidizing agent include compounds in which one or more hydroxyl groups of a monosaccharide or polysaccharide are converted to oxo groups and the remaining hydroxyl groups are protected (for example, 1 , 2: 4,5-di (O-isopropylidene) -D-erythro-2,3-hexodiuro-2,6-pyranose [tetrahedron (Tetrahedro)
n) Vol. 47, p. 2133 (1991)]), and non-natural chiral ketone compounds such as ketone compounds having a chiral biaryl skeleton and natural materials.

Representative examples of the chiral ketone compound include, for example, those represented by the following general formula (IV):

[0099]

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[In the formula, ring Ar is a 1-3-cyclic aromatic ring which may have a substituent, Y is a general formula: (i) -OQ-Alk ^1- , (ii) -Q ^{-O-Alk 2 -, (iii} ) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi) -Q-NR ^2- Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], which is an optical isomer of the ketone compound (IV).

In the ketone compound (IV), the ring Ar
Is a 1-3 cyclic aromatic ring which may have a substituent. Examples of such a 1-3-ring aromatic ring include a benzene ring, a naphthalene ring, a naphthoquinone ring, an anthracene ring, an anthraquinone ring, a phenanthrene ring, and the like. The substitution position of Y bonded to the aromatic ring is not particularly limited as long as it produces axial chirality, but it is preferable that Y is bonded to the ortho position of the bond between two rings Ar.

Examples of the substituent on the aromatic ring include a halogen atom represented by a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a nitro group, a methylsulfonyl group,
-Toluenesulfonyl group, trifluoromethyl group, cyano group, methoxycarbonyl group, methylsulfoxide group,
An electron-withdrawing group such as a sulfonylamide group; a lower alkyl group having 1 to 4 carbon atoms represented by a methyl group, an ethyl group, a propyl group and a butyl group, a methoxy group, an ethoxy group, a propoxy group and a butoxy group C 1-4
A lower alkoxy group, a cyclopropyl group, a cyclobutyl group, a cycloalkyl group having 3 to 7 carbon atoms represented by a cyclopentyl group and a cyclohexyl group, an aralkyl group having 7 to 10 carbon atoms represented by a benzyl group and a phenethyl group, and the like. And electron donating groups. Among these groups, an electron-withdrawing group is preferable, and a halogen atom and a nitro group are particularly preferable.

In the ketone compound (IV), Y is, as described above, (i) -OQ-Alk ^1- , (ii) -QO-Alk ^2- , (iii) -Alk ³ -O ^{-Alk 4 -, (iv) -O} -Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi) -Q-NR 2 -Alk 2 -, (vii) -Alk 3 -NR 2 —Alk ⁴ — or (viii) —NR ² —Alk ⁵ —, Q is a —CO— group or —SO ₂ — group, R ² is a hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group, Alk ¹ , Alk ² , Alk ³ , Alk ⁴ and Alk ⁵ are each a lower alkylene group.

Examples of the alkylsulfonyl group for R ² include an alkylsulfonyl group having an alkyl moiety of 1 to 4 carbon atoms such as a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group and a butylsulfonyl group. Examples of the arylsulfonyl group include an arylsulfonyl group having an aryl moiety having 6 to 10 carbon atoms, such as a benzenesulfonyl group, a p-toluenesulfonyl group, and a naphthylsulfonyl group.

In addition, Alk ¹ , Alk ² , Alk ³ , A
Specific examples of the lower alkylene group in lk ⁴ and Alk ⁵ include, for example, a linear or branched alkylene group represented by a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a methylmethylene group, a methylethylene group and a methyltrimethylene group. A lower alkylene group having 1 to 4 carbon atoms in the branched chain is exemplified.

Among the above Y, the group represented by the above (ii) is preferable, and among them, Q is particularly preferably a carbonyl group. Specifically, as Y,
-CO-O-CH ₂ - group.

More specific examples of the chiral ketone compound include, for example, those represented by the following general formula (VI):

[0108]

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[Wherein, R ^a and R ^b are each a hydrogen atom or a substituent, and R ^c and R ^d are groups satisfying the following conditions: (I) R ^c and R ^d are each a hydrogen atom or a substituent. Or (II) R ^c and R ^d are bonded to each other to form a general formula:

[0110]

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(Where R ^e , R ^f , R ^g and R ^h are
Indicates one of the following: (A) two adjacent groups are bonded to each other, form a benzene ring which may have a substituent together with two carbon atoms between them, and whether the other two groups are a hydrogen atom or a substituent. Or (b) each of which is a hydrogen atom or a substituent), or (III) R ^c and R ^d are bonded to each other to form a general formula:

[0112]

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Wherein R ⁱ , R ^j , R ^k and R ^m each represent a hydrogen atom or a substituent, and Y represents a general formula: (i) —O—Q—Alk ^{1 -, (ii) -Q-} O-Alk 2 -, (iii) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 - (Vi) -Q-NR ² -Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], and optical isomers of the ketone compound (VI) represented by the following formula:

Here, the substituent in R ^{a to} R ^m includes a halogen atom represented by a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a nitro group, a methylsulfonyl group, a p-toluenesulfonyl group, a trifluoro group. An electron-withdrawing group such as a methyl group, a cyano group, a methoxycarbonyl group, a methylsulfoxide group and a sulfonylamide group; a lower alkyl group having 1 to 4 carbon atoms represented by a methyl group, an ethyl group, a propyl group and a butyl group; A lower alkoxy group having 1 to 4 carbon atoms represented by a group, an ethoxy group, a propoxy group and a butoxy group, a cycloalkyl group having 3 to 7 carbon atoms represented by a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, C7-C10 aralkyl groups such as benzyl and phenethyl groups It is possible to increase the electron-donating group. Among these groups, an electron-withdrawing group is preferable,
Of these, a halogen atom and a nitro group are particularly preferred.

As R ^{a to} R ^d , (a) R ^a and R
^b is a hydrogen atom, R ^c and R ^d are bonded to each other

[0116]

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Whether R is^cIs a hydrogen atom, R^d
Is a halogen atom, or R ^cIs a hydrogen atom, R
^dIs a nitro group, or (b) R^aIs a halogen field
Child, R^bIs a hydrogen atom, R^cAnd R^dJoined to each other
hand

[0118]

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It is preferable that R ^a and R ^b be a hydrogen atom and R ^c and R ^d be bonded to each other.

[0120]

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It is preferable that the film is formed.

The Y in the ketone compound (VI) may be the same as the Y in the ketone compound (IV).

In the chiral ketone compound (VI) represented by the general formula (VI), Y represents a --CO--O--CH ₂ -group, R ^a
To R ^d is ^(a) R a and R ^b are hydrogen atoms, bonded R ^c and R ^d are each other

[0124]

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Whether R is^cIs a hydrogen atom, R^d
Is a halogen atom, or R ^cIs a hydrogen atom, R
^dIs a nitro group, or (b) R^aIs a halogen field
Child, R^bIs a hydrogen atom, R^cAnd R^dJoined to each other
hand

[0126]

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It is preferable that R ^a and R ^b be a hydrogen atom and R ^c and R ^d be bonded to each other.

[0128]

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Is preferably formed.

The optical isomers of the ketone compound (VI) include two isomers based on axial chirality, that is, the general formula (VI-a):

[0131]

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[Wherein R ^a , R ^b , R ^c , R ^d and Y
Is the same as described above).
-A), and general formula (VI-b):

[0133]

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[Wherein R ^a , R ^b , R ^c , R ^d and Y
Is the same as described above).
-B). Among them, the general formula (VI-
The chiral ketone compound (VI-a) represented by a)
It can be suitably used in the present invention.

The asymmetric oxidizing agent can be easily obtained by reacting the chiral ketone compound with the oxidizing agent. This reaction can be carried out in a suitable solvent in the presence or absence of an alkali agent.

Examples of the oxidizing agent include peroxo acids such as m-chloroperbenzoic acid, peracetic acid, peroxonitrate, peroxocarbonate, peroxodisulfate, peroxomonosulfate, peroxoboric acid, and formic acid, and alkali metal salts thereof. Salts, peroxides such as hydrogen peroxide and the like. These oxidants may be used as such,
It can also be used in the form of a composition containing an oxidizing agent. For example, as a composition containing an alkali metal salt of peroxomonosulfuric acid, a composition obtained from hydrogen peroxide, fuming sulfuric acid, and an alkali metal hydroxide (such as sodium hydroxide and potassium hydroxide); oxone [2KHSO ₅ · KHSO ₄・
K ₂ SO ₄ ]. These compositions can be suitably used in the method of the present invention because an oxidizing agent such as peroxoacid or an alkali metal salt thereof or a peroxide exists in a stabilized state. In addition, among such oxidizing agents, solvents and raw material compounds,
Metals and the like may be contained as impurities, and a chelating agent may be added to prevent such impurities from participating in the reaction. As the chelating agent,
For example, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, crown ether (e.g., 18-crown-6) and the like can be mentioned. The chelating agent may be added as it is to the solution of the cinnamic acid ester compound (I), or may be dissolved in a solvent in advance to form a solution, and then the chelating agent (I) may be added. It may be added to the solution.

Examples of the alkaline agent include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, and alkali metal acetates such as sodium acetate and potassium acetate. .

Examples of the solvent include 1,2-dimethoxyethane, dimethoxymethane, dimethyl ether,
Ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolan, diglyme; nitrile solvents such as acetonitrile, propionitrile, butyronitrile; methanol, ethanol, propanol, i-propanol, n-butanol , Sec-butanol, t-butanol and the like; alcohol solvents such as methyl acetate and ethyl acetate; dimethylformamide, diethylformamide,
Amide-based solvents such as dimethylacetamide and dimethylimidazolidinone; Sulfoxide-based solvents such as dimethylsulfoxide; and optionally halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, hexane, cyclohexane, and pentane Solvents: organic solvents such as aromatic hydrocarbon solvents which may be halogenated such as toluene, xylene, chlorobenzene and dichlorobenzene; water; and mixed solvents thereof. Among these solvents, ether solvents, nitrile solvents, alcohol solvents, water and their mixed solvents, especially 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, water and their mixed solvents, It can be suitably used.

The reaction temperature is not limited as long as it is a temperature at which an asymmetric oxidizing agent is formed, and can be appropriately selected depending on a desired asymmetric oxidizing agent.
C. is desirable.

The asymmetric oxidizing agent obtained after the above reaction may be once isolated and allowed to act on the cinnamate compound (I), or the asymmetric oxidizing agent is produced without isolation. The cinnamate compound (I) may be allowed to act in the same reaction system as the reaction system.

In the case where the asymmetric oxidizing agent is allowed to act on the cinnamate compound (I) without being isolated, the chiral ketone compound is converted into the asymmetric oxidizing agent, and then the cinnamate compound ( And the reaction of the chiral ketone compound to the asymmetric oxidizing agent in the same reaction system and the reaction of the resulting asymmetric oxidizing agent on the cinnamate compound (I). May be performed in parallel.

When the chiral ketone compound (VI-a) is used, an asymmetric oxidizing agent retaining its axial chirality can be obtained, and the chiral ketone compound (VI-b) can be used. In this case, an asymmetric oxidizing agent retaining the axial chirality is obtained.

The chiral dioxirane compound which is one of the asymmetric oxidizing agents formed from the chiral ketone compound and the oxidizing agent has a dioxirane ring (a three-membered ring composed of carbon-oxygen-oxygen) and has a chirality. Compounds. Chirality includes those based on asymmetric carbon atoms and those based on axial chirality.

As the chiral dioxirane compound, for example, a compound in which one or more hydroxyl groups of a monosaccharide or polysaccharide is converted to an oxo group and the remaining hydroxyl groups are protected (for example, 1,2,4,5-dioxane) (O-isopropylidene)-
Chiral ketone compounds derived from natural products such as D-erythro-2,3-hexodiuro-2,6-pyranose [Tetrahedron 47: 2133 (1991)], and ketones having a chiral biaryl skeleton Non-naturally occurring chiral ketone compounds, such as compounds, can be used, for example, in Chemical Reviews.
s) Compounds obtained by converting the ketone moiety to dioxirane by oxidation according to the method described in Vol. 89, p. 1187 (1989) can be mentioned.

As a typical example of the asymmetric oxidizing agent, for example, a compound represented by formula (V):

[0146]

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[In the formula, ring Ar is an optionally substituted 1-3 ring aromatic ring, Y is a general formula: (i) -OQ-Alk ^1- , (ii) -Q ^{-O-Alk 2 -, (iii} ) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi) -Q-NR ^2- Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], which is an optical isomer of the dioxirane compound (V).

In the dioxirane compound (V),
Ring Ar is a 1-3 cyclic aromatic ring which may have a substituent. Examples of such a 1-3-ring aromatic ring include a benzene ring, a naphthalene ring, a naphthoquinone ring, an anthracene ring, an anthraquinone ring, a phenanthrene ring, and the like. The substitution position of Y bonded to the aromatic ring is not particularly limited as long as it produces axial chirality, but it is preferable that Y is bonded to the ortho position of the bond between two rings Ar.

Examples of the substituent on the aromatic ring include a halogen atom represented by a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a nitro group, a methylsulfonyl group and a p-type group.
-Toluenesulfonyl group, trifluoromethyl group, cyano group, methoxycarbonyl group, methylsulfoxide group,
An electron-withdrawing group such as a sulfonylamide group; a lower alkyl group having 1 to 4 carbon atoms represented by a methyl group, an ethyl group, a propyl group and a butyl group, a methoxy group, an ethoxy group, a propoxy group and a butoxy group C 1-4
A lower alkoxy group, a cyclopropyl group, a cyclobutyl group, a cycloalkyl group having 3 to 7 carbon atoms represented by a cyclopentyl group and a cyclohexyl group, an aralkyl group having 7 to 10 carbon atoms represented by a benzyl group and a phenethyl group, and the like. And electron donating groups. Among these groups, an electron-withdrawing group is preferable, and a halogen atom and a nitro group are particularly preferable.

On the other hand, in the dioxirane compound (V), Y is, as described above, (i) -OQ-Alk ^1- , (ii) -QO-Alk ^2- , (iii) -Alk ^{3 -O-Alk 4 -, (iv} ) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi) -Q-NR 2 -Alk 2 -, (vii) -Alk 3 - NR ² —Alk ⁴ — or (viii) —NR ² —Alk ⁵ —, Q is a —CO— group or —SO ₂ — group, R ² is a hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group, Alk ¹ , Alk ² , Alk ³ , Alk ⁴ and Alk ⁵ are each a lower alkylene group.

Examples of the alkylsulfonyl group for R ² include an alkylsulfonyl group having an alkyl moiety of 1 to 4 carbon atoms such as a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group and a butylsulfonyl group. Examples of the arylsulfonyl group include an arylsulfonyl group having an aryl moiety having 6 to 10 carbon atoms, such as a benzenesulfonyl group, a p-toluenesulfonyl group, and a naphthylsulfonyl group.

Further, Alk ¹ , Alk ² , Alk ³ , A
Specific examples of the lower alkylene group in lk ⁴ and Alk ⁵ include, for example, a linear or branched alkylene group represented by a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a methylmethylene group, a methylethylene group and a methyltrimethylene group. A lower alkylene group having 1 to 4 carbon atoms in the branched chain is exemplified.

Among the above Y, the group represented by the above (ii) is preferable, and among them, Q is particularly preferably a carbonyl group. Specifically, as Y,
-CO-O-CH ₂ - group.

More specific examples of the chiral dioxirane compound include, for example, those represented by the general formula (VII):

[0155]

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[Wherein, R ^a and R ^b each represent a hydrogen atom or a substituent, and R ^c and R ^d each represent a group satisfying the following conditions. (I) R ^c and R ^d are each a hydrogen atom or a substituent, or (II) R ^c and R ^d are bonded to each other to form a general formula:

[0157]

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(Wherein R ^e , R ^f , R ^g and R ^h are
Indicates one of the following: (A) two adjacent groups are bonded to each other, form a benzene ring which may have a substituent together with two carbon atoms between them, and whether the other two groups are a hydrogen atom or a substituent. Or (b) each of which is a hydrogen atom or a substituent), or (V) R ^c and R ^d are bonded to each other to form a general formula:

[0159]

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Wherein R ⁱ , R ^j , R ^k and R ^m each represent a hydrogen atom or a substituent, and Y represents a general formula: (i) —O—Q—Alk ^{1 -, (ii) -Q-} O-Alk 2 -, (iii) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 - (Vi) -Q-NR ² -Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], which is an optical isomer of the dioxirane compound (VII).

Here, the substituent in R ^{a to} R ^m includes a halogen atom represented by a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a nitro group, a methylsulfonyl group, a p-toluenesulfonyl group, a trifluoro group. An electron-withdrawing group such as a methyl group, a cyano group, a methoxycarbonyl group, a methylsulfoxide group and a sulfonylamide group; a lower alkyl group having 1 to 4 carbon atoms represented by a methyl group, an ethyl group, a propyl group and a butyl group; A lower alkoxy group having 1 to 4 carbon atoms represented by a group, an ethoxy group, a propoxy group and a butoxy group, a cycloalkyl group having 3 to 7 carbon atoms represented by a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, C7-C10 aralkyl groups such as benzyl and phenethyl groups It is possible to increase the electron-donating group. Among these groups, an electron-withdrawing group is preferable,
Of these, a halogen atom and a nitro group are particularly preferred.

As R ^{a to} R ^d , (a) R ^a and R
^b is a hydrogen atom, R ^c and R ^d are bonded to each other

[0163]

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Whether R is^cIs a hydrogen atom, R^d
Is a halogen atom, or R ^cIs a hydrogen atom, R
^dIs a nitro group, or (b) R^aIs a halogen field
Child, R^bIs a hydrogen atom, R^cAnd R^dJoined to each other
hand

[0165]

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It is particularly preferable that R ^a and R ^b be a hydrogen atom and R ^c and R ^d be bonded to each other.

[0167]

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The case where is formed is preferable.

The dioxirane compound (VII) has a Y
Examples include the same groups as those for Y in the dioxirane compound (V).

The optical isomers of the dioxirane compound (VII) include two isomers based on axial chirality, that is, the general formula (VII-a):

[0171]

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[Wherein R ^a , R ^b , R ^c , R ^d and Y
Is the same as defined above], and a chiral dioxirane compound (VII-a) represented by the general formula (VII-b):

[0173]

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[Wherein R ^a , R ^b , R ^c , R ^d and Y
Is the same as described above].

The optical isomer of the dioxirane compound (V) and the optical isomer of the dioxirane compound (VII) are, for example, each represented by the general formula (IV):

[0176]

Embedded image

Wherein the rings Ar and Y are the same as those described above, and the general formula (VI):

[0178]

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[Wherein R ^a , R ^b , R ^c , R ^d and Y
Can be easily obtained by oxidizing the corresponding optical isomer of the ketone compound (VI) represented by the same formula. This oxidation reaction can be carried out by oxidizing the optical isomers of the ketone compounds (IV) and (VI) with an oxidizing agent in an appropriate solvent in the presence or absence of an alkali agent. it can.

The oxidizing agent used in the oxidation reaction is as follows:
For example, peroxoacids such as m-chloroperbenzoic acid, peracetic acid, peroxonitrate, peroxocarbonate, peroxodisulfuric acid, peroxomonosulfate, peroxoboric acid, and formic acid, and peroxides such as alkali metal salts and hydrogen peroxide thereof. Things. These oxidizing agents may be used per se or in the form of a composition containing the oxidizing agent. For example, as a composition containing an alkali metal salt of peroxomonosulfuric acid, a composition obtained from hydrogen peroxide, fuming sulfuric acid and an alkali metal hydroxide (such as sodium hydroxide and potassium hydroxide); oxone [2KHS
O ₅ .KHSO ₄ .K ₂ SO ₄ ]. These compositions can be suitably used in the method of the present invention because an oxidizing agent such as peroxoacid or an alkali metal salt thereof or a peroxide exists in a stabilized state. The oxidizing agent, the solvent, and the raw material compound may include a metal or the like as an impurity, and a chelating agent may be added to prevent the impurity from participating in the reaction. Examples of the chelating agent include ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, crown ether (18-crown-6, etc.). The chelating agent may be added as it is to the solution of the cinnamic acid ester compound (I), or may be dissolved in a solvent in advance to form a solution, and then the chelating agent (I) may be added. It may be added to the solution.

Examples of the alkaline agent include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and alkali metal acetates such as sodium acetate and potassium acetate. .

Examples of the solvent include 1,2-dimethoxyethane, dimethoxymethane, dimethyl ether,
Ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolan, diglyme; nitrile solvents such as acetonitrile, propionitrile, butyronitrile; methanol, ethanol, propanol, i-propanol, n-butanol , Sec-butanol, t-butanol and the like; alcohol solvents such as methyl acetate and ethyl acetate; dimethylformamide, diethylformamide,
Amide-based solvents such as dimethylacetamide and dimethylimidazolidinone; Sulfoxide-based solvents such as dimethylsulfoxide; and optionally halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, hexane, cyclohexane, and pentane Solvents: organic solvents such as aromatic hydrocarbon solvents which may be halogenated such as toluene, xylene, chlorobenzene and dichlorobenzene; water; and mixed solvents thereof. Among these solvents, ether solvents, nitrile solvents, alcohol solvents, water and their mixed solvents, especially 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, water and their mixed solvents, It can be suitably used.

The reaction temperature is -5 to 50 ° C, preferably 0 to 50 ° C.
Desirably, it is -40C.

The optical isomers of the dioxirane compounds (V) and (VII) obtained after the above oxidation reaction may be once isolated and allowed to act on the cinnamate compound (I), or may be isolated. Alternatively, the cinnamate compound (I) may be allowed to act in the same reaction system as the reaction system in which the optical isomer of the dioxirane compound is generated.

When acting on the cinnamate compound (I) without isolating the optical isomer of the dioxirane compound, the optical isomer of the chiral ketone compound is converted into the optical isomer of dioxirane, The acid ester compound (I) may be acted on, and in the same reaction system, conversion of a chiral ketone compound into an optical isomer of a dioxirane compound, and cinnamic acid by an optical isomer of a dioxirane compound The asymmetric oxidation reaction of the ester compound (I) may be performed in parallel.

When the chiral ketone compound (VI-a) is used, a chiral dioxirane compound (VII-a) is obtained, and when the chiral ketone compound (VI-b) is used. Yields a chiral oxirane compound (VII-b).

In the production method of the present invention, the asymmetric oxidizing agent can act on the cinnamate compound (I) in a suitable solvent in the presence or absence of an alkali agent.

For example, as the alkali agent and the solvent, any of the alkali agent and the solvent used for reacting the optical isomer of the ketone compound (IV) or (VI) with the oxidizing agent can be suitably used. Among the above solvents, ether solvents, nitrile solvents, alcohol solvents, water, and mixed solvents thereof can be preferably used.

Examples of the method of causing the asymmetric oxidizing agent to act on the cinnamic acid ester compound (I) include, for example, a method of adding the asymmetric oxidizing agent directly to the solution of the cinnamic acid ester compound (I), and cinnamic acid. A method in which a chiral ketone compound and an oxidizing agent corresponding to the asymmetric oxidizing agent are added to the solution of the ester compound (I) to generate the asymmetric oxidizing agent in the same reaction system.

For example, as an asymmetric oxidizing agent, a ketone compound
When using a compound formed from the optical isomer of (IV) or (VI) and an oxidizing agent, (a) a method of adding an asymmetric oxidizing agent to a solution of the cinnamate compound (I); b) An oxidizing agent is added to a mixture of the optical isomer of the ketone compound (IV) or (VI) and the cinnamic acid ester compound (I), and the asymmetric oxidizing agent generated in the same reaction system is converted to the cinnamic acid ester A method of acting on compound (I) can be mentioned.

When the method (a) is used, it is necessary to use a sufficient amount of an asymmetric oxidizing agent to asymmetrically oxidize the cinnamic acid ester compound (I). On the other hand, when the method (b) is used, an amount of the ketone which can form an asymmetric oxidizing agent in the reaction mixture in an amount sufficient to asymmetrically oxidize the cinnamate compound (I). Compound (IV)
Alternatively, an optical isomer of (VI) and an oxidizing agent may be used.

In the above method (b), the ketone compound
An asymmetric oxidizing agent is formed from the optical isomer of (IV) or (VI) by an oxidizing agent, and the asymmetric oxidizing agent asymmetrically oxidizes the cinnamate compound (I) and then reacts with the corresponding original ketone compound ( IV)
Or, it returns to the optical isomer of (VI) and becomes reusable. If 1 to 10 equivalents of the oxidizing agent is used with respect to the cinnamic acid ester compound (I), the ketone compound (I
The optical isomer of V) or (VI) is used only in an amount of about 0.001 to 0.1 mol per mol of the cinnamate compound (I), and the cinnamate compound (I) is asymmetrically oxidized. The desired optically active glycidic acid ester compound (I
Ia) can be preferentially produced, and it is particularly preferable to use the oxidizing agent in a ratio of 1.6 to 2.0 equivalents to the cinnamate compound (I).

In particular, oxone, which is an oxidizing agent, is added to a mixture of the optical isomer of the ketone compound (IV) or (VI) and the cinnamate compound (I) to give the asymmetric form of the cinnamate compound (I). When oxidizing, oxone is compared with cinnamate compound (I) compared to ketone compound (IV)
Alternatively, the optical isomer of (VI) is selectively oxidized to give an asymmetric oxidizing agent. In addition, the asymmetric oxidizing agent asymmetrically oxidizes the cinnamic acid ester compound (I), returns to the corresponding optical isomer of the ketone compound (IV) or (VI), and can be recycled. The asymmetric oxidation of the cinnamic acid ester compound (I) can be carried out in good yield even if only a catalytic amount of the optical isomer of the ketone compound (IV) or (VI) as the asymmetric source is used. , The desired optically active glycidic acid ester compound (IIa) is preferentially formed.

Also, the cinnamic acid ester compound (I)
The temperature at which the asymmetric oxidizing agent acts is not particularly limited, and varies depending on the type of the asymmetric oxidizing agent. However, it is usually about -5 to 50 ° C, preferably about 0 to 40 ° C. Is preferred.

The atmosphere during the reaction is not particularly limited, and may be usually air, or may be, for example, an inert gas such as nitrogen gas.

Next, the cinnamic acid ester compound (I)
The reduction of the unreacted asymmetric oxidizing agent contained in the reaction mixture obtained by allowing the asymmetric oxidizing agent to act on, for example, removing the coexisting oxidizing agent from the reaction mixture by washing with a saline solution or the like. Then, if necessary, by performing reduction using a reducing agent such as hypo, sodium bisulfite, sodium metabisulfite, etc., it is possible to convert the unreacted asymmetric oxidizing agent to the corresponding chiral ketone compound. it can.

When a chiral dioxirane compound is used as an asymmetric oxidizing agent in the production method of the present invention, the compound is converted to a cinnamic acid ester compound (I) in a suitable solvent in the presence or absence of an alkali agent. Can be acted upon.

For example, as the alkaline agent and the solvent, the alkaline agent and the solvent used for producing the optical isomers of the dioxirane compounds (V) and (VII) from the optical isomers of the ketone compounds (IV) and (VI), respectively. Can be suitably used. Among the above solvents,
In particular, an ether solvent, a nitrile solvent, an alcohol solvent, water, and a mixed solvent thereof can be suitably used.

The amount of the cinnamic acid ester compound (I) is not particularly limited, but may be generally about 0.1 to 30 g per 100 ml of the solvent.

The amount of the chiral dioxirane to be used is preferably about 1 to 5 mol, more preferably about 1 to 2 mol, per 1 mol of the cinnamate compound (I). .

Examples of the method of causing a chiral dioxirane compound to act on the cinnamate compound (I) include, for example, a method of directly adding a chiral dioxirane compound to a solution of the cinnamate compound (I), Adding a chiral ketone compound and an oxidizing agent corresponding to the chiral dioxirane compound to the solution of compound (I);
Examples include a method of producing a chiral dioxirane compound in the same reaction system.

For example, when the dioxirane compound (V) or the optical isomer of (VII) is used as the chiral dioxirane compound, (a) the dioxirane compound (V) is added to the solution of the cinnamate compound (I). Or (VII)
(B) ketone compound (IV)
Or a chiral dioxirane compound (V) or (VII) formed in the same reaction system by adding an oxidizing agent to a mixture of the optical isomer of (VI) and the cinnamate compound (I).
In which the optical isomer of the above is allowed to act on the cinnamate compound (I).

When the method (a) is used, a sufficient amount of the dioxirane compound (V) or the optical isomer of (VII) to asymmetrically oxidize the cinnamate compound (I) is used. There is a need. On the other hand, when the method (b) is used, a sufficient amount of the dioxirane compound (V) or the optical isomer of (VII) to asymmetrically oxidize the cinnamate compound (I) is added to the reaction mixture. The amount of the optical isomer of the ketone compound (IV) or (VI) and the oxidizing agent may be used in such amounts that can be formed by

In the above method (b), the ketone compound
An optical isomer of the dioxirane compound (V) or (VII) is formed from the optical isomer of (IV) or (VI) by an oxidizing agent, and the isomer is obtained after asymmetric oxidation of the cinnamate compound (I). When the oxidizing agent is used in an amount of 1 to 10 equivalents to the cinnamate compound (I), it returns to the corresponding optical isomer of the ketone compound (IV) or (VI) and becomes recyclable. The optical isomer of the ketone compound (IV) or (VI), which is an asymmetric source, is used only in an amount of about 0.001 to 0.1 mol per 1 mol of the cinnamate compound (I), and the cinnamate compound (I) ) Can be asymmetrically oxidized to preferentially produce the desired optically active glycidic acid ester compound (IIa), and the oxidizing agent is 1: 1 with respect to the cinnamate compound (I). It is particularly preferred to use 6 to 2.0 equivalents.

In particular, oxone, which is an oxidizing agent, is added to a mixture of the optical isomer of the ketone compound (IV) or (VI) and the cinnamate compound (I) to give the asymmetric form of the cinnamate compound (I). When oxidizing, oxone is compared with cinnamate compound (I) compared to ketone compound (IV)
Alternatively, the optical isomer of (VI) is selectively oxidized to give the optical isomer of the dioxirane compound (V) or (VII).
The optical isomer of the dioxirane compound (V) or (VII) is obtained by asymmetric oxidation of the cinnamate compound (I) and then the corresponding optical isomer of the original ketone compound (IV) or (VI). And can be recycled, so that the cinnamic acid ester compound (I) can be obtained in good yield even if only a catalytic amount of the optical isomer of the ketone compound (IV) or (VI) as the asymmetric source is used. Can be asymmetrically oxidized, and the desired optically active glycidic acid ester compound (IIa) is preferentially formed.

In addition, the cinnamic acid ester compound (I)
The temperature at which the chiral dioxirane compound is allowed to act is not particularly limited, but it is usually preferably about -5 to 50 ° C, particularly preferably about 0 to 40 ° C.

The atmosphere during the reaction is not particularly limited, and may be usually air, or may be, for example, an inert gas such as nitrogen gas.

Next, the cinnamic acid ester compound (I)
The unreacted chiral dioxirane compound contained in the reaction mixture obtained by allowing the chiral dioxirane compound to act on the reaction mixture is removed, for example, by removing the coexisting oxidizing agent and the like from the reaction mixture by washing with a saline solution or the like. The unreacted chiral dioxirane compound can be converted to the corresponding chiral ketone compound by performing a reduction using a reducing agent such as hypo, sodium bisulfite, sodium metabisulfite and the like, if necessary.

In the present invention, as the cinnamate compound (I) represented by the general formula (I), as shown in the following scheme, a cinnamate having a ring A and —CO ₂ R in the trans position is used. When the acid ester compound (I) is used,
When the asymmetric oxidizing agent performs an α-attack, the reaction proceeds in the direction of arrow b, and the (2R, 3S) -optically active glycidic acid ester compound becomes a main product, and the asymmetric oxidizing agent changes to β-
When an attack occurs, the reaction proceeds in the direction of arrow a, and (2)
The (S, 3R) -optically active glycidic acid ester compound is the main product. When the cinnamate compound (I) in which ring A and —CO ₂ R are in the cis position is used, when the asymmetric oxidizing agent α-attacks, the reaction proceeds in the direction of arrow d, When the (2S, 3S) -optically active glycidic acid ester compound is the main product and the asymmetric oxidizing agent is β-attacked, the reaction proceeds in the direction of arrow c, and (2R, 3)
R) -optically active glycidic acid ester compound is the main product.

[0210]

Embedded image

[Wherein rings A and R are the same as defined above]

Among the optically active glycidic acid ester compounds, the (2R, 3S) -optically active glycidic acid ester compound and the (2S, 3R) -optically active glycidic acid ester compound have a ring A and —CO ₂ R. Since it is in the trans position, it has little steric hindrance and can efficiently produce the optically active glycidic acid ester compound which is the object of the present invention, so that it can be suitably used.

In the present invention, a trans-form is used as the cinnamate compound (I), and the asymmetric oxidizing agent obtained from the chiral ketone compound (VI-a) or (VI-b) [for example, chiral dioxirane Compound (VII-a) or (VII-
b)] is preferred. When a trans-isomer is used as the cinnamate compound (I) and an asymmetric oxidizing agent obtained from the chiral ketone compound (VI-a) [eg, a chiral dioxirane compound (VII-a)] is used. Is
The (2R, 3S) -type glycidic acid ester compound is formed as a main product, and the cinnamic acid ester compound (I)
Chiral ketone compound (VI-b)
When an asymmetric oxidizing agent [for example, a chiral dioxirane compound (VII-b)] is used, (2S, 3R)
-Type glycidic acid ester compound is produced as the main product.

In step (B-1), the chiral ketone compound may be removed from the reaction mixture by reducing an asymmetric oxidizing agent such as a dioxirane compound contained in the reaction mixture, if necessary. After that, a chiral ketone compound and an optically active glycidic acid ester compound (I
It can be carried out by a separation method utilizing the difference in solubility between Ia) and (IIb) in an organic solvent.

Examples of the separation method utilizing the difference in solubility include an extraction method using an organic solvent, a crystallization method using an organic solvent, and the like.

Specifically, for example, (a-1) a precipitate formed by adding water to the reaction mixture containing the chiral ketone compound is obtained, and then the precipitate is dissolved in an organic solvent, if necessary. After removing impurities, the solvent is distilled off or (a-
2) The reaction mixture containing the chiral ketone compound is extracted with an organic solvent, and the obtained extract is washed, dried, and then the solvent is distilled off. (B) The residue obtained in this way is a chiral ketone compound. [For example, ketone compound (IV) or (V
The chiral ketone compound can be removed by extracting the optically active glycidic acid ester compounds (IIa) and (IIb) with an organic solvent having such a property that it is difficult to dissolve the compound (I)].

The residue obtained in the step (a-1) or (a-2) is converted into a chiral ketone compound and optically active glycidic acid ester compounds (IIa) and (IIb) at a high temperature.
However, the chiral ketone compound is crystallized depending on the temperature conditions, and the optically active glycidic acid ester compounds (IIa) and (IIb) are once dissolved in an organic solvent having a property that can produce a state that does not crystallize. Either the temperature is lowered to selectively crystallize only the chiral ketone compound, or the reaction mixture is heated at an elevated temperature to obtain the chiral ketone compound and the optically active glycidic acid ester compound (IIa) and (I
Ib) is dissolved, but the chiral ketone compound is crystallized depending on the temperature conditions, and the optically active glycidic acid ester compounds (IIa) and (IIb) are extracted with an organic solvent having a property capable of producing a non-crystallized state, By lowering the temperature of the extract and selectively crystallizing only the chiral ketone compound, the chiral ketone compound can be removed.

Examples of the organic solvent for dissolving the precipitate formed by adding water to the reaction mixture include, for example, halogenated aliphatic hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, ethyl acetate and methyl acetate. Ester solvents such as chlorobenzene, toluene, xylene,
An aromatic hydrocarbon solvent which may be halogenated, such as mesitylene, can be used. Examples of the organic solvent used for extracting the reaction mixture include aromatic hydrocarbon solvents such as toluene; diethyl ether, diisopropyl ether , T-butyl methyl ether, 1,4-dioxane, tetrahydrofuran, diglyme, etc., and it is preferable to use an easily distillable ether solvent.

After distilling off the solvent, the organic solvent used for extracting the residue, which does not easily dissolve the chiral ketone compound but easily dissolves the optically active glycidic acid ester compounds (IIa) and (IIb) includes: Aliphatic hydrocarbon solvents such as hexane; and ester solvents such as ethyl acetate can be used alone or in combination.

On the other hand, at high temperatures, chiral ketone compounds and optically active glycidic acid ester compounds (IIa) and (Ia)
Ib) is dissolved, but the chiral ketone compound is crystallized depending on the temperature conditions, and the optically active glycidic acid ester compounds (IIa) and (IIb) can be in an uncrystallized state. t
Ether solvents such as -butyl methyl ether can be used.

In the step of removing the chiral ketone compound, the chiral ketone compound is purified from the reaction mixture with high purity.
It can be recovered in high yield.

The optically active glycidic acid ester compound (IIa) which is the main product obtained as described above and the optically active glycidic acid ester compound (IIb) which is a by-product
The solvent contained in the reaction mixture is removed from the extract obtained by removing the ketone compound or removing the solvent, if necessary, by distilling the solvent and replacing the mixture, and then crystallizing the optically active glycidic acid ester compound (IIa). Most of the optically active glycidic acid ester compound (IIa) can be obtained with high purity and high optical purity.

For crystallization, diethyl ether, diisopropyl ether, t-
Ether solvents such as butyl methyl ether; alcohol solvents such as methanol, ethanol, i-propanol and n-butanol; aromatic hydrocarbon solvents such as toluene and xylene; n-hexane, n-heptane and n-
Aliphatic hydrocarbon solvents such as octane, alicyclic hydrocarbon solvents such as cyclohexane can be used,
Crystallization of optically active glycidic acid ester compound (IIa),
When the transesterification reaction is performed as it is after the acquisition, it is preferable to use an ether solvent or an aromatic hydrocarbon solvent. The crystallization of the optically active glycidic acid ester compound (IIa) is carried out at a temperature lower than the temperature at which the chiral ketone compound is crystallized, whereby the substantially pure optically active glycidic acid ester compound (IIa) is crystallized.
a) can be obtained.

The residue obtained by removing the chiral ketone compound and crystallizing the optically active glycidic acid ester compound (IIa) contains the target compound represented by the general formula (IIa):

[0225]

Embedded image

(Wherein, rings A and R are the same as above. * Indicates an asymmetric carbon atom) and an optically active glycidic acid ester compound (IIa) represented by the following general formula (IIb): ):

[0227]

Embedded image

(Wherein rings A and R are the same as described above. **
Indicates an asymmetric carbon atom having an absolute configuration opposite to that of the corresponding asymmetric carbon atom of the optically active glycidic acid ester compound (IIa)). I have.

The mixture of the optically active glycidic acid ester compounds (IIa) and (IIb) contained in the residue was added in the presence of an enzyme capable of stereoselectively transesterifying the optically active glycidic acid ester compound (IIb). And the general formula (I
II):

[0230]

Embedded image

Wherein R ¹ represents a group corresponding to an ester residue different from R, and an optically active glycidic acid ester compound (IIb) is reacted with an alcohol compound represented by the general formula (IIb ¹ ):

[0232]

Embedded image

(Wherein rings A, R ¹ and ** are the same as described above), and transesterified to an ester compound (IIb ¹ ), and crystallized from the resulting mixture to obtain only the optically active glycidic acid ester compound (IIa) And can be obtained.

Optically active glycidic acid ester compound (II
b) Enzymes having the ability to stereoselectively transesterify include: (A) an enzyme capable of stereoselectively transesterifying the (2S, 3R) -isomer [(2R, 3S) -isomer does not transesterify, but (2S, 3R) -isomer transesterifies (B) an enzyme capable of stereoselectively transesterifying the (2R, 3S) -isomer [(2S, 3R) -isomer does not transesterify, but (2R, 3S) -isomer (C) an enzyme capable of stereoselectively transesterifying the (2S, 3S) -isomer [(2R, 3R) -isomer does not transesterify, but (2S, 3S)- (D) an enzyme capable of stereoselectively transesterifying the (2R, 3R) -isomer [(2S, 3S) -isomer does not transesterify, but (2R, 3R) -isomer is an ester Enzyme conversion],

Enzymes having the ability to stereoselectively transesterify the (2S, 3R) -isomer include, for example, Serratia, Candida and Mucor
Genus (Mucor), genus Pseudomonas, genus Aspergillus, Alcaligens
es), Absidia, Fusarium
ium), Giberella, Neurospora
spora), Trichoderma, Rhizopus (R
hizopus), Achromobacter, Bacillus, Brevibacter
genus, Corynebacterium genus, Providencia genus, Saccharomycopsis
Examples include esterases derived from microorganisms of the genera (Saccharomycopsis), Nocardia, and Arthrobacter, α-chymotrypsin, pig liver esterase, pig pancreas esterase, and the like. Among these enzymes, esterases derived from microorganisms of the genus Serratia, particularly Serratia marcesc (Serratia marcesc)
ens) Microbial esterases can be suitably used in the present invention.

Specific examples of the enzyme include Absidia corymbifera IFO 4009,
IFO 4010, Aspergillus
ochraceus) IFO 4346, Aspergillus Terreus (A
spergillus terreus) IFO 6123, Fusarium oxysporum IFO 5942, ATCC 659,
Fusarium solani IFO 5232, Gibberella fujikuroi IFO 5368,
Mucor angulimacro
sporus) IAM 6149, Mucor Sircineroides
circinelloides) IFO 6746, Mucor Flavas
or flavus) IAM 6143, Mucor fragiris
ragilis) IFO 6449, Mucor Genevensis
genevensis) IAM 6091, Mucor Globosas
globosus) IFO 6745, Mucor j
anssenii) IFO 5398, Mucor jbanicas
avanicus) IFO 4569, IFO 4570, IFO 4572, IFO
5382, Mucor lamprosporu
s) IFO 6337, Mucorpetr
insularis) IFO 6751, Mucor Plumbeus
plumbeus) IAM 6117, Mucor prai
ni) IAM 6120, Mucorpusillus I
AM 6122, Mucor racemosus IF
O 4581, Mucor ramannianus
IAM 6128, Mucor recurvus IAM
6129, Mucor silvaticus
IFO6753, Mucor spinesce
ns) IAM 6071, Mucor subt.
ilissimus) IFO 6338, neurospora crassa (neuros
pora crassa) IFO 6068, Rhizopus
arrhizus) IFO 5780, Rhizopus d
elemar) ATCC 34612, Rhizop Japonicas
us japonicus) IFO 4758, Trichoderma bilide (Tric
hoderma viride) IFO 4847, Achromobacter cycloastes IAM 1013
, Bacillus sphaericus IFO
3525, Brevibacterium ketoglutamicum
acterium ketoglutamicum) ATCC 15588, Corynebacterium alkanol
yticum) ATCC 21511, Corynebacterium hydrocarboclastum
ATCC 15592, Corynebacterium primorioxydans ATCC 31015, Providencia alcifaciens
alifaciens) JCM 1673, Pseudomonas mutabilis (P
seudomonas mutabilis) ATCC 31014, Pseudomonas
Pseudomonas putida ATCC 17426, ATCC 174
53, 33015, Serratia requestifaciens
liquefaciens) ATCC 27592, Serratia Marcessens
(Serratia marcescens) ATCC 13880, ATCC 14764,
ATCC 19180, ATCC 21074, ATCC 27117, ATCC 212
12, Serratia marcescens
Sr41 (FERM BP-487)
Saccharomycopsi
s lipolytica) IFO 0717, IFO 0746, IFO 1195,
IFO 1209, IFO 1548, Nocardia Asteroides
(Nocardia asteroides) IFO 3384, IFO 3424, IFO
3423, Nocardia gardneri
ATCC 9604, Arthrobacter urea faciliens
Nob Bar (Arthrobacter ureafaciens nov.var.),
Arthrobacter globiformis
obiformis), Cndida cylind
racea). In addition, Serratia marcescens Sr41 (Serratia marcescens Sr4
1) Under the Budapest Treaty, from March 26, 1983 (the date of deposit of Hara), the Research Institute of Microbial Industry and Technology, Ministry of International Trade and Industry [Currently, Institute of Biotechnology and Industrial Technology, Ministry of International Trade and Industry (current address: 1-3-1 Higashi, Tsukuba, Ibaraki, Japan)
No.)] (Postal code: 305-0046) and accession number: FERM BP-
Deposited as 487.

Further, alkaline lipase (derived from Achromobacter, manufactured by Wako Pure Chemical Industries, Ltd.),
Lipase B (Pseudomonas fr
agi) 22-39B, manufactured by Wako Pure Chemical Industries, Ltd.), Lipase M
“Amano” (Mucor javanicu)
s) Origin, Amano Pharmaceutical Co., Ltd.), Lipase type XI
(Derived from Rhizopus arrhizus, manufactured by Sigma), talipase (Rhizopus arrhizus)
delemar), Tanabe Seiyaku Co., Ltd.), Lipase NK-116
(From Rhizopus japonicus, manufactured by Nagase & Co., Ltd.), Lipase N (from Rhizopus niveus, manufactured by Amano Pharmaceutical Co., Ltd.), Lipase SP 435 & 525 (Candida antarctica)
da antarctica), Novo), Alcalase (from Bacillus licheniformis, Novo), lipase type VII (from Candida cylindracea, Sigma), lipase (from pig pancreas) , Wako Pure Chemical Industries, Ltd.
), Esterase (porcine pancreas, Sigma), cholesterol esterase (Candid rugosa (Candid
a rugosa), from Nagase & Co., Ltd.), Lipase OF (from Candida cylindracea),
Meito Sangyo Co., Ltd.), Lipase QL (from Alkaligenes sp., Meito Sangyo Co., Ltd.),
Lipase AL (Achromobact SP
er sp.), lipase PL (derived from Alkaligenes sp., manufactured by Meito Sangyo Co., Ltd.) and the like.

Among these enzymes, Serratia (Serra
tia), Candida, Alcaligenes (Alcal
Esterases derived from microorganisms of the genus Aigenobacter, Achromobacter and the like are preferred. Among these enzymes, Serratia marcescens (Serratia marce
scens), Candida cylindra
cea) Microbial esterases are particularly preferred.

Examples of enzymes capable of stereoselectively transesterifying (2R, 3S) -isomer include, for example, those belonging to the genus Micrococcus and Agrobacterium (A).
genus grobacterium, Microbacte
genus rium, Rhizobium, Citrobacter
Genus (Citrobacter), genus Debaryomyces,
Hanseniaspora genus, Hansenula
senula), Pichia, Rhodosporidium (R
hodosporidium), Schizosacchar
omyces), Sporobolomyces, Kloeckera, Torulaspora
Esterases derived from microorganisms of the genus Streptomyces and the like can be used.

Specific examples of such a microbial enzyme include Micrococcus ureae IAM 1010 (FE
RM BP-2996), Agrobacterium radiobacter (A
grobacterium radiobacter) IAM 1526, IFO 13259,
Microbacterium s
p.) ATCC 21376, Rhizobium melilotti
meliloti) IFO 13336, Citrobacter Freundi
(Citrobacter freundii) ATCC 8090, Debaryomyces
Debaryomyces hansenii v
ar. fabryi) IFO 0015, Debaryomyces nepalensis
(Debaryomyces nepalensis) IFO 0039, Hanseniaspora valbyens IFO 011
5.Hansenula polymorph
a) IFO 1024, Hansenula satulnas
urnus) HUT 7087, Pichia farinosa
osa) IFO 0607, Pichia pastoris
IFO0948, IFO 1013, IAM 12267, Pichia wickerhamii IFO 1278, Rhodosporidium toruloides
IFO 0559, Schizosacch
aromyces pombe) IFO0358, Sporobolomyces gracillis IFO 1033, Kloeckera corticis IFO 0633, Torulaspora delbruecki
i) IFO 0422, Streptomyces griseus subsp.griseu
s) IFO 3430, IFO 3355, Streptomyces lavendula subsp.
vendulae subsp.lavendurae) IFO 3361, IFO 3415,
And esterases derived from IFO3146.

As the enzyme, a commercially available enzyme may be used or may be obtained from a culture solution of microbial cells. Also,
The enzyme may be obtained from a wild strain or a mutant strain of a microorganism, or may be a bacterium induced by a biotechnology technique such as gene recombination or cell fusion.

The microorganism-derived enzyme is disclosed in
No. 398, etc. (for example,
In a medium containing a conventional carbon source, a nitrogen source and inorganic salts, a pH of 5 to 5 is added at room temperature or under heating and under aerobic conditions.
It is obtained by culturing the microorganism in step 8), removing the cells from the culture solution by a conventional method such as centrifugation and filtration, and, if necessary, further removing impurities using an adsorption resin or the like. The solution can be used as it is as an enzyme.

These enzymes can be used as they are, or they can be used after freeze-drying. The polyacrylamide method, the sulfur-containing polysaccharide gel method (for example, carrageenan gel method), the agar gel method, the photocrosslinkable resin method, the polyethylene glycol method, the celite method, the membrane adsorption method, and the like are used for immobilization. You can also.

Further, these immobilized enzymes can be used by packing the immobilized enzyme in a column.

Among the above enzymes, those having a high E value have high stereoselectivity. When an enzyme having a high E value is used, the optically active glycidic acid ester compound (II
While the transesterification amount of a) decreases, the transesterification amount of the by-product optically active glycidic acid ester compound (IIb) increases.

Therefore, when an enzyme having such a high E value is used, the precipitation of the optically active glycidic acid ester compound (IIa) is inhibited.
Since the amount of the transesterified product of (IIa) is reduced, the amount of the optically active glycidic acid ester compound (IIa) precipitated can be increased. Further, the amount of transesterification of the optically active glycidic acid ester compound (IIb) as a by-product increases, and the optically active glycidic acid ester compound (I
Since the amount of the ester compound (IIb ¹ ) that inhibits precipitation of Ib) is increased, the optically active glycidic acid ester compound
The precipitation of (IIb) can be suppressed.

Incidentally, the “E value” is widely used as an index indicating the stereoselectivity of an enzyme.

In general, as the transesterification proceeds, the enzyme is deactivated and a side reaction occurs, so that the measurement error of the E value tends to increase.

Therefore, in the present invention, in order to determine the E value when the side reaction and the like are relatively small and the measurement error is small, the E value for the transesterification at a conversion of 10% is measured. The “conversion rate of 10%” refers to the optically active glycidic acid ester compounds (IIa) and (Ia).
Means that 10% of Ib) is transesterified.

The conversion in the transesterification reaction was determined by the stereoselectivity of the enzyme and the optically active glycidic acid ester compound (I
Can be appropriately selected according to the content of Ia) and the like.

The E value is calculated by the following formula: E = ln [(1-c) (1-eeX)] ÷ ln [(1-c) (1 + eeX)] wherein c and eeX are represented by the following formulas. Therefore it can be determined.

C = (optically active glycidic acid ester compound (IIa) and optically active glycidic acid ester compound (I
Amount (mol) of transesterified product from Ib) ÷ (amount (mol) of transesterified product, amount (mol) of optically active glycidic acid ester compound (IIa) remaining after transesterification and optically active glycid Sum with acid ester compound (IIb) amount (mol))

EeX = (amount (mol) of optically active glycidic acid ester compound (IIa) remaining after transesterification
−Amount (mol) of optically active glycidic acid ester compound (IIb) ÷ (amount (mol) of optically active glycidic acid ester compound (IIa) remaining after transesterification + amount (mol) of optically active glycidic acid ester compound (IIb) ))]. The E value varies depending on the type of the enzyme.

When the conversion of the transesterification is constant at 10% and the E value is determined, the ratio of the optical isomers after the transesterification, the optical purity of the obtained crystals and the yield, regardless of the type of the enzyme. Rate can be predicted.

In the present invention, the E value is preferably at least 20 and preferably at least 50 from the viewpoint of the stereoselectivity of the enzyme.

The amount of the enzyme used depends on the type of the enzyme used, the form of use, and the like, and cannot be unconditionally determined. However, usually, the amount of the enzyme used is 1 × 10 5 It is preferably an amount having an olive oil hydrolysis activity of 〜1 × 10 ⁵ units, preferably 1 × 10 ² -1 × 10 ⁴ units.

[0257] The olive oil hydrolysis activity is measured by a fat digestion test method ["Pharmaceutical Research" 11 [3] (1980), which measures the amount of fatty acids that increase with the cleavage of ester bonds when lipase acts on olive oil. ) p.505-506].

Further, R in the alcohol compound (III)
¹ is an optically active glycidic acid ester compound (II
In the solvent used to crystallize a), the ester product (IIb ¹ ) formed by transesterification corresponds to an ester residue whose solubility is higher than that of the optically active glycidic acid ester compound (IIa). Preferred groups are:

Specific examples of R ¹ in the alcohol compound (III) include the following.

A halogen atom (for example, a fluorine atom,
A straight-chain or branched-chain alkyl group having a carbon number greater than R, which may have a chlorine atom, a bromine atom or an iodine atom (for example, n-propyl group, i-propyl group, n-butyl) Group, sec-butyl group, t-butyl group, n-pentyl group, 2-
Pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group, 3-hexyl group, n-heptyl group, 2-heptyl group, 3-heptyl group, 4-heptyl group, n-octyl group, 2- Octyl group, 3-octyl group, 4-octyl group, n-nonyl group, 2-nonyl group, 3-nonyl group, 4-nonyl group, 5-nonyl group, n-decyl group, 2-decyl group, 3- A decyl group, a 4-decyl group or a 5-decyl group) The above-mentioned R which may have a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom);
Straight-chain or branched-chain alkoxyalkyl groups having more carbon atoms (eg, methoxymethyl group, ethoxymethyl group, propoxymethyl group, methoxyethyl group, methoxypropyl group, methoxybutyl group, ethoxyethyl group, propoxypropyl group A) linear or branched alkyl group (for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, sec-butyl group, t-butyl group, n-pentyl group, 2 -Pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group or 3-hexyl group), linear or branched alkoxy group (for example, methoxy group, ethoxy group, n-propoxy group, i- Propoxy group, n-butoxy group, sec-butoxy group,
t-butoxy group, n-hexyloxy group, 2-hexyloxy group,
A 3-hexyloxy group) or an arylalkyl group (for example, a benzyl group, a phenethyl group, a phenylpropyl group, or a naphthylmethyl group) which may have a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom) )

Preferred examples of R ¹ in the alcohol compound (III) include, when the ester residue R of the optically active glycidic acid ester compound (IIa) is a methyl group or an ethyl group, an i-propyl group, an n- Butyl group, sec-butyl group, t-butyl group, n-pentyl group, n-hexyl group, n-
Examples include an octyl group, an n-nonyl group, an n-decyl group, a benzyl group and a phenethyl group. Among these, it is more preferred that R is a methyl group and R ¹ is an n-butyl group.

The amount of the alcohol compound (III) used is based on 1 mol of the optically active glycidic acid ester compound (IIb).
0.5 to 8 mol, preferably 1 to 4 mol,
It is desirable from the viewpoint of suppressing the deactivation of the enzyme and increasing the reaction rate.

The optically active glycidic acid ester compound
The transesterification of (IIb) is usually carried out at room temperature to under heating, preferably 10 to 50 ° C, more preferably 20 to 40 ° C.
It is desirable to carry out at about the same temperature.

The transesterification can be carried out in a suitable solvent or without a solvent.

As the solvent, an aromatic organic solvent (for example,
Benzene, toluene, xylene), halogenated aromatic organic solvents (eg, chlorobenzene, dichlorobenzene), aliphatic organic solvents (eg, hexane, heptane,
Cyclohexane), halogenated aliphatic organic solvents (eg, dichloromethane, chloroform, carbon tetrachloride, trichloroethane), ketone solvents (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone), ether solvents (eg, dimethyl ether, diethyl ether, diisopropyl) Ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane), ester solvents (eg, ethyl acetate, butyl acetate) and the like. Among them, toluene, xylene, hexane, carbon tetrachloride, tert-butyl methyl ether and diisopropyl ether are preferred in that the deactivation of the enzyme is small and the reaction rate is high.

The amount of the solvent used is such that the concentration of the optically active glycidic acid ester compound (IIa) is 0.02 to 4 mol / L.
It is desirable to adjust it to a degree, preferably 0.5 to 2 mol / L, from the viewpoint of increasing the reaction rate and miniaturizing the equipment for the transesterification reaction.

If water is present in the reaction system,
A hydrolysis reaction occurs together with the transesterification reaction, which may cause a decrease in yield. Therefore, it is preferable to avoid mixing of water as much as possible during the transesterification reaction.

Crystallization of only the optically active glycidic acid ester compound (IIa) from the mixture produced by transesterification can reduce the difference in solubility between the optically active glycidic acid ester compound (IIa) and the ester compound (IIb ¹ ) in a solvent. It can be done using.

Further, the ester compound (IIb ¹ ) present in the mixture inhibits the crystallization of the optically active glycidic acid ester compound (IIb) having a common absolute configuration. It is not necessary to transesterify all of the glycidic acid ester compound (IIb) into the ester compound (IIb ¹ ), and even if the transesterification is terminated while the optically active glycidic acid ester compound (IIb) remains, most The active glycidic acid ester compound (IIa) can be obtained by crystallization.

Optically active glycidic acid ester compound (II
The solvent that can be used for crystallizing a) may be any solvent that can be used for recrystallization of the optically active glycidic acid ester compound (IIa). Representative examples of the solvent include alcohol solvents such as methanol, ethanol, n-propanol, i-propanol and n-butanol; ether solvents such as diethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Benzene, toluene,
Aromatic hydrocarbon solvents which may be substituted with halogen atoms such as xylene, chlorobenzene, and dichlorobenzene; hexane, cyclohexane, n-heptane, n-octane, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc. Aliphatic hydrocarbon solvents which may be substituted by halogen atoms; ester solvents such as methyl acetate and ethyl acetate; and the like, and these can be used alone or as a mixture of two or more.

The solvent may be an optically active glycidic acid ester compound (IIa), an optically active glycidic acid ester compound
It can be appropriately selected and used depending on the type of ester residue of (IIb) and the generated ester compound (IIb ¹ ).
Among the above-mentioned solvents, the solubility of the optically active glycidic acid ester compound (IIa) greatly changes due to a change in temperature, and the solubility of the ester compound (IIb ¹ ) is much higher than that of the optically active glycidic acid ester compound (IIa). It is preferable to use a larger one.

As one example, for example, the optically active glycidic acid ester compound (IIa) is an optical isomer of trans-3- (4-methoxyphenyl) glycidic acid methyl ester, and the ester residue of the ester compound (IIb ¹ ) Is n-
In the case of butyl ester, diisopropyl ether, methanol, ethanol, xylene and the like can be suitably used as the solvent.

The amount of the solvent used depends on the type of the optically active glycidic acid ester compound (IIa), the optically active glycidic acid ester compound (IIb) and the produced ester compound (IIb ¹ ), their composition, crystallization temperature and the like. Because they are different, they cannot be determined unconditionally. When a solvent having a high solubility of the optically active glycidic acid ester compound (IIa) and the optically active glycidic acid ester compound (IIb) and a large change in solubility due to a temperature change is used, the amount of the solvent can be reduced. Usually, the amount of the solvent used is such that the concentration of the optically active glycidic acid ester compound (IIa) in the solution before crystallization is 0.5 to 4 mol / L.
It is preferable to adjust the temperature to the extent.

The amount of the ester compound (IIb ¹ ) formed by transesterification of the optically active glycidic acid ester compound (IIb) is such that the optically active glycidic acid ester compound (IIa) precipitates, It is preferable to adjust the amount so as to inhibit the precipitation of the ester compound (IIb). Since the amount of the ester compound (IIb ¹ ) to be formed differs depending on the composition and type of the optically active glycidic acid ester compound (IIa) and the optically active glycidic acid ester compound (IIb) contained in the reaction product, they are unconditional. Cannot be determined. From this, the ester compound (IIb
¹ ) The amount is preferably selected experimentally.

[0275] Also, in general, the production of the ester compound as the amount of (IIb ¹⁾ is increased, but so crystallization of optically active glycidic acid ester compound (IIb) is further suppressed, the ester compound (IIb ¹⁾ As the amount increases,
Since the amount of the optically active glycidic acid ester compound (IIb) decreases and the transesterification rate decreases, a large amount of enzyme,
A long reaction time is required, and the optically active glycidic acid ester compound (IIa) is also easily transesterified. Therefore, the transesterification reaction is preferably completed at an appropriate stage.

After the transesterification, the ratio of the optically active glycidic acid ester compound (IIa), the optically active glycidic acid ester compound (IIb) and the ester compound (IIb ¹ ) is as follows:
Since it differs depending on the type of the solvent used for crystallization and the like, it cannot be unconditionally determined.
In the case of 1), the optically active glycidic acid ester compound (I
Ia) / optically active glycidic acid ester compound (IIb) [molar ratio] is about 1/1 to 10/1, preferably 2/1 to 5
/ Ester compound (IIb ¹ ) / optically active glycidic acid ester compound (IIb) [molar ratio] is 5 /
It is desirably about 3 to 10/1, preferably about 2/1 to 7.8 / 1.

For example, 49 g of (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester as the optically active glycidic acid ester compound (IIa) and (2S, 3) as the optically active glycidic acid ester compound (IIb)
Xylene containing 14 g of R) -3- (4-methoxyphenyl) glycidic acid methyl ester and 39 g of (2S, 3R) -3- (4-methoxyphenyl) glycidic acid n-butyl ester as ester compound (IIb ¹ ) 10
When 0 ml of the solution was cooled to -10 ° C, (2R, 3
Even if 40 g of (S) -3- (4-methoxyphenyl) glycidic acid methyl ester is obtained by crystallization, (2S,
3R) -3- (4-methoxyphenyl) glycidic acid n
-Butyl ester and (2S, 3R) -3- (4-methoxyphenyl) glycidic acid methyl ester do not precipitate at all.

Therefore, even when the transesterification of the optically active glycidic acid ester compound (IIb) is stopped halfway, the optically active glycidic acid ester compound (IIb)
The optically active glycidic acid ester compound (IIa) can be crystallized and obtained until a) is much smaller than the optically active glycidic acid ester compound (IIb).

After transesterification, the temperature at which the optically active glycidic acid ester compound (IIa) is crystallized is such that the optically active glycidic acid ester compound (IIa) crystallizes,
The optically active glycidic acid ester compound (IIb) and the ester compound (IIb ¹ ) must be at a temperature at which they do not crystallize (however, when they are left to stand for a long time, they include a temperature at which they do not precipitate until precipitation starts).

The crystallization temperature depends on the type of the optically active glycidic acid ester compound (IIa), the solvent, and the composition of the solution to be crystallized. However, the stability of the oxirane ring of the optically active glycidic acid ester compound (IIa) is determined. From the viewpoint, it is not preferable to dissolve by heating to a very high temperature when preparing a solution to be crystallized. Therefore, it is preferable to dissolve at a temperature of about 70 ° C. or lower and crystallize at a low temperature of room temperature or lower.

When a large amount of the solvent is used, generally,
The crystallization of the optically active glycidic acid ester compound (IIa) tends to be difficult to proceed unless the temperature is low, and when the amount of the solvent used is small, the crystallization of the optically active glycidic acid ester compound (IIa) is generally performed. Tends to progress even at relatively high temperatures. Therefore, in consideration of industrial productivity, it is preferable to minimize the amount of the solvent and crystallize the solution from a concentrated solution at around room temperature. On the other hand, when crystallizing as the amount of solvent decreases, the content of impurities tends to increase, so from the viewpoint of obtaining high purity, the amount of solvent is increased, and crystallization at a low temperature can be performed. preferable.

Therefore, in order to efficiently crystallize the optically active glycidic acid ester compound (IIa), the type of the optically active glycidic acid ester compound (IIa), the type of the optically active glycidic acid ester compound (IIb), The optimum temperature range is preferably set experimentally in consideration of the type of the compound (IIb ¹ ), the type of the solvent, the composition of the reaction product, and the like.

As one example, for example, the optically active glycidic acid ester compound (IIa) and the optically active glycidic acid ester compound (IIb) are methyl esters, and the optically active glycidic acid ester compound (IIb) is stereoselectively esterified. When the ester compound (IIb ¹ ) obtained by the exchange is an n-butyl ester, when crystallization of the optically active glycidic acid ester compound (IIa) is performed using methanol, a temperature of about −30 to 15 ° C. It is preferred that

When the optically active glycidic acid ester compound (IIb) precipitates, the amorphous of the optically active glycidic acid ester compound (IIb) and the ester compound (IIb ¹ ) becomes cloudy and precipitates. The optically active glycidic acid ester compound (IIa) and the amorphous can be easily distinguished from each other in appearance, and the crystallization limit of the optically active glycidic acid ester compound (IIa) can be easily determined using the cloudiness of the amorphous as an index. You can know experimentally.

Optically active glycidic acid ester compound (II
The crystallization of a) ¹) Must exist
Optically active glycidic acid ester compound (IIb)
However, the ester compound (IIb¹), Optical activity
The glycidic acid ester compound (IIa) crystallizes,
No biologically active glycidic acid ester compound (IIb) precipitates
Optically active glycidic acid ester compound (I
Preferably, Ia) is obtained by crystallization.

As described above, the asymmetric oxidizing agent formed from the chiral ketone compound and the oxidizing agent is allowed to act on (A) the cinnamic acid ester compound (I), and the (B-1) chiral ketone compound is converted from the reaction mixture. After removing the compound, the optically active glycidic acid ester compound (IIa) contained in excess is obtained by crystallization, and the optically active glycidic acid ester compound (IIa) and (IIb) contained in the residue are obtained. In the mixture, an optically active glycidic acid ester compound (II
b) is reacted with an alcohol compound (III) in the presence of an enzyme that stereoselectively transesterifies the compound to crystallize the optically active glycidic acid ester compound (IIa), thereby obtaining a cinnamate compound ( From I), the optically active glycidic acid ester compound (IIa) can be prepared with high yield and high optical purity.

The removal of the chiral ketone compound from the reaction mixture, which is an optional step in the step (B-2),
It can be carried out in the same manner as the removal of the chiral ketone compound in the step (B-1).

The reaction mixture from which the chiral ketone compound was not removed or the extract obtained after the removal of the chiral ketone compound and the mixture of the optically active glycidic acid ester compounds (IIa) and (IIb) contained in the mother liquor were added to the optical mixture. In the presence of an enzyme capable of stereoselectively transesterifying the active glycidic acid ester compound (IIb), the alcohol compound (III) is allowed to act to convert the optically active glycidic acid ester compound (IIb) into the ester compound (IIb ^1). If the chiral ketone compound was not removed before transesterification, the chiral ketone compound was removed and only the optically active glycidic acid ester compound (IIa) was crystallized from the resulting mixture. , Can be obtained.

Optically active glycidic acid ester compound (II
In the transesterification reaction of b), the chiral ketone compound is not changed.Therefore, the removal of the chiral ketone compound may be performed before or after the transesterification reaction. Regardless of whether or not it is removed, it can be carried out in exactly the same manner as in the transesterification reaction in step (B-1).

However, in the step (B-2), unlike the case of the step (B-1), the optically active glycidic acid ester (IIa) is obtained by crystallization from the reaction mixture of the asymmetric oxidation reaction. However, since the reaction solution before transesterification contains a large amount of optically active glycidic acid ester (IIa), the optically active glycidic acid ester (IIa) / optically active glycidic acid ester (IIb) (molar ratio) Is about 6/1 to 100/1, preferably 7/1 to
It is desirable to be about 50/1.

The removal of the chiral ketone compound after transesterification can be carried out by removing the chiral ketone compound from the optically active glycidic acid ester compounds (IIa) and (IIb) and the ester compound (I
It can be carried out by a separation method utilizing a difference in solubility of Ib ¹ ) with an organic solvent.

As the separation method utilizing the difference in solubility,
As in the step (B-1), an extraction method using an organic solvent, a crystallization method using an organic solvent, and the like can be given. The ester compound (IIb ¹ ) is an optically active glycidic acid ester compound.
Since the solubility in organic solvents is higher than that of (IIa) and (IIb), the method used for removing the chiral ketone compound from the mixture of the optically active glycidic acid ester compounds (IIa) and (IIb) is directly applied. be able to.

The chiral ketone compound is not affected by an enzyme having the ability to stereoselectively transesterify the optically active glycidic acid ester compound (IIb), and when diisopropyl ether is used as a solvent for transesterification, Since the chiral ketone compound hardly dissolves under the temperature conditions of the transesterification reaction, the enzyme and the chiral ketone compound are removed at once by simply filtering the reaction solution under heating after the transesterification reaction is completed. It is particularly preferable because it can be used.

The subsequent crystallization of the optically active glycidic acid ester compound (IIa) from the product can be carried out in the same manner as in the crystallization after transesterification in the step (B-1). Also in this case, the ester compound (IIb ¹ ) generated by the transesterification reaction inhibits the precipitation of the optically active glycidic acid ester compound (IIb), so that the crystallization of the optically active glycidic acid ester compound (IIa) is efficiently performed. Can do it.

In particular, if the ester compound (IIb ¹ ) does not exist, the optically active glycidic acid ester compound (IIb) precipitates from the mixture produced by the transesterification, but the optically active glycidic acid ester compound (IIb ¹ ) exists. The active glycidic acid ester compound (IIa) crystallizes, but the optically active glycidic acid ester compound (IIb) does not precipitate, and the optically active glycidic acid ester compound (II
Preferably, a) is crystallized.

As described above, the asymmetric oxidizing agent formed from the chiral ketone compound and the oxidizing agent is allowed to act on (A) the cinnamic acid ester compound (I), and the (B-2) reaction mixture is optionally used. After removing the chiral ketone compound with the optically active glycidic acid ester compound (I
The alcohol compound (III) is allowed to act on the mixture of (Ia) and (IIb) in the presence of an enzyme capable of stereoselectively transesterifying the optically active glycidic acid ester compound (IIb). If the ketone compound was not removed, the ketone compound was removed and the optically active glycidic acid ester compound (IIa) was crystallized to obtain the optically active glycidic acid ester compound (I). The ester compound (IIa) can be prepared with high yield and high optical purity.

Next, the optically active glycidic acid ester compound (IIa) represented by the general formula (IIa) obtained above was used as a starting material, and the compound represented by the general formula (VII) was obtained by a conventionally known method.
I):

[0298]

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Wherein ring A, ring B and * are the same as described above, R ³ represents a hydrogen atom or a substituted alkyl group, and R ⁴ represents a lower alkanoyl group. Its pharmaceutically acceptable salts can be prepared.

In the method for producing such a 1,5-benzothiazepine derivative, ring B represents a substituted or unsubstituted benzene ring. Specifically, the ring B includes an unsubstituted benzene ring, a lower alkyl group, a phenyl lower alkyl group, a lower alkoxy group and a benzene ring having 1 to 3 substituents selected from the group consisting of halogen atoms. Is raised. Examples of the lower alkyl group include an alkyl group having 1 to 4 carbon atoms represented by a methyl group, an ethyl group, a propyl group, and a t-butyl group. Examples of the phenyl lower alkyl group include a phenylalkyl group having 7 to 10 carbon atoms represented by a benzyl group and a phenethyl group. Examples of the lower alkoxy group include alkoxy groups having 1 to 4 carbon atoms represented by a methoxy group, an ethoxy group, a propoxy group and a butoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

R ⁴ is a lower alkanoyl group, specifically, for example, a lower alkanoyl group having 1 to 4 carbon atoms represented by an acetyl group, a propionyl group and a butyryl group.

R ³ is a hydrogen atom or a substituted alkyl group. Specific examples of the substituted alkyl group include, for example, those having 1 to 4 carbon atoms in which the alkyl portion is represented by a methyl group, an ethyl group, a propyl group and a butyl group. Which are lower alkyl groups.

Examples of the substituent of the alkyl group include a di-lower alkylamino group represented by a dimethylamino group and a diethylamino group, and a substituted phenylpiperazino group represented by a 4- (2-methoxyphenyl) piperazino group. Can be given. As R ³ , a 2- (dimethylamino) ethyl group and a 3- [4- (2-methoxyphenyl) piperazino] propyl group are particularly preferred.

Specific examples of the thus obtained 1,5-benzothiazepine derivative (VIII) or a pharmaceutically acceptable salt thereof include, for example, (2S, 3S) -2- (4-methoxyphenyl) -3 -Acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one (diltiazem),
(2S, 3S) -2- (4-methoxyphenyl) -3-
Acetoxy-5- [2- (dimethylamino) ethyl]-
8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one, (2S, 3S) -3-acetoxy-5- [3- [4- (2-methoxyphenyl) piperazino ] Propyl] -2,3-dihydro-2- (4-methoxyphenyl) -8-chloro-1,5-benzothiazepin-4 (5H) -one, (2S, 3S) -3-acetoxy-8- Benzyl-2,3-dihydro-5- [2-
(Dimethylamino) ethyl] -2- (4-methoxyphenyl) -1,5-benzothiazepine-4 (5H) -one, (2R, 3R) -2- (4-methylphenyl) -3
-Acetoxy-5- [2- (dimethylamino) ethyl]
And -8-methyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one, and pharmacologically acceptable salts thereof.

The 1,5-benzothiazepine derivative (VIII) or a pharmaceutically acceptable salt thereof obtained by the production method of the present invention can be used for heart diseases such as angina pectoris, myocardial infarction and arrhythmia, hypertension, coronary vessels It is a useful compound for cardiovascular diseases such as infarction and cerebral infarction.

More specifically, for example, Japanese Patent Publication No. 46-167
No. 49, Japanese Patent Publication No. 63-13994,
-201865, JP-A-2-289558, JP-B-2-28594, Chemical &
Pharmaceutical Bulletin (Chem. Ph.
arm. Bull. ) 18 (10), 2028-20
37 (1970), JP-A-2-17168, JP-A-2-229180, JP-A-4-234866, JP-A-5-222016, JP-A-4-22
1376, JP-A-5-202013, JP-A-2-17170, JP-A-2-286672, JP-A-6-279398, JP-A-58-99
471, JP-A-8-269026, JP-A-61-118377, JP-A-6-228117, JP-A-2-78673, JP-A-5-435
No. 64, etc., according to the general formula (II
optically active glycidic acid ester compound represented by a)
From (IIa), a 1,5-benzothiazepine derivative represented by the general formula (VIII) or a pharmaceutically acceptable salt thereof can be produced.

More specifically, for example, as the optically active glycidic acid ester compound (IIa), its (2R, 3
When the (S) -isomer is used, the (2R, 3S) -isomer is converted into (A-1) a general formula (IX):

[0308]

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[Wherein, ring B is the same as defined above, R ⁵ is a hydrogen atom, a 2- (dimethylamino) ethyl group, or a compound represented by the formula:

[0310]

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And the aminothiophenol derivative (IX) (for example, 2-aminothiophenol, 2-amino-5-chlorothiophenol,
2-amino-5-benzylthiophenol, 2-[[2
-(Dimethylamino) ethyl] amino] thiophenol, general formula:

[0312]

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(Wherein, ring B is the same as defined above)) or (A-2)
(X):

[0314]

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(Wherein ring B is as defined above) (X) (for example, 2-nitrothiophenol, 2-nitro-5-chlorothiophenol, 2-nitro-5-benzyl Thiophenol) and then reducing the nitro group to form a compound of the general formula:

[0316]

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(Wherein ring A, ring B, R and R ⁵ are the same as described above). (2S, 3S) -3- (2-aminophenylthio) -3-phenyl-2-hydroxypropionic acid An ester compound is prepared and (B) hydrolyzed, if necessary, and then closed intramolecularly to obtain an ester compound having the general formula:

[0318]

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(Wherein ring A, ring B and R ⁵ are the same as described above). (2S, 3S) -2-phenyl-3-
A hydroxy-1,5-benzothiazozepine derivative,
(C) If necessary, modify the nitrogen atom at the 5-position and acetylate the hydroxyl group substituted at the 3-position, and (D) convert the product into a pharmaceutically acceptable salt, if necessary. By the general formula:

[0320]

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Wherein a ring (A), ring (B) and R ( ⁵⁾ are the same as defined above, or a (2S, 3S) -1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof. Can be.

Further, for example, when the (2S, 3R) -isomer is used as the optically active glycidic acid ester compound (IIa), the (2S, 3R) -isomer is replaced with (A-
1) reacting with aminothiophenol derivative (IX) or
Or (A-2) reacting with a nitrothiophenol derivative (X), and then reducing the nitro group to obtain a compound represented by the general formula:

[0323]

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(Wherein ring A, ring B, R and R ⁵ are the same as described above). (2R, 3R) -3- (2-aminophenylthio) -3-phenyl-2-hydroxypropionic acid An ester compound is prepared and (B) hydrolyzed, if necessary, and then closed intramolecularly to obtain an ester compound having the general formula:

[0325]

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(Wherein ring A, ring B and R ⁵ are the same as described above). (2R, 3R) -2-phenyl-3-
A hydroxy-1,5-benzothiazozepine derivative,
(C) modifying the compound, if necessary, by modifying the nitrogen atom at the 5-position and acetylating the hydroxyl group substituted at the 3-position,
(D) optionally, converting the product to a pharmaceutically acceptable salt to form a compound of the general formula:

[0327]

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Wherein the ring A, ring B and R ⁵ are as defined above, or a (2R, 3R) -1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof. Can be.

As one example, Diltiazem (Diltiazem)
m) and the stereochemistry for its enantiomers can be summarized, for example, by the formula:

[0330]

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When the aminothiophenol represented by the following formula is reacted with the optically active glycidic acid ester compound (IIa), the reaction proceeds as follows. That is,
When the (2S, 3R) -isomer is reacted with the aminothiophenol to cause cis-cleavage and when the (2S, 3S) -isomer is reacted with the aminothiophenol and trans-cleaved, the (2R, 3R) ) -Propionic acid derivative is obtained. When the (2R, 3S) -isomer is reacted with the aminothiophenol to cause cis-cleavage and when the (2R, 3R) -isomer is reacted with the aminothiophenol and trans-cleaved, the (2S , 3
An S) -propionic acid derivative is obtained.

[0332]

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[Wherein rings A and R are the same as defined above]

Next, as shown in the following scheme,
The (2R, 3R) -propionic acid derivative or (2R, 3R) -propionic acid derivative
(S, 3S) -Propionic acid derivative is hydrolyzed and closed intramolecularly to give 2-phenyl-3-hydroxy- obtained.
By dimethylaminoethylating the nitrogen atom at the 5-position of the 1,5-benzothiazepine derivative and acetylating the hydroxyl group at the 3-position, the (2R, 3R) -1,5-benzothiazepine derivative or (2S, 3S) -1,5-
A benzothiazepine derivative is obtained.

[0335]

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[Wherein rings A and R are the same as defined above]

Further, the compound represented by the general formula (II) obtained by the production method of the present invention
optically active glycidic acid ester compound represented by a)
Using (IIa) as a starting material, by a conventionally known method,
A general formula useful as an optical resolving agent:

[0338]

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(Wherein ring A and ring B are as defined above, *
Represents an asymmetric carbon atom), or a salt thereof.

In the method for producing such a nitrocarboxylic acid compound, the ring A and the ring B may be the same as those in the method for producing the 1,5-benzothiazepine derivative. Group, ring B
Is the formula:

[0341]

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(Wherein Hal represents a halogen atom), and is preferably a substituted benzene ring.
Is a 4-methoxyphenyl group, and ring B is Ha in the above formula.
Those in which 1 is a chlorine atom are particularly preferred.

Specifically, as the nitrocarboxylic acid compound, for example, an optically active glycidic acid ester compound (I
Ia) and the general formula:

[0344]

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A nitrothiophenol compound represented by a compound represented by the formula (wherein Hal is the same as described above) is reacted with a method described in JP-B-61-18549 and the like. And Pharmaceutical Bulletin (Chem. Phar
m. Bull. ) 18 (10) 2028-2037
It can be produced by hydrolyzing the product according to the method described in (1970).

In this method, when the (2R, 3S) -optically active glycidic acid ester compound is used, (2S, 3S)
An (S) -optically active nitrocarboxylic acid compound can be obtained, and if a (2S, 3R) -optically active glycidic acid ester compound is used, a (2R, 3R) -optically active nitrocarboxylic acid compound can be obtained.

By the way, among the ketone compounds (IV),
Y is (i) -O-Q-Alk ¹ -or (v) -NR ² -Q
-Alk ¹ -is a ketone compound represented by the general formula (XI):

[0348]

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Wherein Z represents —O— or —NR ² —, and Ar and R ² are the same as defined above; and a compound represented by the general formula (XII):

[0350]

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Wherein Prot represents a hydroxyl-protecting group, Alk ¹ and Q are the same as defined above, or a reactive derivative thereof, and Z is -NH-
If necessary, if necessary, N-alkylsulfonylation or N-arylsulfonylation to form a general formula (XIII):

[0352]

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Wherein Ar, Prot, Z, Alk ¹ and Q are the same as defined above, and after removing the hydroxyl-protecting group from the compound represented by the formula:
Can be manufactured.

In the ketone compound (IV), Y is
(ii) -Q-O-Alk 2 - or (vi) -Q-NR ² -A
The ketone compound represented by lk ² — has the general formula (XIV):

[0355]

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Wherein Ar and Q are as defined above, or a reactive derivative thereof, and a compound represented by the general formula (X
V):

[0357]

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[Wherein Z and Alk ² are the same as above]
Is reacted with a compound represented by the formula
Is -NH-, if necessary, it can be produced by N-alkylsulfonylation or N-arylsulfonylation.

In the ketone compound (IV), Y is (iii)
-Alk ³ -O-Alk ⁴ -or (vii) -Alk ^3-
The ketone compound represented by NR ² -Alk ^4- has the general formula (XV
I):

[0360]

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Wherein Ar is the same as defined above to reduce the compound represented by the general formula (XVII):

[0362]

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A compound represented by the formula: wherein Ar is the same as described above, is produced. If necessary, the alkyl chain bonded to the hydroxyl group of the compound is extended, and the hydroxyl group is converted to an amino group. N-alkylsulfonylation or N-arylsulfonylation according to the general formula (XVIII):

[0364]

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Wherein Ar, Alk ³ and Z are the same as those described above, and then the compound represented by the general formula (XIX):

[0366]

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Wherein L is a leaving group and Alk ⁴ is the same as defined above, and Z is -N
When it is H-, it can be produced by N-alkylsulfonylation or N-arylsulfonylation as necessary.

In the ketone compound (IV), Y is (iv)
The ketone compound represented by —O-Alk ⁵ — or (viii) —NR ² —Alk ⁵ — is a compound represented by the general formula (XI) and a compound represented by the general formula (XX):

[0369]

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[Wherein L and Alk ⁵ are the same as above]
When Z is -NH-, the compound can be produced by N-alkylsulfonylation or N-arylsulfonylation, if necessary.

In the ketone compound (IV), when Y is —NR ² —Alk ⁵ —, a compound represented by the general formula (XI) wherein Z is —NH— and Q is carbonyl A compound obtained by reacting a compound represented by the general formula (XII) or a reactive derivative thereof, that is, a compound represented by the general formula (XIII) in which Z is -NH- and Q is a carbonyl group. The compound can be produced by reducing the compound represented by N-alkylsulfonylation or N-arylsulfonylation as necessary, removing the protecting group for the hydroxyl group, and subjecting it to an oxidation reaction.

The compound represented by the general formula (XI) and the compound represented by the general formula (XI)
Reaction with the compound represented by the formula (XII) or a reactive derivative thereof, and reaction between the compound represented by the general formula (XIV) or the reactive derivative thereof and the compound represented by the general formula (XV) or a dimer thereof Can be carried out according to a conventional method of ester synthesis or amide synthesis.

As the reactive derivative of the compound represented by the general formula (XII) and the compound represented by the general formula (XIV), common reactive derivatives of carboxylic acid and sulfonic acid, for example, acid chloride, acid bromide, acid Acid halides such as iodide; mixed acid anhydrides such as isobutyl chlorocarbonate, 2,6-dichlorobenzoic acid chloride or mixed acid anhydrides with 2,4,6-trichlorobenzoic acid chloride; N, N ′
-Dicyclohexylcarbodiimide (hereinafter referred to as DCC), a combination of DCC and 1-hydroxybenzotriazole, and an active ester formed using benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate. be able to.

The protecting group for the hydroxyl group in the compound represented by the formula (XII) may be a commonly used protecting group for a hydroxyl group, for example, a lower alkanoyl group, a substituted silyl group, an optionally substituted benzyl group and the like. Groups can be used.

The dimer of the compound represented by the general formula (XV) has a carbonyl group of the compound represented by the general formula (XV)
A compound represented by the general formula (XV), which is formed by adding an HZ group of another molecule to another compound, and a carbonyl group and an HZ group are mutually added between two molecules to form a cyclic structure. It may be. Such a dimer can also be used in equilibrium with the monomer.

A compound represented by the general formula (XI) and a compound represented by the general formula:
Reaction with a compound represented by the formula (XII);
V) is reacted with a compound represented by the general formula (XV) or a dimer thereof, a suitable solvent, for example,
Optionally halogenated aliphatic hydrocarbon solvents (hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, etc.), and optionally halogenated aromatic hydrocarbon solvents (toluene,
Among solvents such as xylene, mesitylene, chlorobenzene, dichlorobenzene, etc., nitrile solvents (acetonilyl, propionitrile, butyronitrile, etc.), ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, diglyme, etc.) For example, DC
It can be carried out at room temperature or under heating in the presence of a condensing agent such as C, N-methylpyridinium halide. At this time, if necessary, a deoxidizing agent such as triethylamine, diisopropylethylamine, or pyridine may be added.

On the other hand, the reaction of the compound represented by the general formula (XI) with the reactive derivative of the compound represented by the general formula (XII), and the reaction of the compound represented by the general formula (XIV) with the reactive derivative of the general formula (XIV) The reaction with the compound represented by the formula (XV) or a dimer thereof is carried out by a suitable solvent [for example, an aliphatic hydrocarbon solvent which may be halogenated (hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, tetrachloride) Carbon), optionally halogenated aromatic hydrocarbon solvents (toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, etc.), nitrile solvents (acetonitrile, propionitrile, butyronitrile, etc.), ether solvents (diethyl ether,
In tetrahydrofuran, 1,4-dioxane, diglyme, etc.) in the presence or absence of a deoxidizing agent [for example, an organic base (eg, triethylamine, trimethylamine, pyridine, diisopropylethylamine)] at room temperature or under heating. can do.

The compound represented by the general formula (VIII) and the general formula
Reaction with a compound represented by the formula (XIX),
The reaction of the compound represented by I) with the compound represented by the general formula (XX) can be carried out according to a conventional method of O-alkylation of an alcohol or N-alkylation of an amine.

The leaving group L in the compound represented by the general formula (XIX) and the compound represented by the general formula (XX) may be a conventional leaving group [for example, a halogen atom such as a chlorine atom, a bromine atom and an iodine atom] , An alkylsulfonyloxy group or an arylsulfonyloxy group (tosyloxy group, methanesulfonyloxy group)] and the like.

The reaction between the compound represented by the general formula (XVIII) and the compound represented by the general formula (XIX) and the reaction between the compound represented by the general formula (XI) and the compound represented by the general formula (XX) A suitable solvent [for example, an aliphatic hydrocarbon solvent which may be halogenated (hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and the like), an aromatic hydrocarbon which may be halogenated In a solvent such as toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, or a nitrile solvent (acetonitrile, propionitrile, butyronitrile), a deoxidizing agent [for example, an organic base (triethylamine, trimethylamine, pyridine, diisopropylethylamine)] )] At room temperature or under heating. Kill.

In the step of removing the hydroxyl-protecting group from the compound represented by the general formula (XIII), a conventional method for removing a hydroxyl-protecting group (for example, hydrolysis, catalytic hydrogenation, fluorination, Hydrogen acid treatment) can be applied. For example, a compound represented by the general formula (XIII) can be treated with a suitable solvent [for example, an alcohol solvent (methanol, ethanol), an ether solvent (tetrahydrofuran, 1,4
-Dioxane, diglyme)] in a base [eg, alkali metal hydroxide (potassium hydroxide, sodium hydroxide), alkali metal carbonate (potassium carbonate, sodium carbonate), organic acid (formic acid, trifluoroacetic acid), inorganic acid (Hydrochloric acid, hydrofluoric acid)].

In the subsequent oxidation reaction, a conventional method for converting a hydroxymethylene group into a carbonyl group (for example, chromic acid oxidation, ruthenium oxide oxidation, Swern oxidation [SwernO.
xidation, Merck Index # 12
Edition ONR-89], Dess-Martin oxidation [Dess-Martin
Oxidation, Merck Index # 12
Edition ONR-22]). For example, a product obtained by a reaction for removing a protecting group for a hydroxyl group is converted into a suitable solvent [for example, an aliphatic hydrocarbon solvent which may be halogenated (hexane). , Cyclohexane, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride),
An oxidizing agent [for example, chromic acid or the like] in an aromatic hydrocarbon solvent (toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene) which may be halogenated, Derivatives (pyridinium chlorochromate), ruthenium oxide, oxalic acid dichloride
Dimethylsulfoxide, 1,1,1-tris (acetyloxy) -1,1-dihydro-1,2-benziodoxol-3 (1H) -one].

The reduction reaction of the compound represented by the general formula (XVI) can be carried out according to a conventional method for reduction of a carboxylic acid. For example, the compound represented by the general formula (XVI) is dissolved in a suitable solvent [eg, ether-based Solvent (diethyl ether, tetrahydrofuran, 1,4-dioxane, diglyme)]
Inside, it can be carried out by treating with a reducing agent (for example, diborane, lithium aluminum hydride, or the like).

The extension of the alkyl moiety bonded to the hydroxyl group of the compound represented by formula (XVII) obtained by this reduction reaction can be carried out according to a conventional method. For example, the compound represented by the general formula (XVII) is treated with a halogenating agent [for example, thionyl halide (thionyl chloride, thionyl bromide) or the like], or the compound represented by the general formula (XV
The hydroxyl group of the compound represented by II) is converted to a leaving group with, for example, p-toluenesulfonyl halide (p-toluenesulfonyl chloride, p-toluenesulfonyl bromide) and the like, followed by treatment with the halogenating agent to form a compound. The reaction can be carried out by reacting a halide with magnesium to form a Grignard reagent, reacting with an alkyl aldehyde or alkyl ketone, and then treating with water. The conversion of a hydroxyl group to an amino group can also be carried out according to a conventional method. For example, the general formula (XVI
It can be carried out by treating the compound represented by I) or the compound having an extended alkyl chain bonded to its hydroxyl group with the same halogenating agent, and then reacting with ammonia.

On the other hand, the reduction reaction of the compound represented by the general formula (XIII) wherein Z is —NH— and Q is a carbonyl group is carried out by the same method as the reduction reaction of the compound represented by the general formula (XVI). , Can be implemented. After the reduction reaction, N
Removing the protecting group of the hydroxyl group from the product obtained by -alkylsulfonylation or N-arylsulfonylation,
The oxidation reaction can be carried out in the same manner as the removal of the protecting group for the hydroxyl group and the oxidation reaction of the compound represented by the general formula (XIII).

The N-alkylsulfonylation reaction and N-arylsulfonylation reaction, which are optional steps, can be carried out according to a conventional method for sulfonylation of an amine. The reaction can be carried out using an alkylsulfonic acid, an arylsulfonic acid or a reactive derivative thereof. Examples of the reactive derivative include an acid halide (acid chloride, acid bromide, acid iodide) and the like.

When an alkylsulfonic acid or an arylsulfonic acid is used, the reaction is preferably performed in a suitable solvent in the presence of a condensing agent. On the other hand, when a reactive derivative is used, the reaction is performed in a suitable solvent. It is preferable to carry out in the presence or absence of a deoxidizing agent.

Further, a compound represented by the general formula (XI):
After optically resolving a compound represented by the general formula (XIV), a compound represented by the general formula (XVI), a compound represented by the general formula (XVII) and a compound represented by the general formula (XVIII) by a conventional method, By applying the above synthesis method, the ketone compound (IV) can be obtained in the form of an optical isomer.

As the optical resolution method, for example, a method of fractionally crystallizing a diastereomer salt with an optical resolution agent can be applied. As the optical resolving agent, those generally used for optical resolution can be appropriately used. As the optical resolving agent, for example, optically active amines are preferable, and in particular, optical isomers such as quinidine, cinchonidine, optically active amino acid, optically active amino acid ester, quinine, brucine, and optically active amino alcohol are preferable.

The cinnamic acid used in the method of the present invention is
Of the stele compound (I), -CO _TwoR is low-grade alkoxy
Compounds that are cycarbonyl groups have the general formula:

[0391]

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(Wherein ring A represents a substituted or unsubstituted benzene ring) with a lower alkyl acetic acid ester in the presence or absence of a solvent in the presence of a base, If necessary, the product can be transesterified in the presence or absence of an acid to produce the product in good yield.

As the lower alkyl acetate, any of methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate and the like can be preferably used. Lower alkyl acetates that can be used as a solvent (for example, methyl acetate, When using (ethyl acetate), it is not always necessary to add another solvent.

As the base used in the condensation reaction between benzaldehyde and a lower alkyl acetic acid ester, an alkali metal alkoxide (for example, lithium methoxide, lithium ethoxide, lithium n-butoxide, lithium t-toxide) can be used.
Butoxide, sodium methoxide, sodium ethoxide, sodium n-butoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium n-butoxide, potassium t-butoxide, a metal alkali metal (eg, metal lithium, metal sodium) , Metal potassium), alkali metal hydrides (eg, lithium hydride, sodium hydride, potassium hydride),
Examples include strong inorganic bases such as alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, and potassium hydroxide).

The condensation reaction is carried out at room temperature to under heating.
C. to 60.degree. C. can be suitably carried out.

When the ester residue of the condensation product does not have the desired ester residue, it can be converted to a compound having the desired ester residue by a usual transesterification reaction.

The transesterification can be carried out using a lower alkanol corresponding to the desired ester residue. When this alcohol also serves as a solvent, it is not always necessary to add another solvent.

The acids used in the transesterification reaction include:
Inorganic acids (e.g., sulfuric acid, hydrochloric acid, phosphoric acid) and organic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid) can be given. The transesterification reaction can be carried out by directly adding an alcohol to the reaction mixture of the condensation reaction. The reaction is carried out at room temperature to the reflux temperature of the solvent, especially
It is preferably carried out at 0 ° C.

[0399]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to only these examples.

Example 1 (1) Oxidation reaction Trans-4-methoxycinnamic acid methyl ester 9.6
1 g (0.05 mol) and (R) -2 as an asymmetric catalyst
-Oxotrimethylene 1,1'-binaphthyl-2,2 '
991 mg of dicarboxylate in 100 ml of acetone
, And 45 ml of water was added.

While stirring the resulting mixture at 25 ° C., 30.74 g of oxone and 13.02 g of sodium hydrogen carbonate
Was added approximately every 5 minutes for 1.5 hours.

After completion of the addition, the mixture was further stirred at the same temperature for 2 hours. After the reaction, the mixture was extracted twice with 200 ml of toluene, and the toluene layer was dehydrated with magnesium sulfate and filtered.
The filtrate was concentrated under reduced pressure to obtain a residue.

The obtained residue contains (2R, 3S) -3-
7.1 g of (4-methoxyphenyl) glycidic acid methyl ester, 2.3 g of (2S, 3R) -3- (4-methoxyphenyl) glycidic acid methyl ester and (R)
-2-oxotrimethylene 1,1'-binaphthyl-2,
2'-dicarboxylate was included.

(2) Transesterification reaction The residue was mixed with 100 ml of diisopropyl ether and n-
1.6 ml of butanol and 10 mg of the esterase (freeze-dried sample, 1.96 × 10 ⁵ U / g olive oil activity) obtained in Reference Example 11 were added, and the mixture was stirred at 30 ° C. for 6 hours.

After completion of the reaction, the mixture was heated to 40 to 50 ° C., and 3- (4-methoxyphenyl) glycidic acid methyl ester was dissolved in the residue, and the insoluble (R) -2-oxotrimethylene 1,1′- Binaphthyl-2,2'-dicarboxylate and enzyme were removed by filtration.

The filtered product contained 690 mg of (R) -2-oxotrimethylene 1,1′-binaphthyl-2,2′-dicarboxylate (recovery:
70%).

(3) Crystallization Next, the amount of the filtrate was reduced by half under reduced pressure, cooled to -10 ° C and stirred for 1 hour, and then the crystals were filtered to obtain (2R, 3S)
6.7 g (yield: 64.4% based on trans-4-methoxycinnamic acid methyl ester) of crystals of -3- (4-methoxyphenyl) glycidic acid methyl ester were obtained.

The (2R, 3S) -isomer obtained had an optical purity of 99.2%.

(2R, 3) generated in the above (1) to (3)
S) -3- (4-methoxyphenyl) glycidic acid methyl ester, (2S, 3R) -3- (4-methoxyphenyl) glycidic acid methyl ester and (2S, 3
R) -3- (4-Methoxyphenyl) glycidic acid n-
Table 1 shows the amount of butyl ester.

[0410]

[Table 1]

From the results shown in Table 1, according to the method of Example 1, (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester can be selectively obtained in high yield. We can see that we can do it.

Example 2 In Example 1, 1,2-dimethoxyethane 1 was used in place of 100 ml of acetone used in the oxidation reaction (1).
The reaction was carried out in the same manner as in Example 1 except that 00 ml was used.

As a result, the obtained residue contained (2R, 3
8.3 g of (S) -3- (4-methoxyphenyl) glycidic acid methyl ester and 1.0 g of (2S, 3R) -3- (4-methoxyphenyl) glycidic acid methyl ester were contained.

The residue was subjected to an enzymatic reaction and crystallization in the same manner as in Example 1 to give crystals of methyl (2R, 3S) -3- (4-methoxyphenyl) glycidate.
9 g (yield: 75.9% from trans-4-methoxycinnamic acid methyl ester) was obtained (optical purity was 99.1%).
ee).

This residue contained 650 mg of (R) -2-oxotrimethylene 1,1′-binaphthyl-2,2′-dicarboxylate (recovery: 66).
%).

The (2R, 3) generated in the above (1) to (3)
S) -3- (4-methoxyphenyl) glycidic acid methyl ester, (2S, 3R) -3- (4-methoxyphenyl) glycidic acid methyl ester and (2S, 3
R) -3- (4-Methoxyphenyl) glycidic acid n-
Table 2 shows the amount of butyl ester.

[0417]

[Table 2]

From the results shown in Table 2, according to the method of Example 2, methyl (2R, 3S) -3- (4-methoxyphenyl) glycidate can be selectively obtained in high yield. We can see that we can do it.

Example 3 (1) Oxidation Reaction Trans-4-methoxycinnamic acid methyl ester 192
mg (1.0 mol) in 1,2-dimethoxyethane 15m
After dissolving at room temperature, 10 ml of a 4 × 10 ^-4 M aqueous solution of disodium ethylenediaminetetraacetate was added, and then (R) -2-oxotrimethylene 1,1′-binaphthyl-2,2′-dicarboxylate was added. 40 mg of latet,
It was cooled to 0 ° C. by an external bath.

Next, Oxone 6.14 was added to the obtained solution.
g and 2.6 g of sodium bicarbonate were added hourly in six portions. After completion of the addition, the mixture was further stirred for 2 hours, and the obtained reaction mixture was poured into half-saturated saline and extracted with ether. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate.

After drying, anhydrous magnesium sulfate was separated by filtration.
The solvent was distilled off from the filtrate to obtain a residue. (2) Transesterification / Crystallization The obtained residue was mixed with ethylene acetate and n-hexane at a ratio of 1: 8.
(Volume ratio) 9 ml of the mixture was added, and the mixture was stirred at room temperature for 1 hour.

The precipitated white powder was collected by filtration and dried under reduced pressure to recover 32 mg of (R) -2-oxotrimethylene 1,1'-binaphthyl-2,2'-dicarboxylate (recovery rate: 80%).

On the other hand, the obtained filtrate (yield by HPLC:
91%) by flash column chromatography on silica gel (mobile phase: ethyl acetate: n-hexane = 1: 8).
(Volume ratio)) to give (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester 135m
g was obtained (81% ee).

Next, the mother liquor was concentrated under reduced pressure, and the obtained residue was treated in the same manner as in Example 1 (2) transesterification and (3) crystallization to give (2R, 3S) -3-
Crystals of (4-methoxyphenyl) glycidic acid methyl ester could be obtained.

Example 4 Example 3 was repeated except that the solvent used in the oxidation reaction of Example 3 was changed to acetone.
By performing the same processing as in (2R, 3S) -3-
Crystals of (4-methoxyphenyl) glycidic acid methyl ester can be obtained.

Examples 5 to 9 In Example 1, (1) 991 mg of (R) -2-oxotrimethylene 1,1'-binaphthyl-2,2'-dicarboxylate was used as an asymmetric catalyst in the oxidation reaction. Instead of the formula:

[0427]

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A compound represented by the formula [Example 5], having the formula:

[0429]

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A compound represented by the following formula (Example 6):

[0431]

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[Example 7] or a compound represented by the formula:

[0433]

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[Example 8] or a compound represented by the formula:

[0435]

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The reaction was carried out in the same manner as in Example 1 except that the compound [Example 9] was used,
In any of Examples 5 to 9, as in Example 1,
(2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester can be obtained selectively and in high yield.

Example 10 Trans-4-methoxycinnamic acid methyl ester 2.1
99 g (11.44 mmol) and the formula:

[0438]

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244 mg of a ketone catalyst (0.
8.4 ml of an aqueous solution of 3.88 g (46.14 mmol) of sodium hydrogen carbonate was added to 30 ml of a 1,4-dioxane solution of 62 mmol), and the mixture was stirred at 15 ° C. To this, the suspension of the oxidizing agent prepared in Reference Example 13 is added at intervals of 20 minutes over 2 hours and 20 minutes, and 3.4 ml of water is further added. After the addition, the mixture was stirred at 27 ° C for 17 hours,
Then, the resulting mixture was extracted with 100 ml of chloroform. The aqueous layer was extracted again with chloroform (50 ml × 2), and the organic layers were combined, washed with saturated saline, and dried over anhydrous sodium sulfate.

The obtained residue was analyzed by HPLC. As a result, 2.153 g of (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester was obtained (yield: 90.
It was presumed to be a mixture of 4%, optical purity: 75.5% ee), 48.4 mg of trans-4-methoxycinnamic acid methyl ester and 192.7 mg of the compound.

The conditions of the HPLC are as follows. [Column] Chiral OD [Mobile phase] Hexane: isopropanol = 10: 1 (volume ratio) [Flow rate] 1.0 ml / min [Absorption wavelength] 220 nm [Column temperature] 40 ° C

Further, this residue was used in Example 1 (2)
By treating in the same manner as (3) or (2) of Example 3, (2R, 3S) -3- (4-methoxyphenyl)
Glycidic acid methyl ester can be obtained selectively and in high yield.

Example 11 In a 100 ml three-necked flask, 1.664 g (8.66 mm) of trans-4-methoxycinnamic acid methyl ester was placed.
ol), the formula:

[0444]

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172 mg of the asymmetric catalyst represented by the formula (0.4
3mmol) and 3.637 g of sodium hydrogen carbonate
(43.29 mmol) of 1,4-dioxane-water (2
(2.5 ml-5.9 ml), and the mixture was stirred in a constant temperature bath at 20 ° C. To this, the solution of the oxidizing agent prepared in Reference Example 14 was added every 15 minutes for about 2.5 hours. At this time, about 0.9 ml of a single addition was dropped over about 2 minutes. Finally, it was washed with 1 ml of water. After the addition, the reaction solution was stirred in a thermostat at 27 ° C. for 19 hours.

To the reaction mixture was added 100 ml of water, and the mixture was extracted with chloroform (15 ml × 3 times).
After washing with 0 ml, it was dried over magnesium sulfate.

The obtained residue was treated with H in the same manner as in Example 10.
Analysis by PLC showed (2R, 3S) -3- (4-
Methoxyphenyl) glycidic acid methyl ester 1.5
35 g (Yield: 85.1%, optical purity: 74.8% e)
e), trans-4-methoxycinnamic acid methyl ester 176 mg (yield: 10.6%) and ketone compound 1
Presumed to be 65 mg of mixture.

Further, this residue was used in Example 1 (2)
By treating in the same manner as (3) or (2) of Example 3, (2R, 3S) -3- (4-methoxyphenyl)
Glycidic acid methyl ester can be obtained selectively and in high yield.

Reference Example 1 (1) Optical Resolution of Bianthraquinonecarboxylic Acid Racemic 1,1′-bis (2-anthraquinonecarboxylic acid) (hereinafter referred to as Bianthraquinonecarboxylic acid)
2.40 g was dissolved in 120 ml of ethanol and heated to reflux. Then, in this solution, the formula:

[0450]

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After gradually adding 3.13 g of quinidine represented by the above formula, the mixture was heated under reflux for 15 minutes. Thereafter, the mixture was allowed to cool to room temperature and left overnight, and the precipitated quinidine salt of bianthraquinone carboxylic acid was collected by filtration, washed with ethanol, and added with 114 ml of a 1% aqueous sodium hydroxide solution.
Was added and heated at 60 ° C. for 30 minutes. After heating, the mixture was allowed to cool to room temperature, and 3.5% hydrochloric acid was added to adjust the pH to 2.
Stirred for 0 minutes.

Next, ethyl acetate was added to the reaction mixture for extraction, followed by drying and distilling off the solvent. The obtained extract was dissolved in methanol, recrystallized, and distilled until about 17 ml of the solvent remained.
The obtained crystals were collected by filtration.

Next, the obtained crystals were heated at 60-70 ° C. for 16 hours.
After drying under reduced pressure for a period of time, 890 mg of a (-)-form of Bianthraquinonecarboxylic acid was obtained.

The physical properties of the obtained (−)-form Bianthraquinonecarboxylic acid are as follows.

Decomposition point (dp): 196.8-220.6 ° C. [α] _D ²⁵ : -225 ° (C = 0.8, MeOH) IR
(Nujol) ν _max (cm ^-1 ): 3490, 172
1,1670,1584 LC-MS (ESI) m / z: 501 (M-H) 1 H-NMR (DMSO-d 6): δ 7.80-7.
95 (m, 6H), 8.21-8.26 (m, 2H),
8.33 (d, J = 8 Hz, 2H), 8.41 (d, J
= 8 Hz, 2H), 13.0 (brs, 2H)

Next, HPLC was measured under the following conditions, and no contamination of the (+)-form was observed.

LiChro CART 250-4 Chira Dec 5 μm MeOH: 1 / 45M phosphate buffer (pH 6.5) (50/50)

(2) Synthesis of Chiral Ketone Compound Under an argon atmosphere, 0.144 ml of oxalic acid chloride and 1 drop of dimethylformamide were added to a solution of 331 mg of (−)-formianthraquinonecarboxylic acid in 8 ml of tetrahydrofuran, and the mixture was added at room temperature. For 1 hour.

The reaction solution was dissolved in tetrahydrofuran (102 ml).
Diluted with the formula:

[0460]

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89 mg of 1,3-dihydroxyacetone dimer and 0.551 of triethylamine
20 ml of tetrahydrofuran solution (suspension)
Drop in 0 minutes, then 20m
1, the 1,3-dihydroxyacetone dimer remaining in the dropping funnel was washed away.

After stirring at room temperature for 22 hours, the solvent was distilled off under reduced pressure, methylene chloride and water were added to the residue, and the mixture was extracted with methylene chloride.

The organic layer was dried over anhydrous sodium sulfate,
The solvent was distilled off. The residue was purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (1:
2-2: 1)], and the solvent is distilled off from the eluate.
formula:

[0464]

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A chiral ketone compound 199 represented by the following formula:
mg was obtained as an amorphous powder (yield: 54
%).

The properties of the obtained chiral ketone compound are as follows:
It is as follows. IR (nujol) ν _max (cm ^-1 ): 1756, 17
37,1672 LC-MS (APCI, ammonium acetate added) m / z =
^{_{574 (M + NH 4) +}} 1 H-NMR (CDCl 3): δ 4.20 (d, J =
15 Hz, 2H), 5.49 (d, J = 15 Hz, 2
H), 7.64-7.80 (m, 4H), 7.91-
7.96 (m, 2H), 8.01 (d, J = 8 Hz, 2
H), 8.29-8.33 (m, 2H), 8.58
(D, J = 8Hz, 2H)

Reference Example 2 In an argon atmosphere, a (-)-form 1,1'-bis (2
-Anthracenecarboxylic acid) (hereinafter referred to as Bianthracenecarboxylic acid) To a solution of 750 mg of methylene chloride in 35 ml of methylene chloride, 0.37 ml of oxalic acid chloride and several drops of dimethylformamide were added, followed by stirring at room temperature for 2 hours.

The reaction solution was diluted with methylene chloride (420 ml), and 1,3-dihydroxyacetone dimer (230 mg) was added.
Then, 80 ml of a methylene chloride solution (suspension) of 1.4 ml of triethylamine was added dropwise over 1 hour and 30 minutes, and then 1,3-dihydroxyacetone dimer remaining in the dropping funnel was washed away with 20 ml of methylene chloride.

After stirring at room temperature for 42 hours, the solvent was distilled off under reduced pressure, and chloroform and an aqueous solution of sodium hydrogen carbonate were added to the residue, followed by extraction with chloroform.

After washing the organic layer with water and saturated saline, it was dried over anhydrous sodium sulfate, and the solvent was distilled off.
The residue was purified by silica gel column chromatography [solvent: chloroform], and the solvent was distilled off from the eluate.
formula:

[0471]

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A chiral ketone compound 671 represented by the following formula:
mg was obtained as an amorphous powder (yield: 78
%).

The properties of the obtained chiral ketone compound are as follows:
It is as follows. IR (nujol) ν_max(Cm^-1): 1753, 17
35, 1239 LC-MS (APCI, ammonium acetate added) m / z
= 514 (M + NH_Four) ⁺

¹ H-NMR (COCl ₃ ): δ 4.21
(D, J = 15 Hz, 2H), 5.59 (d, J = 15
Hz, 2H), 7.29 (ddd, J = 1.7, 8H
z, 2H), 7.46 (ddd, J = 1.7, 7.9H
z, 2H), 7.52 (d, J = 9 Hz, 2H), 7.
67 (d, J = 9 Hz, 2H), 7.89 (S, 2
H), 8.03 (d, J = 8 Hz, 2H), 8.26
(D, J = 9 Hz, 2H), 8.59 (S, 2H)

Reference Example 3 Chem. Pharm. Bull. 37 (8) 2207-2208 (1
(R)-(+) obtained according to the method described in 989).
-6,6'-Dichloro-2,2'-diphenic acid 2.37
g and 1,5-dihydroxyacetone dimer 2.05 g
Was added to a solution of 700 ml of anhydrous acetonitrile, and the mixture was stirred at room temperature for 15 minutes. To this solution, 15.5 g of 2-chloro-1-methylpyridinium iodide was added, and the mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere, and further heated under reflux for 1 hour. The solvent of the reaction mixture was distilled off under reduced pressure, methylene chloride and water were added to the residue,
Extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (2: 1)], and the solvent was distilled off from the eluate.

[0476]

Embedded image

A chiral ketone compound 450 represented by the following formula:
mg was obtained as an amorphous powder (yield: 16
%).

The properties of the obtained chiral ketone compound are as follows:
It is as follows.

¹ H-NMR (CDCl ₃ ): δ 4.19
(D, J = 15 Hz, 2H), 5.50 (d, J = 15
Hz, 2H), 7.40-7.73 (m, 6H)

Reference Example 4 6.81 g (50 mmol) of p-anisaldehyde, 35.2 g (400 mmol) of ethyl acetate and 12.5 g of a methanol solution of sodium methoxide (28%, 6
5 mmol) and stirred at 60 ° C. for 6 hours. The solvent was distilled off from the reaction mixture under reduced pressure, and 8.8 g of concentrated sulfuric acid was added to the residue.
(90 mmol) in 30 ml of methanol was added, and 8
Heated to reflux for an hour. The solvent was distilled off from the reaction mixture under reduced pressure,
30 ml of methanol was added, and the mixture was refluxed again for 9 hours. Further, the solvent was distilled off from the reaction mixture, and methanol 3
After adding 0 ml and heating under reflux for 4 hours, water and ethyl acetate were added, and the ethyl acetate layer was separated. When a part was separated from the ethyl acetate layer and quantified by HPLC, trans-4-methoxycinnamic acid methyl ester 8.01 g was obtained.
(83.4%). After concentrating the ethyl acetate layer, the residue was dissolved in 30 ml of 70% aqueous methanol by heating, and the solution was allowed to cool to room temperature with stirring, and further cooled to room temperature.
Cooled to 4 ° C. overnight. The precipitated crystals were collected by filtration, washed with cold methanol, and dried at 50 ° C. to give trans-4-methoxycinnamic acid methyl ester (7.58 g, yield: 7).
8.9%).

Reference Example 5 An ethanol solution of 6.81 g (50 mmol) of p-anisaldehyde, 35.2 g (400 mmol) of ethyl acetate and sodium ethoxide [metal sodium 1.6
Prepared by dissolving 1 g (70 mmol) in 25 ml of ethanol], and stirred at room temperature for 13 hours and at 50 ° C. for 3 hours. The solvent was distilled off from the reaction mixture under reduced pressure, 30 ml of methanol was added to the residue, and the mixture was reacted at room temperature for 5 hours. After evaporating the reaction mixture under reduced pressure, 30 ml of methanol was added to the residue, and the mixture was reacted at 50 ° C. for 18 hours. Acetic acid 4.2 was added to the reaction mixture.
After adding g to terminate the reaction, water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was separated. A portion was collected from the ethyl acetate layer and quantified by HPLC. As a result, it was estimated that 7.78 g (81.0%) of trans-4-methoxycinnamic acid methyl ester was contained.

Reference Examples 6 to 9 In the method of Reference Example 1 or 2, instead of a methanol solution of sodium methoxide or an ethanol solution of sodium ethoxide, a condensation reaction was carried out using another base, and Similarly, the transesterification reaction yielded the results shown in Table 3.

[0483]

[Table 3]

Reference Example 10 Bulletin Chemical Society of Japan (Bull. Chem. Soc. Jpn.) Vol. 57, pp. 1943-1947 (1984)
Formula in year):

[0485]

Embedded image

In a nitrogen gas stream, 0.105 ml (1.20 mmol) of oxalic acid chloride and one drop of dimethylformamide are dissolved in 160 ml (0.48 mmol) of the chiral dicarboxylic acid compound represented by the formula (6 ml) in a stream of nitrogen gas at room temperature. Was added and the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted by adding 80 ml of tetrahydrofuran.
65 mg of 1,3-dihydroxyacetone dimer (0.3
6 mmol) and 0.4 ml of triethylamine (2.
(88 mmol) in 20 ml of tetrahydrofuran was added dropwise over about 40 minutes, and the mixture was stirred overnight at the same temperature.

The solvent was distilled off from the obtained reaction solution, the residue was dissolved in chloroform, washed with saturated saline and dried.
The solvent was distilled off. The crude product obtained was purified by silica gel flash column chromatography [pre-treatment with hexane-triethylamine (100: 1), solvent: hexane-ethyl acetate (1: 1)] to obtain a compound represented by the formula:

[0488]

Embedded image

A chiral ketone compound 41m represented by the following formula:
g (22%).

Reference Example 11 (1) Dextrin 1%, ammonium sulfate 0.2%
Meast S (manufactured by Asahi Breweries, Ltd.) 2%, monopotassium phosphate 0.2%, magnesium sulfate 0.05%, ferrous sulfate 0.001%, span85 (sorbitan trioleate surfactant, Kao Corporation ) Manufactured by Rheodol SP-3
Liquid medium 18L (p) containing 1.5 w / v% and 0.2 v / v% of a polyalkylene glycol derivative-based surfactant (Caralin 102, manufactured by Sanyo Chemical Industries, Ltd.)
H7.0) was placed in a 30 L jar fermenter, sterilized, and then cultured in a reciprocating shaker at 27.5 ° C. for 20 hours in the same medium, Serratia marcescens Sr41 (FERM B).
P-487) was inoculated with 200 ml of a preculture, and 0.33 vvm at 25 ° C, 0.5 kg / cm ² · G, 3000 r
The culture was performed for 28 hours under the condition of pm while continuously adding L-proline 1.5%. After removing 10 L of the culture solution by centrifugation, impurities were removed with an adsorption resin SP207 (manufactured by Mitsubishi Chemical Corporation).

[0493] The obtained supernatant was subjected to an ultrafiltration membrane (SLP1).
053, manufactured by Asahi Kasei Kogyo Co., Ltd.) to obtain 1080 ml of esterase having an activity of decomposing olive oil of 1.0 × 10 ⁴ U / ml.

[0492] 1000 ml of the concentrated enzyme solution thus obtained.
Was freeze-dried to obtain 54 g of an esterase having an olive oil-decomposing activity of 1.96 × 10 ⁵ U / g.

Reference Example 122 A mixture of 225 ml of polyvinyl alcohol (trade name: Poval 117, manufactured by Kuraray Co., Ltd.) and 75 ml of olive oil was emulsified at 5,500 rpm for 10 minutes at 14,500 rpm. 5.0 ml of olive oil emulsion and 0.25 M Tris-HCl buffer (pH
8.0) 4.0 ml (containing 2.5 mM calcium chloride) were preheated at 37 ° C for 10 minutes. 1 ml for this
After reacting at 37 ° C. for 20 minutes, the reaction was stopped by adding 20 ml of an acetone-ethanol mixed solution (1: 1), and the reaction was stopped using phenolphthalein as an indicator.
Titration with a 05N NaOH solution. The amount of the enzyme that releases 1 μmol of fatty acid per minute by the above method was defined as 1 unit.

Reference Example 13 To 4.549 g of fuming sulfuric acid (SO ₃ content: 60%) was added 1.86 ml of a 60% aqueous hydrogen peroxide solution at −10 ° C. with stirring.
The mixture was added dropwise over 10 minutes and stirred at 10 ° C. for 15 minutes. The solution was cooled to −10 ° C., and 8.32 g of a 49.5% aqueous solution of potassium hydroxide was added dropwise thereto over 15 minutes.
5 ml was added for dilution to obtain a suspension of the oxidizing agent.

Reference Example 14 In a 20 ml eggplant-shaped flask, fuming sulfuric acid (SO ₃ content: 6) was added.
0%) in an ice-methanol bath (bath temperature:
1.66% hydrogen peroxide in water at -15 to -14 ° C)
9 ml was added dropwise over about 5 minutes. After the dropwise addition, the reaction solution was stirred for about 15 minutes in an ice-water bath (bath temperature: 5 ° C), and then ice-cooled again.
It was cooled in a methanol bath (bath temperature: -11 to -10 ° C), and 2.356 g of a 50% aqueous sodium hydroxide solution was added thereto for about 1 hour.
The mixture was added dropwise over 0 minutes, and diluted with 2 ml of water. After the dropwise addition, the reaction solution was stirred in an ice water bath (bath temperature: 5 ° C.) for about 5 minutes, and further at room temperature. As the liquid temperature rose, the reaction liquid became a colorless solution.

[0496]

According to the production method of the present invention, a cinnamate compound having no symmetry element and a complex compound is converted from a chiral ketone compound and an oxidizing agent (for example, a chiral oxidizing agent). Asymmetric oxidation (asymmetric epoxidation) using a dioxirane compound) and subjecting the reaction product to an enzymatic transesterification reaction to give the desired optically active glycidic acid ester compound in high yield and high optical purity. In addition, an excellent effect can be obtained in that the compound can be obtained with a high selectivity and the chiral ketone compound, which is a raw material of the asymmetric oxidizing agent used in the production thereof, can be reused.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 303/48 C07D 303/48 // C07M 7:00 F term (Reference) 4C036 AB05 AB10 AB16 AB19 4C048 AA01 BB31 CC01 UU03 XX02 4C086 AA04 BC92 GA16 ZA36 ZA42 4H006 AA02 AC63 AC81 TA04 TB35 TB56

Claims (22)

[Claims] (A) General formula (I): (Wherein ring A represents a substituted or unsubstituted benzene ring, and R represents an ester residue), an asymmetric oxidizing agent formed from a chiral ketone compound and an oxidizing agent. And the main product of the general formula (IIa)
: (Wherein, rings A and R are the same as above. * Indicates an asymmetric carbon atom) and an optically active glycidic acid ester compound (IIa) represented by the general formula (II)
b): embedded image (Wherein, rings A and R are the same as described above. ** indicates an asymmetric carbon atom having an opposite absolute configuration to the corresponding asymmetric carbon atom of the optically active glycidic acid ester compound (IIa)). Optically active glycidic acid ester compound represented
(B-1) removing a chiral ketone compound from the reaction mixture, and then removing an excess amount of the optically active glycidic acid ester compound (IIb).
After obtaining only (IIa) by crystallization, the optically active glycidic acid ester compounds (IIa) and (II
b) The optically active glycidic acid ester compound
In the presence of an enzyme capable of stereoselectively transesterifying (IIb), a compound of the general formula (III): (Wherein R ¹ represents a group corresponding to an ester residue different from R) by reacting an alcohol compound represented by the general formula (IIb)
b ¹ ): (Wherein ring A, R ¹ and ** are as defined above) ester compound represented by (IIb ¹⁾ to transesterification, optically active glycidic acid ester compound from the resulting mixture (IIa)
(B-2) after removing a chiral ketone compound as required from the reaction mixture, and then obtaining an optically active glycidic acid ester compound (IIb).
Is reacted with an alcohol compound (III) in the presence of an enzyme capable of stereoselectively transesterifying the compound to convert the optically active glycidic acid ester compound (IIb) into the ester compound (I
Transesterification to Ib ¹ ), and if the chiral ketone compound was not removed before transesterification, the chiral ketone compound was removed, and only the optically active glycidic acid ester compound (IIa) was crystallized from the resulting mixture. Optically active glycidic acid ester compound (II
a) Manufacturing method. 2. The method according to claim 1, wherein the chiral ketone compound is removed from the reaction mixture, if necessary, and then the alcohol compound is removed in the presence of an enzyme capable of stereoselectively transesterifying the optically active glycidic acid ester compound (IIb). III) to transesterify the optically active glycidic acid ester compound (IIb) to the ester compound (IIb ¹ ) .If the chiral ketone compound was not removed before the transesterification, the chiral ketone compound was removed. The process according to claim 1, wherein only the optically active glycidic acid ester compound (IIa) is crystallized from the resulting mixture. 3. After removing the chiral ketone compound from the reaction mixture, crystallizing only the optically active glycidic acid ester compound (IIa) contained in excess is obtained,
In the presence of an enzyme capable of stereoselectively transesterifying the optically active glycidic acid ester compound (IIb) to the mixture of the optically active glycidic acid ester compounds (IIa) and (IIb) contained in the residue, Compound (II
I) to react with the optically active glycidic acid ester compound
(IIb) is transesterified to an ester compound (IIb ¹ ), and the resulting mixture is used to form an optically active glycidic acid ester compound (I
2. The process according to claim 1, wherein only Ia) is obtained by crystallization. 4. After transesterification, the optically active glycidic acid ester compound (IIa) is crystallized, and the optically active glycidic acid ester compound (IIa) is crystallized, but the ester compound (IIb ¹ ) is dissolved in a solvent. The method according to any one of claims 1 to 3, wherein the method is performed. 5. An optically active glycidic acid ester compound (IIb) precipitates from the mixture produced by transesterification unless the ester compound (IIb ¹ ) is present, but the optically active glycidic acid ester compound (IIb ¹ ) is present. The optically active glycidic acid ester compound (IIa) is crystallized until the active glycidic acid ester compound (IIa) crystallizes but the optically active glycidic acid ester compound (IIb) does not precipitate. 5. The production method according to any one of (1) to (4). 6. A chiral ketone compound represented by the general formula (IV): [Wherein, ring Ar may have a substituent, 1-3 cyclic aromatic ring, and Y represents a general formula: (i) -OQ-Alk ^1- , (ii) -QO ^{-Alk 2 -, (iii) -Alk} 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi) -Q-NR 2 - Alk ² —, (vii) —Alk ³ —NR ² —Alk ⁴ — or (viii) —NR ² —Alk ⁵ —, Q is a —CO— group or —SO ₂ — group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], and the optical isomer of the ketone compound (IV) represented by the formula: 7. An asymmetric oxidizing agent represented by the general formula (V): [In the formula, ring Ar is a 1-3 aromatic ring which may have a substituent, Y is a general formula: (i) -OQ-Alk ^1- , (ii) -QO- ^{Alk 2 -, (iii) -Alk} 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi) -Q-NR 2 -Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], which is an optical isomer of the dioxirane compound (V). 8. The chiral ketone compound represented by the general formula (VI): [Wherein, R ^a and R ^b are a hydrogen atom or a substituent, R ^c
And R ^d are groups satisfying the following conditions: (I) R ^c and R ^d are each a hydrogen atom or a substituent, or (II) R ^c and R ^d are bonded to each other to form a general formula: 9 (Wherein, R ^e , R ^f , R ^g, and R ^h represent any of the following: (a) two adjacent groups are bonded to each other, and a substituent is present together with the two carbon atoms therebetween. And the other two groups are a hydrogen atom or a substituent, or (b) each is a hydrogen atom or a substituent). Or
(III) R ^c and R ^d are bonded to each other to form a general formula: (Wherein R ⁱ , R ^j , R ^k and R ^m each represent a hydrogen atom or a substituent), and Y is a general formula: (i) —O—Q—Alk ¹ —, (ii) -Q-O-Alk 2 -, (iii) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi ) -Q-NR ² -Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q represents a -CO- group or -SO ₂ -group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], which is an optical isomer of the ketone compound (VI). 9. The asymmetric oxidizing agent has the general formula (VII): [Wherein, R ^a and R ^b are each a hydrogen atom or a substituent, and R ^c and R ^d are groups satisfying the following conditions: (I) R ^c and R ^d are each a hydrogen atom or a substituent, Or (II) R ^c and R ^d are bonded to each other to form a compound of the general formula: (Wherein, R ^e , R ^f , R ^g, and R ^h represent any of the following: (a) two adjacent groups are bonded to each other, and a substituent is present together with the two carbon atoms therebetween. And the other two groups are a hydrogen atom or a substituent, or (b) each is a hydrogen atom or a substituent). Or (III) R ^c and R ^d are bonded to each other to form a compound of the general formula: (Wherein R ⁱ , R ^j , R ^k and R ^m each represent a hydrogen atom or a substituent), and Y is a general formula: (i) —O—Q—Alk ¹ —, (ii) -Q-O-Alk 2 -, (iii) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi ) -Q-NR ² -Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q represents a -CO- group or -SO ₂ -group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], which is an optical isomer of the dioxirane compound (VII). 10. A chiral keto represented by the general formula (VI)
In compound (VI), Y is -CO-O-CH_Two-Group,
R^a~ R^dIs (a) R^aAnd R^bIs a hydrogen atom, R^cYou
And R^dCombined with each otherOr R^cIs a hydrogen atom, R^dIs a halogen field
Is a child or R ^cIs a hydrogen atom, R^dIs a nitro group
Or (b) R^aIs a halogen atom, R^bBut water
Elemental atom, R^cAnd R^dCombined with each otherThe method according to claim 8, wherein 11. The chiral ketone compound (VI) represented by the general formula (VI), wherein R ^a and R ^b are a hydrogen atom, R
^{When c} and R ^d bind to each other, The method according to claim 10, wherein 12. The reaction according to claim 1, wherein the reaction of the chiral ketone compound with the oxidizing agent and the reaction of the resulting asymmetric oxidizing agent on the cinnamate compound (I) are performed in the same reaction system. The method according to any one of 8, 10 and 11. 13. An optically active glycidic acid ester compound, wherein the cinnamate compound (I) is in a trans form.
(IIa) is the (2R, 3S) -isomer and the optically active glycidic acid ester compound (IIb) is (2S, 3R)-
Isomer or optically active glycidic acid ester compound (IIa) is (2S, 3R) -isomer and optically active glycidic acid ester compound (IIb) is (2R, 3
The process according to any one of claims 1 to 12, which is an S) -isomer. 14. The cinnamate compound (I) is in a trans form, and the chiral ketone compound is represented by the general formula (VI-
a): embedded image [Wherein, R ^a and R ^b are each a hydrogen atom or a substituent, and R ^c and R ^d are groups satisfying the following conditions: (I) R ^c and R ^d are each a hydrogen atom or a substituent, Or (II) R ^c and R ^d are bonded to each other to form a general formula: (Wherein, R ^e , R ^f , R ^g, and R ^h represent any of the following: (a) two adjacent groups are bonded to each other, and a substituent is present together with the two carbon atoms therebetween. And the other two groups are a hydrogen atom or a substituent, or (b) each is a hydrogen atom or a substituent). Or (III) R ^c and R ^d are bonded to each other to form a compound of the general formula: (Wherein R ⁱ , R ^j , R ^k and R ^m each represent a hydrogen atom or a substituent), and Y is a general formula: (i) —O—Q—Alk ¹ —, (ii) -Q-O-Alk 2 -, (iii) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 2 -Q-Alk 1 -, (vi ) -Q-NR ² -Alk ^2- , (vii) -Alk ³ -NR ² -Alk ⁴ -or (viii) -NR ² -Alk ^5- , Q represents a -CO- group or -SO ₂ -group, R ² is a hydrogen atom,
An alkylsulfonyl group or an arylsulfonyl group, A
^{lk 1, Alk 2, Alk 3} , Alk 4 and Alk ⁵
Each represents a lower alkylene group], wherein the optically active glycidic acid ester compound (IIa) is an (2R, 3S) -isomer and the optically active glycidic acid ester compound (IIb) is (2
The process according to claim 13, which is an (S, 3R) -isomer. 15. The process according to any one of claims 1 to 14, wherein the enzyme capable of stereoselectively transesterifying has an E value of 20 or more for transesterification at a conversion of 10%. 16. The method according to claim 15, wherein the enzyme capable of stereoselectively transesterifying is an esterase derived from a microorganism of the genus Serratia. 17. An enzyme capable of stereoselectively transesterifying is Serratia marcescens.
2. An esterase derived from a microorganism.
6. The production method according to 6. 18. An optically active glycidic acid ester compound
More than 70% of (IIb) transesterifying, according to claim 1 to 17 to a high ester compound solubility in solvent (IIb ¹⁾
The production method according to any of the above. 19. In the cinnamate compound (I) represented by the general formula (I), ring A is a 4-lower alkoxyphenyl group, R is a methyl group or an ethyl group, and the compound is formed by transesterification. Ester compound (IIb
¹ ) wherein R ¹ may have a halogen atom,
A linear or branched alkyl group having more carbon atoms than R; a linear or branched alkoxyalkyl group optionally having a halogen atom and having more carbon atoms than R; or a straight or branched chain The method according to any one of claims 1 to 18, which is an alkyl group, a linear or branched alkoxy group, or an arylalkyl group optionally having a halogen atom. 20. The method according to claim 19, wherein Ring A is a 4-methoxyphenyl group, R is a methyl group, and R ^{1 of} the ester compound (IIb ¹ ) formed by transesterification is an n-butyl group. . 21. An optically active glycidic acid ester compound (IIa) obtained according to any one of claims 1 to 20, using the general formula (VIII): (Wherein, ring B is a substituted or unsubstituted benzene ring, R ³ is a hydrogen atom or a substituted alkyl group, R ⁴ is a lower alkanoyl group, and rings A and * are as defined above) A process for producing a 1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof, which comprises producing a thiazepine derivative or a pharmaceutically acceptable salt thereof. 22. The optically active glycidic acid ester compound (IIa) obtained in any one of claims 1 to 20, using the general formula: (Wherein, ring A and ring B are substituted or unsubstituted benzene rings, * is an asymmetric carbon atom), and a nitrocarboxylic acid characterized by producing a salt thereof. A method for producing a compound or a salt thereof.