JP3234190B2 - Preparation of optically active phenyloxirane compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an optically active phenyloxirane compound. More specifically, the present invention relates to a method for producing an optically active phenyloxirane compound by asymmetric oxidation and a method for producing a 1,5-benzothiazepine derivative from the optically active phenyloxirane compound obtained by the method.

[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 method of the glycidic acid derivative is (A) a method of synthesizing by an asymmetric hydrolysis method (Japanese Patent Application Laid-Open No. 4-501).
Japanese Patent Publication No. 360, Japanese Patent Publication No. 6-78, Japanese Patent Publication No. 7-12
No. 1231), (B) a production method by an asymmetric transesterification method (JP-A-4-228095, JP-A-5-76389, JP-A-6-78790), and (C) chemical optical resolution. (JP-A-60-13776, Japanese Patent Publication No. 4-2826)
No. 8, JP-A-2-231480), and (D) a method of synthesizing by an asymmetric amidation method (International Publication No. 95/95).
No. 07359 pamphlet) and the like are known.

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.

[0011] However, there is no description or suggestion in the above-mentioned literature regarding the method for producing the optically active phenyloxirane compound aimed at by the present invention.

[0012]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned prior art, and produces a styrene derivative which is a complex compound having no symmetric element from a chiral ketone compound and an oxidizing agent. By performing asymmetric oxidation (asymmetric epoxidation) using an asymmetric oxidizing agent (eg, a chiral dioxirane compound), an optically active phenyloxirane compound can be obtained with high yield and high optical purity. It is an object of the present invention to provide a production method excellent in productivity and economy in which a chiral ketone compound which is a raw material of an asymmetric oxidizing agent used in the production can be reused.

[0013]

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

[0014]

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(Wherein ring A is a substituted or unsubstituted benzene ring, R is a group represented by —CO ₂ R ^q or a group convertible ^thereto , and R ^q is an ester residue) A general formula (II) characterized by reacting (I) with an asymmetric oxidizing agent formed from a chiral ketone compound and an oxidizing agent:

[0016]

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(Wherein rings A and R are the same as above, * indicates an asymmetric carbon atom), and a process for producing an optically active phenyloxirane compound (II), , General formula (V):

[0018]

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[In the formula, ring Ar may have a substituent, 1-3 cyclic aromatic rings, 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 1 -Q-Alk 1 -, (vi) -Q- NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a —CO— group or —SO ₂ — group, and R ¹ represents 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 production method according to the above [1], wherein the chiral ketone compound is an optical isomer of the ketone compound (V) represented by the general formula (VI):

[0020]

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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 hydrogen atoms or substituents Or (II) R ^c and R ^d are bonded to each other to form a general formula:

[0022]

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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:

[0024]

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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 1 -Q-Alk 1 - , (Vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ¹ 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 method according to the above [1] or [2], which is an optical isomer of the ketone compound (VI) represented by the formula [4], wherein the reaction and formation of the chiral ketone compound with the oxidizing agent The method according to any one of the above [1] to [3], wherein the reaction of causing the asymmetric oxidizing agent to act on the styrene derivative (I) is performed in the same reaction system, [5] the general formula (I):

[0026]

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(Wherein ring A is a substituted or unsubstituted benzene ring, R is a group represented by —CO ₂ R ^q or a group convertible ^thereto , and R ^q is an ester residue) General formula (II) characterized in that a chiral dioxirane compound is allowed to act on (I):

[0028]

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(Wherein rings A and R are the same as above, * indicates an asymmetric carbon atom), and a method for producing an optically active phenyloxirane compound (II) represented by the following formula: , The general formula (III):

[0030]

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[In the formula, the ring Ar is a ^{1- to} 3-cyclic aromatic ring which may have a substituent, 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 1 -Q-Alk 1 -, (vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 method according to the above-mentioned [5], which is an optical isomer of the dioxirane compound (III) represented by the formula [IV]:

[0032]

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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:

[0034]

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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:

[0036]

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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 1 -Q-Alk 1 - , (Vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ¹ 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 [5] or [6], which is an optical isomer of the dioxirane compound (IV) represented by the following formula [VI]:

[0038]

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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 hydrogen atoms or substituents Or (II) R ^c and R ^d are bonded to each other to form a general formula:

[0040]

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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:

[0042]

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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 1 -Q-Alk 1 - , (Vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO _2- A group, R ¹ 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] by reacting an optical isomer of a ketone compound (VI) with an oxidizing agent and reacting the resulting chiral dioxirane compound (IV) with a styrene derivative (I). ~ [7] any one of the production method,

[9] Reaction of optical isomer of ketone compound (VI) with oxidizing agent and resulting chiral dioxirane compound
The process according to the above [8], wherein the reaction of (IV) with the styrene derivative (I) is carried out in the same reaction system. [10] The styrene derivative (I) is a trans form and the optically active phenyloxirane compound (II) Is a (2R, 3S) -isomer or a (2S, 3R) -isomer.

[9]
[11] Styrene derivative (I)
Is a trans form, and the chiral ketone compound has the general formula (VI-a):

[0044]

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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:

[0046]

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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:

[0048]

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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 1 -Q-Alk 1 - (Vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ¹ 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 phenyloxirane compound (II) is the (2R, 3S) -isomer [1] to [4]. [12] The styrene derivative (I) is in a trans form, and the chiral ketone compound is represented by the general formula (VI-b):

[0050]

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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:

[0052]

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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:

[0054]

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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 1 -Q-Alk 1 - (Vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ¹ 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 phenyloxirane compound (II) is the (2S, 3R) -isomer [1] to [4]. [13] The method according to any one of [13], wherein the styrene derivative (I) is in a trans form and the chiral dioxirane compound is represented by the general formula (IV-a):

[0056]

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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:

[0058]

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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:

[0060]

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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 1 -Q-Alk 1 - (Vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ¹ 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 phenyloxirane compound (II) is a (2R, 3S) -isomer.

[9] The method for producing the optically active phenyloxirane compound (II) according to any one of [14], wherein the styrene derivative (I) is in a trans form and the chiral dioxirane compound is represented by the general formula (IV-b):

[0062]

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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:

[0064]

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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:

[0066]

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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 1 -Q-Alk 1 - (Vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ¹ 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 phenyloxirane compound (II) is a (2S, 3R) -isomer.

[9] Any of the production methods described in [1]
5] Y is a —CO—O—CH ₂ — group, and R ^{a to} R ^d are
(A) R ^a and R ^b are hydrogen atoms, R ^c and R ^d are bonded to each other

[0068]

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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

[0070]

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The above [3], [4],
[7], [8],

[9], [11], [12], [1
3] or [14], the procedure described, [16] R ^a and R ^b are hydrogen atoms, bonded R ^c and R ^d are each other

[0072]

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The manufacturing method according to the above [15], wherein
[17] A ketone compound formed by reducing a chiral dioxirane compound from a reaction mixture obtained by reacting a styrene derivative (I) represented by the general formula (I) with a chiral dioxirane compound, and an optically active phenyloxirane Compound (II) was produced by reducing the asymmetric oxidizing agent contained in the reaction mixture according to the above-mentioned [5], wherein the asymmetric oxidizing agent contained in the reaction mixture was produced at a high purity by a separation method utilizing a difference in solubility in an organic solvent. The production method according to the above [1], wherein the ketone compound and the optically active phenyloxirane compound (II) are produced in high purity by a separation method utilizing a difference in solubility in an organic solvent, and the ketone compound represented by the general formula (V) ):

[0074]

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[Wherein, ring Ar may have a substituent, 1-3 cyclic aromatic rings, and Y represents a general formula: (i) -OQ-Alk ^1- , (ii)- ^{Q-O-Alk 2 -,} (iii) -Alk 3 -O-Alk 4 -, (iv) -O-Alk 5 -, (v) -NR 1 -Q-Alk 1 -, (vi) -Q- NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a —CO— group or —SO ₂ — group, and R ¹ represents 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 [17] or [18], which is an optical isomer of the ketone compound (V) represented by the general formula (VI):

[0076]

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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:

[0078]

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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:

[0080]

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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 1 -Q-Alk 1 - , (Vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ¹ 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) represented by the above [17] to [1]
9] The method according to any one of the above, [21] wherein ring A is 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, and R is -CO ₂ R ^q (R ^q represents an ester residue), the production method according to any one of the above [1] to [20], wherein [2]
2] The method of the above-mentioned [21], wherein ring A is a 4-lower alkylphenyl group or a 4-lower alkoxyphenyl group, and R ^q is a lower alkyl group.
The method of the above-mentioned [22], wherein the compound is a methoxyphenyl group and R ^q is a methyl group, [24] a general formula (II):

[0082]

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(Wherein, ring A is a substituted or unsubstituted benzene ring, R is a group represented by —CO ₂ R ^q or a group convertible ^thereto , R ^q is an ester residue. From the optically active phenyloxirane compound (II) represented by the general formula (VII):

[0084]

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Wherein ring B is a substituted or unsubstituted benzene ring, R ² is a hydrogen atom or a substituted alkyl group, R ³ is a lower alkanoyl group, and rings A and * are as defined above. In a method for producing a 5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof, the use of the optically active phenyloxirane compound (II) obtained by the production method according to any one of the above [1] to [23], A method for producing a characteristic 1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof, and [25] a compound represented by the general formula (I
I):

[0086]

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(Wherein, ring A is a substituted or unsubstituted benzene ring, R is a group represented by —CO ₂ R ^q or a group convertible ^thereto , R ^q is an ester residue. From the optically active phenyloxirane compound (II) represented by the general formula:

[0088]

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Wherein ring A and ring B represent a substituted or unsubstituted benzene ring, and * represents an asymmetric carbon atom, or a salt thereof. As the active phenyloxirane compound (II), the optically active phenyloxirane compound (II) obtained by the method according to any one of the above [1] to [23]
And a method for producing a nitrocarboxylic acid compound or a salt thereof.

[0090]

DETAILED DESCRIPTION OF THE INVENTION According to the process of the present invention, the starting material is represented by the general formula (I):

[0091]

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[0092] (wherein ring A is a substituted or unsubstituted benzene ring, R represents -CO ₂ R ^q groups or groups in convertible group represented by, R ^q represents an ester residue) styrene derivative represented by (I) is used.

In the styrene derivative (I) represented by the general formula (I), the ring A is a substituted or unsubstituted benzene ring as described above. Specifically, as ring A,
Examples include 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. The lower alkyl group includes a methyl group, an ethyl group, a propyl group and t
And an alkyl group having 1 to 4 carbon atoms represented by -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 preferred are 4-methylphenyl group and 4-methoxyphenyl group.

The R is a group represented by —CO ₂ R ^q (where R ^q is the same as described above) or a group convertible thereto. Examples of the group that can be converted into —CO ₂ R ^q include, for example, a general formula:

[0095]

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Wherein R ^r represents the same group as R ^q, and a general formula:

[0097]

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(Wherein R^sAnd R^tAre both hydrogen atoms
Or one is a hydrogen atom and the other is R ^qGroup similar to
Or together R^qSimilar to
Even if it has a substituent together with the adjacent nitrogen atom
To form a good heterocyclic ring)
Group, thiocarboxyl group, carboxyl group, cyano group, etc.
Can be given.

[0099] As R ^q, if conventional ester residue, either can be used.

Specific examples of R ^q include those having 1 to carbon atoms represented by methyl, ethyl, propyl, butyl and the like.
And a cycloalkyl group having 3 to 7 carbon atoms typified by a lower alkyl group 4, a cyclopentyl group, a cyclohexyl group, and the like, and an aryl group typified by a phenyl group, a naphthyl group, and the like. These lower alkyl group, cycloalkyl group and aryl group may have a substituent. As the substituent for the lower alkyl group and the cycloalkyl group, a substituted or unsubstituted phenyl group, a halogen atom,
Examples of the substituent of the aryl group include a lower alkyl group having 1 to 4 carbon atoms, 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 ^Rq , a lower alkyl group is preferable, and a methyl group is particularly preferable.

The heterocyclic ring formed by R ^s and R ^t together with an adjacent nitrogen atom includes a 5- to 6-membered nitrogen-containing heterocyclic ring such as a pyrrolidine ring, a piperidine ring, a morpholine ring and a piperazine ring. These heterocycles may have a substituent such as a lower alkyl group having 1 to 4 carbon atoms and a halogen atom.

Regarding the geometrical isomer of the styrene derivative (I) represented by the general formula (I), the positional relationship between the ring A bonded to the —CH ＝ CH— group and —R can be either cis or trans. There may be.

In the styrene derivative (I), in formula (I), ring A is a methoxyphenyl group or a methylphenyl group, R is a methoxycarbonyl group, and ring A and R are bonded to trans. The styrene derivative (I) used, 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.

The chiral ketone compound used for producing the asymmetric oxidizing agent is, for example, a compound obtained by converting one or more hydroxyl groups of a monosaccharide or polysaccharide to an oxo group and protecting the remaining hydroxyl groups (for example, 1 , 2: 4,5-di (O-isopropylidene) -D-erythro-2,3-hexodiuro-2,6-pyranose [tetrahedron (Tetrahedro)
n) 47, p. 2133 (1991)]) and non-natural chiral ketone compounds such as a ketone compound having a chiral biaryl skeleton and a natural chiral ketone compound having a biaryl skeleton.

As a typical example of the chiral ketone compound, for example, a compound represented by formula (V):

[0107]

Embedded image

[In the formula, 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 1 -Q-Alk 1 -, (vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 (V).

In the ketone compound (V), 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. Further, the substitution position of Y bonded to the aromatic ring is
There is no particular limitation as long as axial chirality is produced, but it is preferable that Y is bonded to the ortho position of the bond between the 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; having 1 carbon atom represented by a methyl group, an ethyl group, a propyl group and a butyl group
Carbon atoms represented by lower alkoxy groups having 1 to 4 carbon atoms, such as lower alkyl groups, methoxy groups, ethoxy groups, propoxy groups, and butoxy groups; cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups; Examples thereof include electron-donating groups such as an aralkyl group having 7 to 10 carbon atoms, such as a cycloalkyl group having 3 to 7 groups, a benzyl group and a phenethyl group. 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 ketone compound (V),
, As described above, (i) -O-Q- Alk 1 -, (ii) -Q-O-Alk 2 -, (iii) -Alk 3 -O-Alk 4 -, (iv) -O- Alk ^5- , (v) -NR ¹ -Q-Alk ^1- , (vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ —Alk ⁵ —, Q is a —CO— group or —SO ₂ — group, R ¹ is a hydrogen atom, an alkylsulfonyl group or an arylsulfonyl group, Alk ¹ , Alk ² , Alk ³ , Alk ⁴ and Alk ⁵ are each It is a lower alkylene group.

Examples of the alkylsulfonyl group for R ¹ include an alkylsulfonyl group having an alkyl moiety having 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 methylene, ethylene, trimethylene, tetramethylene, methylmethylene, methylethylene and methyltrimethylene groups. Examples thereof include a lower alkylene group having 1 to 4 carbon atoms and having a branched chain.

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 - is preferred.

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

[0116]

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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:

[0118]

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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:

[0120]

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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 1 -Q-Alk 1 - (Vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ¹ 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, examples of the substituent for R ^{a to} R ^m 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, 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, 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; Group, an ethoxy group, a lower alkoxy group having 1 to 4 carbon atoms represented by 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, Such as aralkyl groups having 7 to 10 carbon atoms represented by benzyl group and phenethyl group; It is possible to increase the donating group. Among these groups, an electron-withdrawing group is preferable, and a halogen atom and a nitro group are particularly preferable.

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

[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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It is preferable that the film is formed.

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

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

[0132]

Embedded image

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

[0134]

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

An asymmetric oxidizing agent can be easily obtained by reacting the optical isomer of the ketone compound (V) and the optical isomer of the ketone compound (VI) with an oxidizing agent.
The reaction with the oxidizing agent can be carried out in a suitable solvent in the presence or absence of an alkali agent.

The oxidizing agent used in the reaction with the oxidizing agent includes, for example, m-chloroperbenzoic acid, peracetic acid, peroxonitric acid, peroxocarbonic acid, peroxodisulfuric acid, peroxomonosulfuric acid, peroxoboric acid, formic acid and the like. And peroxides such as alkali metal salts thereof and hydrogen peroxide. Among these oxidizing agents, oxone, which is an oxidizing agent containing potassium peroxomonosulfate, can be suitably used in the present invention. 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 styrene derivative (I), or may be dissolved in a solvent in advance to form a solution and then added to the solution of the styrene derivative (I). Good.

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, dimethoxyethane, 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 solvents such as dimethylacetamide and dimethylimidazolidinone; Sulfoxide solvents such as dimethylsulfoxide; 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 styrene derivative (I). The styrene derivative (I) may be allowed to act in the same reaction system.

When acting on the styrene derivative (I) without isolating the asymmetric oxidizing agent, the optical isomers of the ketone compounds (V) and (VI) are converted into the asymmetric oxidizing agent,
The styrene derivative (I) may be acted on, and the ketone compounds (V) and (VI) may be converted into an asymmetric oxidizing agent in the same reaction system, and the dioxirane compound (II)
The asymmetric oxidation reaction of the styrene derivative (I) with the optical isomers (I) and (IV) may be performed in parallel.

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

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

[0147]

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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 1 -Q-Alk 1 -, (vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 (III).

In the dioxirane compound (III),
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; having 1 carbon atom represented by a methyl group, an ethyl group, a propyl group and a butyl group
Carbon atoms represented by lower alkoxy groups having 1 to 4 carbon atoms, such as lower alkyl groups, methoxy groups, ethoxy groups, propoxy groups, and butoxy groups; cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups; Examples thereof include electron-donating groups such as an aralkyl group having 7 to 10 carbon atoms, such as a cycloalkyl group having 3 to 7 groups, a benzyl group and a phenethyl group. 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 (III), as described above, Y represents (i) -OQ-Alk ^1- , (ii) -QO-Alk ^2- , (iii) -Alk ^{3 -O-Alk 4 -, (iv} ) -O-Alk 5 -, (v) -NR 1 -Q-Alk 1 -, (vi) -Q-NR 1 -Alk 2 -, (vii) -Alk 3 - NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a —CO— group or —SO ₂ — group, R ¹ 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 ¹ 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 methylene, ethylene, trimethylene, tetramethylene, methylmethylene, methylethylene and methyltrimethylene groups. Examples thereof include a lower alkylene group having 1 to 4 carbon atoms and having a branched chain.

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 - is preferred.

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

[0156]

Embedded image

[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:

[0158]

Embedded image

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:

[0160]

Embedded image

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 1 -Q-Alk 1 - (Vi) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a -CO- group or -SO _2-. A group, R ¹ 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 (IV).

Here, the substituent for 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, Such as aralkyl groups having 7 to 10 carbon atoms represented by benzyl group and phenethyl group; It is possible to increase the donating group. Among these groups, an electron-withdrawing group is preferable, and a halogen atom and a nitro group are particularly preferable.

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

[0164]

Embedded image

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

[0166]

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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.

[0168]

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The case where is formed is preferred.

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

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

[0172]

Embedded image

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

[0174]

Embedded image

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

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

[0177]

Embedded image

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

[0179]

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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 (V) 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 for the oxidation reaction includes:
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. Among these oxidizing agents, oxone, which is an oxidizing agent containing potassium peroxomonosulfate, can be suitably used in the present invention. 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 styrene derivative (I), or may be dissolved in a solvent in advance to form a solution and then added to the solution of the styrene derivative (I). Good.

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 solvents such as dimethylacetamide and dimethylimidazolidinone; Sulfoxide solvents such as dimethylsulfoxide; 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 (III) and (IV) obtained after the above oxidation reaction may be once isolated and allowed to act on the styrene derivative (I). The styrene derivative (I) may be allowed to act on the same reaction system as that in which the optical isomer of the dioxirane compound (III) or (IV) is produced.

When acting on the styrene derivative (I) without isolating the optical isomer of the dioxirane compound (III) or (VI), the optical isomer of the ketone compound (V) or (VI) is converted to the dioxirane compound ( After conversion into the optical isomer of III) or (IV), the compound may be allowed to act on the styrene derivative (I), or the dioxirane compound may be converted from the optical isomer of the ketone compound (V) or (VI) in the same reaction system. Conversion of (III) or (IV) into optical isomers and dioxirane compounds
The asymmetric oxidation reaction of the styrene derivative (I) with the optical isomer of (III) or (IV) may be performed in parallel.

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

In the production method of the present invention, the asymmetric oxidizing agent can act on the styrene derivative (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 when reacting the optical isomer of the ketone compound (V) or (VI) with the oxidizing agent 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.

Examples of the method of causing the asymmetric oxidizing agent to act on the styrene derivative (I) include a method of adding the asymmetric oxidizing agent directly to the solution of the styrene derivative (I), and a method of applying the asymmetric oxidizing agent to the solution of the styrene derivative (I). There is a method in which a chiral ketone compound and an oxidizing agent corresponding to the oxidizing agent are added to generate an asymmetric oxidizing agent in the same reaction system.

For example, when an asymmetric oxidizing agent is used which is formed from an optical isomer of a ketone compound (V) or (VI) and an oxidizing agent, (a) a solution of the styrene derivative (I) is used. A method of adding an asymmetric oxidizing agent, (b) adding an oxidizing agent to a mixture of an optical isomer of a ketone compound (V) or (VI) and a styrene derivative (I), and forming an asymmetric oxidizing agent in the same reaction system. A method in which an oxidizing agent is allowed to act on the styrene derivative (I).

When the method (a) is used, it is necessary to use a sufficient amount of an asymmetric oxidizing agent to asymmetrically oxidize the styrene derivative (I). On the other hand, when the method (b) is used, the ketone compound (V) is used in such an amount that a sufficient amount of an asymmetric oxidizing agent for asymmetric oxidation of the styrene derivative (I) can be formed in the reaction mixture. ) Or (VI) and an oxidizing agent.

In the above method (b), an asymmetric oxidizing agent is formed from an optical isomer of the ketone compound (V) or (VI) by an oxidizing agent, and the asymmetric oxidizing agent converts the styrene derivative (I) into an asymmetric oxidizing agent. After oxidation, the corresponding original ketone compound (V)
Or, it returns to the optical isomer of (VI) and becomes reusable. Therefore, if an oxidizing agent is used in an amount of 1 to 10 equivalents to the styrene derivative (I), the ketone compound (V) or ( The optical isomer of VI) is only used in an amount of about 0.001 to 0.1 mol per 1 mol of the styrene derivative (I), and the styrene derivative (I) is asymmetrically oxidized to give the desired optically active phenyloxirane compound (II) And it is particularly preferable to use the oxidizing agent in a ratio of 1.6 to 2.0 equivalents to the styrene derivative (I).

In particular, when oxone which is an oxidizing agent is added to a mixture of the optical isomer of the ketone compound (V) or (VI) and the styrene derivative (I) to carry out asymmetric oxidation of the styrene derivative (I), Oxone selectively oxidizes the optical isomer of the ketone compound (V) or (VI) as compared with the styrene derivative (I) to give an asymmetric oxidizing agent. Also,
The asymmetric oxidizing agent, after asymmetrically oxidizing the styrene derivative (I), returns to the corresponding optical isomer of the ketone compound (V) or (VI) and can be recycled and used. Even if only a catalytic amount of a certain ketone compound (V) or (VI) is used, the asymmetric oxidation of the styrene derivative (I) can be carried out in good yield and the desired optical purity is high. The active phenyloxirane compound (II) is obtained.

The temperature at which the asymmetric oxidizing agent is allowed to act on the styrene derivative (I) is not particularly limited, and varies depending on the type of the asymmetric oxidizing agent.
It is preferably about 50 ° C, especially 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 reduction of the unreacted asymmetric oxidizing agent contained in the reaction mixture obtained by allowing the asymmetric oxidizing agent to act on the styrene derivative (I) is carried out, for example, by the coexisting oxidizing agent from the reaction mixture. Are removed by washing with a saline solution, etc., and if necessary, reducing with a reducing agent such as hypo, sodium bisulfite, sodium metabisulfite, etc. to deal with unreacted asymmetric oxidizing agents. Can be converted to a chiral ketone compound.

When a chiral dioxirane compound is used in the production method of the present invention, the compound can be allowed to act on the styrene derivative (I) in a suitable solvent in the presence or absence of an alkali agent.

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

The amount of the styrene derivative (I) to be used is not particularly limited, but is usually 0.1 to 100 ml of the solvent.
It may be about 30 g.

The amount of the chiral dioxirane to be used is preferably about 1 to 5 mol, and particularly preferably about 1 to 2 mol, per 1 mol of the styrene derivative (I).

Examples of the method of causing a chiral dioxirane compound to act on the styrene derivative (I) include a method of directly adding a chiral dioxirane compound to a solution of the styrene derivative (I) and a method of adding a chiral dioxirane compound to the solution of the styrene derivative (I). There is a method in which a chiral ketone compound and an oxidizing agent corresponding to the dioxirane compound are added to generate a chiral dioxirane compound in the same reaction system.

For example, when an optical isomer of the dioxirane compound (III) or (IV) is used as the chiral dioxirane compound, the dioxirane compound (III) or (IV) is added to the solution of (a) the styrene derivative (I). (B) adding an oxidizing agent to a mixture of the optical isomer of the ketone compound (V) or (VI) and the styrene derivative (I), and forming a chiral compound in the same reaction system. A method in which an optical isomer of the dioxirane compound (III) or (IV) is allowed to act on the styrene derivative (I).

When the method (a) is used, it is necessary to use a sufficient amount of the optical isomer of the dioxirane compound (III) or (IV) to asymmetrically oxidize the styrene derivative (I). On the other hand, when the method (b) is used, a sufficient amount of the optical isomer of the dioxirane compound (III) or (IV) to asymmetrically oxidize the styrene derivative (I) is formed in the reaction mixture. It is sufficient to use as much of the ketone compound (V) or (VI) as the optical isomer and the oxidizing agent.

In the above method (b), an optical isomer of the dioxirane compound (III) or (IV) is formed from the optical isomer of the ketone compound (V) or (VI) by an oxidizing agent, and the isomer is styrene. After asymmetric oxidation of derivative (I),
Since it returns to the corresponding optical isomer of the ketone compound (V) or (VI) and can be reused, if an oxidizing agent is used in an amount of 1 to 10 equivalents to the styrene derivative (I), an asymmetric source The optical isomer of the ketone compound (V) or (VI) is 0.001 to 0.001 mol per mol of the styrene derivative (I).
The styrene derivative (I) can be asymmetrically oxidized by using only about 0.1 mol to obtain a desired optically active phenyloxirane compound (II). . It is particularly preferred to use 6 to 2.0 equivalents.

In particular, when oxone which is an oxidizing agent is added to a mixture of the optical isomer of the ketone compound (V) or (VI) and the styrene derivative (I) to carry out asymmetric oxidation of the styrene derivative (I), Oxone selectively oxidizes the optical isomer of the ketone compound (V) or (VI) as compared with the styrene derivative (I) to give the dioxirane compound (III) or (IV). Further, the optical isomer of the dioxirane compound (III) or (IV) returns to the corresponding optical isomer of the ketone compound (V) or (VI) after asymmetric oxidation of the styrene derivative (I), Since it can be recycled, even when only a catalytic amount of the optical isomer of the ketone compound (V) or (VI) as the asymmetric source is used,
The styrene derivative (I) can be asymmetrically oxidized in good yield, and the desired optically active phenyloxirane compound (II) having high optical purity can be obtained.

The temperature at which the chiral dioxirane compound is allowed to act on the styrene derivative (I) is not particularly limited, but it is usually about -5 to 50 ° C, preferably about 0 to 40 ° C. preferable.

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

Next, the reduction of the unreacted chiral dioxirane compound contained in the reaction mixture obtained by allowing the chiral dioxirane compound to act on the styrene derivative (I) is carried out, for example, by the coexisting oxidizing agent from the reaction mixture. Etc. after washing with saline, etc., and then removing hypo,
By performing reduction using a reducing agent such as sodium hydrogen sulfite or sodium metabisulfite, an unreacted chiral dioxirane compound can be converted to a corresponding chiral ketone compound.

From the reaction mixture containing the chiral ketone compound obtained as described above, a ketone compound produced by reducing an asymmetric oxidizing agent such as a chiral dioxirane compound and the optically active phenyloxirane compound (II) are obtained. , Respectively, can be produced with high purity by a separation method utilizing a difference in solubility 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 catalyst, 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. The extraction of a chiral ketone compound by using an organic solvent having a property of hardly dissolving [for example, ketone compound (V) or (VI)] but easily dissolving optically active phenyloxirane compound (II) can be achieved. It can be recovered in yield.

The residue obtained in the step (a-1) or (a-2) dissolves both the chiral ketone compound and the optically active phenyloxirane compound (II) at a high temperature. The chiral ketone compound crystallizes, and the optically active phenyloxirane compound (II) is once dissolved in an organic solvent capable of causing no crystallization, then the solution temperature is lowered to selectively crystallize only the chiral ketone compound Or the reaction mixture dissolves both the chiral ketone compound and the optically active phenyloxirane compound (II) at high temperature, but the chiral ketone compound crystallizes depending on the temperature conditions, and the optically active phenyloxirane compound (II) Extract with an organic solvent that has the property of generating a state that does not crystallize, lower the temperature of the extract, and selectively crystallize only chiral ketone compounds By also possible to recover the chiral ketone compound at a high yield.

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 and carbon tetrachloride, ethyl acetate and methyl acetate. Ester solvents such as, chlorobenzene, toluene, xylene, and 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 toluene and the like. Aromatic hydrocarbon solvents; diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane,
Although ether solvents such as tetrahydrofuran and diglyme can be used, it is preferable to use ether solvents which are easily distilled off.

The organic solvent which is difficult to dissolve the chiral ketone compound and is easy to dissolve the optically active phenyloxirane compound (II) used for extraction of the residue after distilling off the solvent includes aliphatic solvents such as hexane. A hydrocarbon solvent; an ester solvent such as ethyl acetate or the like can be used alone or as a mixture.

On the other hand, at a high temperature, both the chiral ketone compound and the optically active phenyloxirane compound (II) are dissolved, but the chiral ketone compound crystallizes and the optically active phenyloxirane compound (II) does not crystallize depending on the temperature conditions. As an organic solvent capable of generating a state, for example, an ether-based solvent such as diisopropyl ether, t-butyl methyl ether and the like can be used.

In this way, a chiral ketone compound can be recovered from the reaction mixture with high purity and high yield.

The extract of the optically active phenyloxirane compound (II) obtained as described above or the mother liquor after recovering the ketone compound is purified by column chromatography, crystallization, etc. to obtain the optically active phenyloxirane compound. (II) can be obtained with high purity and high optical purity.

As the column chromatography,
For example, ordinary silica gel chromatography or the like can be suitably used.

In the case of performing purification by crystallization, it is preferable to use an ether solvent such as diisopropyl ether as the organic solvent, and the crystallization is performed at a temperature lower than the temperature at which the chiral ketone compound is crystallized. Thereby, substantially pure optically active phenyloxirane compound (II) can be obtained.

In the present invention, as the styrene derivative (I) represented by the general formula (I), a styrene derivative (I) in which rings A and R are in the trans position as shown in the following scheme was used. In this case, when the asymmetric oxidizing agent has an α-attack, the reaction proceeds in the direction of arrow b, and (2R, 3
When (S) -optically active phenyloxirane compound is obtained, and when the asymmetric oxidizing agent is β-attacked, the reaction proceeds in the direction of arrow a to obtain (2S, 3R) -optically active phenyloxirane compound. Further, when the styrene derivative (I) in which the rings A and R are in the cis position is used, when the asymmetric oxidizing agent is α-attacked, the reaction proceeds in the direction of arrow d,
When the (2S, 3S) -optically active phenyloxirane compound is obtained, and when the asymmetric oxidizing agent is β-attacked, the reaction proceeds in the direction of arrow c to form the (2R, 3R) -optically active phenyloxirane compound. can get.

[0222]

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Among the above optically active phenyloxirane compounds, the (2R, 3S) -optically active phenyloxirane compound and the (2S, 3R) -optically active phenyloxirane compound are steric because rings A and R are in the trans position. Since the optically active phenyloxirane compound aimed at by the present invention can be efficiently obtained with little hindrance, it can be suitably used.

In the present invention, the styrene derivative (I)
Chiral ketone compound (VI-a)
Alternatively, it is preferable to use an asymmetric oxidizing agent obtained from (VI-b) [eg, a chiral dioxirane compound (IV-a) or (IV-b)]. In addition, using a trans form as the styrene derivative (I), an asymmetric oxidizing agent obtained from the chiral ketone compound (VI-a) [for example, a chiral dioxirane compound (I
Va)], a (2R, 3S) -type phenyloxirane compound is obtained, and the styrene derivative (I)
Chiral ketone compound (VI-b)
When an asymmetric oxidizing agent [e.g., a chiral dioxirane compound (IV-b)] is used, (2S, 3R)-
A phenyloxirane compound is obtained.

Thus, the general formula (II):

[0226]

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(Wherein, rings A, R and * are the same as described above)
Optically active phenyloxirane compound (II) represented by
Is obtained with high yield and high optical purity.

Next, among the optically active phenyloxirane compounds (II) represented by the general formula (II) obtained above, R
There using compounds is a group represented by -CO ₂ R ^q as a starting material, by conventional known methods, the general formula (VII):

[0229]

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Wherein ring A, ring B and * are the same as described above, R ² is a hydrogen atom or a substituted alkyl group, and R ³ is a lower alkanoyl group. Can be manufactured.

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 ³ 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 ² is a hydrogen atom or a substituted alkyl group. Specific examples of the substituted alkyl group include, for example, those having an alkyl moiety of 1 to 4 carbon atoms 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 ² , 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 (VII) 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 (VII) or a pharmacologically acceptable salt thereof obtained by the production method of the present invention includes heart diseases such as angina pectoris, myocardial infarction and arrhythmia, hypertension, coronary It is a useful compound for cardiovascular diseases such as infarction and cerebral infarction.

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)
A 1,5-benzothiazepine derivative represented by the general formula (VII) can be produced from the optically active phenyloxirane compound (II) represented by the following formula:

More specifically, for example, when R is —CO ₂ R
^When the (2R, 3S) -isomer is used as the optically active phenyloxirane compound (II) which is a group represented by ^q , the (2R, 3S) -isomer is converted to a compound represented by the general formula (V-1)
III):

[0239]

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Wherein ring B is the same as above, R ⁴ is a hydrogen atom, a 2- (dimethylamino) ethyl group or a compound represented by the formula:

[0241]

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(VIII) (for example, 2-aminothiophenol, 2-amino-5-chlorothiophenol, 2-amino-5-benzylthiophenol, −
[[2- (dimethylamino) ethyl] amino] thiophenol, general formula:

[0243]

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

[0245]

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(Wherein ring B is as defined above) (IX) (eg, 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:

[0247]

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(Wherein ring A, ring B, R and R ⁴ are the same as defined 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:

[0249]

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(Wherein ring A, ring B and R ⁴ 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:

[0251]

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(Wherein ring A, ring B and R ⁴ are the same as described above), or preparing a (2S, 3S) -1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof. Can be.

[0253] Further, example, R is an optically active phenyl oxirane compound is a group represented by -CO ₂ R ^q as (II), the (2S, 3R) - When using the isomers, the (2
The (S, 3R) -isomer is reacted with (A-1) an aminothiophenol derivative (VIII) or (A-2) a nitrothiophenol derivative (IX), and then the nitro group is reduced. By the general formula:

[0254]

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(Wherein ring A, ring B, R and R ⁴ 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:

[0256]

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(Wherein ring A, ring B and R ⁴ are the same as defined 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:

[0258]

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Wherein ring A, ring B and R ⁴ are the same as defined above, or a (2R, 3R) -1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof is prepared. Can be.

One example is Diltiazem.
m) and the stereochemistry for its enantiomers can be summarized, for example, by the formula:

[0261]

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An aminothiophenol represented by the formula:
There when reacted with optically active phenyl oxirane compound (II) and a group represented by -CO ₂ R ^q is the reaction proceeds as follows. That is, when the (2S, 3R) -form is reacted with the aminothiophenol to cause cis-cleavage, and when the (2S, 3S) -form is reacted with the aminothiophenol to cause trans-cleavage, (2
An (R, 3R) -propionic acid derivative is obtained. Also,
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, 3S) ) -Propionic acid derivative is obtained.

[0263]

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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.

[0265]

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[0266] On the other hand, optically active phenyl oxirane compound R has a group convertible into a group represented by -CO ₂ R ^q
(II) or a salt thereof, after converted into a group represented by -CO ₂ R ^q, is reacted in the same manner as described above, or, 1,5
- Before benzothiazepine ring forming reaction, if converted into a group represented by -CO ₂ R ^q, as if R is a group represented by -CO ₂ R ^q, 1,5-benzothiazepine derivatives Can be led to.

[0267] The -CO ₂ R ^q convertible to a group represented by a group as a way to convert a group represented by -CO ₂ R ^q is,
Conventional methods can be used depending on the type of base.

[0268] For example, carboxyl groups, by esterification with conventional methods, can be converted into a group represented by -CO ₂ R ^q, general formula:

[0269]

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Wherein R ^r is the same as defined above, and a general formula:

[0271]

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In the formula, R ^s and R ^t are the same as those described above, and the cyano group is converted into a carboxyl group by a hydrolysis reaction of a thiol ester, an amide and a cyano group, respectively. in by esterification, it can be converted into a group represented by -CO ₂ R ^q.

The thiocarboxyl group was once converted into thiol ester by a conventional method,
It can be converted to a group represented by CO ₂ R ^q .

Further, R is a general formula:

[0275]

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Wherein R ^r is the same as defined above, and a general formula:

[0277]

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Wherein R ^s and R ^t are the same as defined above, or an optically active phenyloxirane compound (II), which is a carboxyl group, or a salt thereof, wherein R is -C
O ₂ optically active phenyl oxirane compound is a group represented by R ^q same manner as the (II), without converting R to the group represented by -CO ₂ R ^q, 1,5-benzothiazepine derivatives You can also guide.

Furthermore, the compound represented by the general formula (II) obtained by the production method of the present invention:
Using an optically active phenyloxirane compound (II) represented by the following formula as a starting material, a general formula useful as an optical resolving agent by a conventionally known method:

[0280]

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(Wherein ring A and ring B are the same as defined above, *
Represents an asymmetric carbon atom).

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:

[0283]

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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.

[0285] Specific examples of the nitro acid compound, eg, R is an optically active phenyl oxirane compound is a group represented by -CO ₂ R ^q and (II), the general formula:

[0286]

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A nitrothiophenol compound typified 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. Pharm.
Bull. ) 18 (10) 2028-2037 (197
It can be produced by hydrolyzing the product according to the method described in 0).

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

Also, an optically active phenyloxirane compound
(II), the wherein the R ^q as defined above], R is -CO ₂ R ^q if a group can be converted into a group represented by is obtained by reaction of a nitro thiophenol compound Was converted to -C using the conventional method used for the conversion of a compound to a 1,5-benzothiazepine derivative.
After conversion to a compound represented by O ₂ R ^q (where R ^q is the same as described above), the compound is hydrolyzed by a conventional method, or used for conversion to a 1,5-benzothiazepine derivative. using the method, (wherein, R ^q is as defined above) R is -CO ₂ R ^q without converting the compound is a group represented by, by direct R is converted to the compound which is a carboxyl group And an optically active nitrocarboxylic acid compound can be obtained.

In the ketone compound (V), Y is (i) -OQ-Alk ¹ -or (v) -NR ¹
The ketone compound represented by -Q-Alk ¹ -has a general formula (X):

[0291]

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[Wherein Z represents -O- or -NR ^1- , and Ar and R ¹ are the same as those described above] and a compound represented by the general formula (XI):

[0293]

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Wherein Prot represents a hydroxyl-protecting group, Alk ¹ and Q are 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 (XII):

[0295]

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

In the ketone compound (V), Y
Is (ii) -Q-O-Alk ² -or (vi) -Q-NR ^1-
The ketone compound represented by Alk ² — has the general formula (XIII):

[0298]

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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 (XI
V):

[0300]

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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 (V), Y is (ii)
i) -Alk ³ -O-Alk ⁴ -or (vii) -Alk
^The ketone compound of ^3- NR ¹ -Alk ⁴ — has a general formula
(XV):

[0303]

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

[0305]

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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-alkylsulphonylation or N-arylsulphonylation according to general formula (XVII):

[0307]

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

[0309]

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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 (V), Y
There (iv) -O-Alk ⁵ - or (viii) -NR ¹ -Alk
^The ketone compound represented by 5- is a ketone compound represented by the general formula (X) and a general formula (XIX):

[0312]

Embedded image

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

In the ketone compound (V), Y
Is -NR ¹ -Alk ^5- , then Z is -NH-
A compound represented by the general formula (X) wherein Q is a carbonyl group or a reactive derivative thereof, that is, a compound obtained by reacting a compound represented by the general formula (XI) And the compound represented by the general formula (XII) wherein Q is a carbonyl group is reduced, and if necessary, N-alkylsulfonylated or N-arylsulfonylated to remove the hydroxyl-protecting group, followed by oxidation. It can be produced by subjecting it to a reaction.

The compound represented by the general formula (X) and the compound represented by the general formula (X)
Reaction with the compound represented by (XI) or a reactive derivative thereof, and reaction between the compound represented by the general formula (XIII) or the reactive derivative thereof and the compound represented by the general formula (XIV) 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 (XI) and the compound represented by the general formula (XIII),
Conventional reactive derivatives of carboxylic acids, sulfonic acids, for example acid halides such as acid chloride, acid bromide, acid iodide; isobutyl chlorocarbonate, 2,6-dichlorobenzoic acid chloride or 2,4,6-trichlorobenzoic acid chloride Mixed acid anhydrides such as mixed acid anhydrides with N; N'-
Active esters formed using dicyclohexylcarbodiimide (hereinafter referred to as DCC), a combination of DCC and 1-hydroxybenzotriazole, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, and the like. Can be.

In the compound represented by the general formula (XI), the protecting group for a hydroxyl group includes a commonly used protecting group for a hydroxyl group,
For example, a protecting group such as a lower alkanoyl group, a substituted silyl group and an optionally substituted benzyl group can be used.

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

The compound represented by the general formula (X)
Reaction with a compound represented by (XI), and general formula (XIII)
Is reacted with a compound represented by the general formula (XIV) or a dimer thereof by a suitable solvent, for example, an aliphatic hydrocarbon solvent which may be halogenated (hexane, cyclohexane, methylene chloride). , Ethylene chloride, chloroform, carbon tetrachloride, etc.), optionally halogenated aromatic hydrocarbon solvents (toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, etc.), nitrile solvents (acetonylyl, propionitrile, butyronitrile) ), Ether solvents (diethyl ether, tetrahydrofuran, 1,4-dioxane, diglyme, etc.).
It can be carried out at normal temperature or under heating in the presence of a condensing agent such as 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 (X) with the reactive derivative of the compound represented by the general formula (XI), and the reaction of the compound represented by the general formula (XIII) with the reactive derivative of the general formula (XIII) The reaction with the compound represented by the formula (XIV) 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, tetrahydrofuran, 1,4-dioxane, diglyme, etc.) For example, the reaction can be carried out in the presence or absence of an organic base (such as triethylamine, trimethylamine, pyridine, and diisopropylethylamine) at normal temperature or under heating.

A compound represented by the general formula (XVII)
The reaction with the compound represented by the formula (XVIII) and the reaction between the compound represented by the formula (X) and the compound represented by the formula (XIX) can be carried out by O-alkylation of an alcohol or N-alkylation of an amine. It can be carried out according to a conventional method.

The leaving group L in the compound represented by the general formula (XVIII) and the compound represented by the general formula (XIX) includes 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.

A compound represented by the general formula (XVII)
The reaction with the compound represented by the formula (XVIII) and the reaction between the compound represented by the general formula (X) and the compound represented by the general formula (XIX) can be carried out in a suitable solvent [for example, a fatty acid which may be halogenated. Aromatic hydrocarbon solvents (hexane, cyclohexane, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, etc.), aromatic hydrocarbon solvents which may be halogenated (toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, etc.) ,
Nitrile solvents (acetonitrile, propionitrile,
Butyronitrile)] in the presence of a deoxidizing agent [for example, an organic base (triethylamine, trimethylamine, pyridine, diisopropylethylamine, etc.)] at room temperature or under heating.

The step of removing the hydroxyl-protecting group from the compound represented by the general formula (XII) may be carried out by a conventional method for removing a hydroxyl-protecting group (for example, a hydrolysis method, a catalytic hydrogenation method, a fluorinated method). Hydrogen acid treatment) can be applied. For example, a compound represented by the general formula (XII) 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 to a carbonyl group (for example, chromic acid oxidation, ruthenium oxide oxidation, Swann 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 (XV) can be carried out according to a conventional method for reduction of a carboxylic acid. For example, the compound represented by the general formula (XV) is reacted with a suitable solvent [for example, an ether-based solvent]. In a solvent (diethyl ether, tetrahydrofuran, 1,4-dioxane, diglyme)], it can be carried out by treating with a reducing agent (for example, diborane, lithium aluminum hydride, etc.).

The extension of the alkyl moiety bonded to the hydroxyl group of the compound represented by formula (XVI) obtained by this reduction reaction can be carried out according to a conventional method. For example, after the compound represented by the general formula (XVI) is treated with a halogenating agent [eg, thionyl halide (thionyl chloride, thionyl bromide) or the like], or the hydroxyl group of the compound represented by the general formula (XVI) is changed to, for example, p -Toluenesulfonyl halide (p-toluenesulfonyl chloride,
p-toluenesulfonyl bromide) or the like, followed by treatment with the halogenating agent, reaction of the resulting halide with magnesium to form a Grignard reagent, and reaction with an alkyl aldehyde or alkyl ketone. It can be carried out by 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 reaction can be carried out by treating a compound represented by the general formula (XVI) or a 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 (XII) 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 (XV). , Can be implemented. After the reduction reaction, N-
The reaction of removing the hydroxyl-protecting group from the product obtained by alkylsulfonylation or N-arylsulfonylation and oxidizing is the same as the removal and oxidation of the hydroxyl-protecting group of the compound represented by the general formula (XIV). Can be implemented.

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 alkyl sulfonic acid or an aryl sulfonic acid is used, it is preferably carried out in a suitable solvent in the presence of a condensing agent. On the other hand, when a reactive derivative is used, the reaction is carried out 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 (X):
The compound represented by the general formula (XIII), the compound represented by the general formula (XV), the compound represented by the general formula (XVI) and the compound represented by the general formula (XVII), after optical resolution by a conventional method, By applying the above synthesis method, the ketone compound (V) 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 optical isomers such as quinidine, cinchonidine, amino acid, amino acid ester, quinine, brucine and amino alcohol are particularly preferable.

In the styrene derivative (I) used in the method of the present invention, the compound wherein R is a lower alkoxycarbonyl group is represented by the following general formula:

[0334]

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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 suitably used, and 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.

The base used for the condensation reaction between benzaldehyde and acetic acid lower alkyl ester includes an alkali metal alkoxide (for example, lithium methoxide, lithium ethoxide, lithium n-butoxide, lithium t-toxide).
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 (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide).

The condensation reaction is carried out at room temperature to under warming,
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 reaction can be carried out using a lower alkanol corresponding to a desired ester residue. When this alcohol also serves as a solvent, it is not always necessary to add another solvent.

As the acid used for the transesterification reaction,
Inorganic acids (e.g., sulfuric acid, hydrochloric acid, phosphoric acid) and organic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid) can be given, but the reaction proceeds favorably even in the absence of an acid. 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 a temperature between room temperature and the reflux temperature of the solvent, especially between 20 and 80.
It is preferably carried out at 0 ° C.

[0342]

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.

Production Example 1 Formula:

[0344]

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A chiral ketone compound represented by the following formula: 0.0
1 mmol of 7.5 ml of acetonitrile and 4 × 10
^-4 M ethylenediaminetetraacetic acid (EDTA) dissolved in a mixture of 5 ml of an aqueous solution of disodium salt, and 2.5 mmol of oxone and 7.7 mmol of sodium bicarbonate were added thereto.
(nmass spectrum), the equation:

[0346]

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It was confirmed that the peak at 412 (M ⁺ ) supporting the formation of the chiral dioxirane compound represented by the formula was gradually increased in comparison with the peak at 396 (M ⁺ ) of the chiral ketone compound. Was done.

Next, the chiral ketone compound 0.1 m
mol of acetonitrile-d ₃ 3.8 ml-4 × 10 ^-4
M in EDTA disodium salt heavy water solution (2.5 ml).
After stirring for 24 hours, the supernatant of the reaction mixture was taken, and its MS (mass spectrometry) and ¹ H-NMR were measured.

First, exact mass spectrometry was performed to find that the M ⁺ ion (C
₂₅ H ₁₆ O ₆ , theory: 412.0947, measured: 41
2.0950) was detected.

In ¹ H-NMR (400 MHz), the peak estimated as the hydrogen atom of the methylene group of the chiral dioxirane compound was 3.85 ppm (d, J =
11.8 Hz) and 4.56 ppm (d, J = 15.
5 Hz).

The peak estimated as the hydrogen atom of the methylene group of the chiral ketone compound was 4.21 ppm.
(D, J = 15.5 Hz) and 5.49 ppm (d, J
J = 15.4 Hz).

In the ¹³ C-NMR, the quaternary carbon of the dioxirane portion of the chiral dioxirane compound was 9
It was found at 5.6 ppm.

The carbonyl carbon of the chiral dioxirane compound was found at 2.305 ppm.

[0354] These, ¹³ C-NMR definitive DEPT (d
istortionless enhancement bypolarization transfer)
The measurement showed that it was a quaternary carbon, and the hydrogen peak of the methylene group (3.85 ppm and 4.56 pp)
m) was confirmed by the recognition of long-range coupling.

Example 1 Trans-4-methoxycinnamic acid methyl ester 192m
g (1.0 mmol) in 1,2-dimethoxyethane 15
After dissolving at room temperature in 10 ml, 10 ml of a 4 × 10 ⁻⁴ M ethylenediaminetetraacetic acid disodium salt aqueous solution was added,
Then the formula:

[0356]

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40m of a chiral ketone compound represented by the following formula:
g (0.1 mmol) was added and cooled to 0 ° C. by an external bath. After that, 6.14 g of Oxone (10 mmo
l) and 2.6 g (31 mmol) of sodium bicarbonate were added in six portions every hour. After the addition is complete,
After stirring for an hour, 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 filtered off,
The solvent was distilled off from the filtrate. To the obtained residue, 9 ml of a mixture of ethyl acetate and n-hexane (1: 8 (volume ratio)) 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 the chiral ketone compound (recovery rate: 80% by weight).

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)) and purified by the formula:

[0361]

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There was obtained 135 mg of an optically active phenylglycidate represented by the following formula (isolation yield: 65%). When the optical purity of the obtained optically active phenylglycidic acid ester was determined by HPLC, it was 81% ee.

Example 2 Trans-4-methoxycinnamic acid methyl ester 192
mg (1.0 mmol) of 1,2-dimethoxyethane 1
After dissolving in 5 ml at room temperature, 10 ml of 4 × 10 ⁻⁴ M aqueous solution of ethylenediaminetetraacetic acid disodium salt is added, and then the formula:

[0364]

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A chiral asymmetric ketone compound 5 represented by the following formula:
5 mg (0.1 mmol) was added and stirred at room temperature.
Thereafter, a mixture of 2.06 g (3.3 mmol) of oxone and 860 mg (10.3 mmol) of sodium bicarbonate was added over 1 hour. After the addition was completed, the mixture was further stirred for 1 hour, the obtained reaction mixture was poured into half-saturated saline, extracted with ether, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.

The obtained product was treated in the same manner as in Example 1 to obtain 0.126 g of an optically active phenylglycidic acid ester similar to that in Example 1 (isolation yield: 6
1%).

The optical purity of the obtained optically active phenylglycidic acid ester was determined by HPLC.
% Ee.

Further, the chiral ketone compound could be recovered by the same method as in Example 1 (recovery rate: 88% by weight).

Example 3 Trans-4-methoxycinnamic acid methyl ester 192
mg (1.0 mmol) was dissolved in 7.5 ml of 1,2-dimethoxyethane at room temperature, and 5 ml of a 4 × 10 ⁻⁴ M aqueous solution of disodium ethylenediaminetetraacetic acid was added.

[0370]

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Chiral ketone compound 46m represented by the following formula:
g (0.1 mmol) was added and cooled to 0 ° C. After that, 1.84 g (3 mmol) of oxone and 780 sodium bicarbonate
mg (9.3 mmol) was added over 7 hours. After completion of the addition, the mixture was further stirred for 17 hours, the obtained reaction mixture was poured into half-saturated saline, extracted with ether, washed with saturated saline, and then dried over anhydrous magnesium sulfate.

By subjecting the obtained product to the same treatment as in Example 1, the yield and optical purity of the obtained optically active phenylglycidic acid ester as in Example 1 were determined by HPLC. 74% and 8 respectively
It was 5% ee.

Example 4 Trans-4-methoxycinnamic acid methyl ester 192
mg (1.0 mmol) was dissolved in 3.8 ml of 1,2-dimethoxyethane at room temperature, and 2.5 ml of 4 × 10 ⁻⁴ M aqueous solution of ethylenediaminetetraacetic acid disodium salt was added.

[0374]

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4 mg of a chiral ketone compound represented by the following formula:
(0.01 mmol) was added and kept at room temperature. After that, 1.23 g (2 mmol) of oxone and 521 of sodium bicarbonate were added.
mg (6.2 mmol) was added. After completion of the addition, the mixture was further stirred, and the obtained reaction mixture was washed and dried in the same manner as in Example 1.

By subjecting the obtained product to the same treatment as in Example 1, the yield and optical purity of the obtained optically active phenylglycidic acid ester as in Example 1 were determined by HPLC. 70% and 6 respectively
It was 2% ee.

Example 5 Trans-4-methoxycinnamic acid methyl ester 192
mg (1.0 mmol) was dissolved in 7.5 ml of 1,2-dimethoxyethane at room temperature, and 5 ml of a 4 × 10 ⁻⁴ M aqueous solution of disodium ethylenediaminetetraacetic acid was added.

[0378]

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4 mg of a chiral ketone compound represented by the following formula:
(0.01 mmol) was added and kept at room temperature. Thereafter, 1.54 g (2.5%) of oxone was added to the obtained mixture.
mmol) and 650 mg (7.7 mmol) of sodium bicarbonate were added. After completion of the addition, the resulting mixture was 4.5
After stirring for an hour, the mixture was washed and dried in the same manner as in Example 1.

The obtained product (yield: 92 by HPLC)
%) Is treated in the same manner as in Example 1 to obtain the same optically active phenylglycidic acid ester 13 as in Example 1.
8 mg (isolation yield: 66%) were obtained.

The optical purity of the obtained product was determined by HPLC and found to be 74% ee.

Further, the chiral ketone compound could be recovered by the same method as in Example 1 (recovery rate: 80% by weight).

Example 6 Trans-4-methoxycinnamic acid methyl ester 192
mg (1.0 mmol) was dissolved in 3.8 ml of 1,2-dimethoxyethane at room temperature, and 2.5 ml of 4 × 10 ⁻⁴ M aqueous solution of ethylenediaminetetraacetic acid disodium salt was added.

[0384]

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4 mg of a chiral ketone compound represented by the following formula:
(0.01 mmol) was added and kept at room temperature. After that, 1.23 g (2 mmol) of oxone and 521 of sodium bicarbonate were added.
mg (6.2 mmol) was added. After completion of the addition, the mixture was further stirred for 8 hours, and the obtained reaction mixture was washed and dried in the same manner as in Example 1.

By subjecting the product (HPLC yield: 93%) to the same treatment as in Example 1, 137 mg of an optically active phenylglycidic acid ester similar to that in Example 1 was obtained.
(Isolation yield: 66%) was obtained.

The optical purity of the obtained optically active phenylglycidic acid ester was determined by HPLC.
% Ee.

Example 7 Trans-4-methoxycinnamic acid methyl ester 192
mg (1.0 mmol) was dissolved in 1,2-dimethoxyethane (15 ml) at room temperature, and 4 × 10 ⁻⁴ M ethylenediaminetetraacetic acid disodium salt aqueous solution (10 ml) was added.

[0389]

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50m of a chiral ketone compound represented by the following formula:
g (0.1 mmol) was added and kept at room temperature. After that, 2.06 g (3.3 mmol) of oxone and 8 sodium bicarbonate
A mixture with 66 mg (10.3 mmol) was added over 1 hour. After completion of the addition, the mixture was further stirred for 30 minutes, the obtained reaction mixture was poured into half-saturated saline, extracted with ether, and the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate.

By subjecting the obtained product to the same treatment as in Example 1, 107 mg of an optically active phenylglycidic acid ester similar to that in Example 1 (isolation yield: 51%)
I got

The optical purity of the obtained optically active phenylglycidic acid ester was determined by HPLC.
% Ee.

Example 8 Formula:

[0394]

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159 mg (1 mmol) of the compound
l) was dissolved in 15 ml of 1,2-dimethoxyethane at room temperature, 10 ml of 4 × 10 ⁻⁴ M aqueous solution of disodium ethylenediaminetetraacetate was added, and then the same chiral ketone used in Example 1 40mg (0.1mmo
l) was added and cooled to 0 ° C.

After that, 3.07 g of oxone (5 mmo
l) and 1.3 g (15.5 mmol) of sodium bicarbonate
It was added hourly in portions.

After stirring at room temperature for 18 hours, the reaction mixture was poured into half-saturated saline, extracted with ether, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.

After drying, anhydrous magnesium sulfate was filtered off.
The solvent was distilled off from the filtrate. 9 ml of a 1: 8 (volume ratio) mixture of ethyl acetate and n-hexane was added to the obtained residue, 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 a chiral ketone compound. On the other hand, the obtained filtrate is purified by flash column chromatography on silica gel (mobile phase: ethyl acetate: n-hexane = 1: 8 (volume ratio);

[0400]

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90 mg (isolation yield: 51%) of an optically active phenyloxirane compound represented by the following formula: was obtained.

The optical purity of the obtained optically active phenyloxirane compound was determined by HPLC.
e.

The obtained optically active phenyloxirane compound had the following physical properties.

¹ H-NMR (300 MHz, CDCl ₃ )
: Δ 3.40 (1H, d, J = 1.8 Hz,);
82 (3H, S), 4.24 (1H, d, J = 1.8H
z), 6.91 (2H, m), 7.19 (2H, m)

The conditions for the HPLC were as follows. [Column] Chiral OD [Mobile phase] Hexane: ethanol = 9: 1 (volume ratio) [Flow rate] 0.5 ml / min

Examples 9 to 15 General formulas:

[0407]

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(Wherein R ^x represents a group shown in Table 1).

After dissolving 1.0 mmol of the cinnamic acid derivative in 15 ml of a solvent shown in Table 1 at room temperature, 4 × 1
0 ^-4 M aqueous solution of disodium ethylenediaminetetraacetic acid 1
0 ml was added, followed by the same chiral ketone compound used in Example 1 and kept at room temperature. Thereafter, a mixture of 6.14 g (10 mmol) of oxone and 2.6 g (31 mmol) of sodium bicarbonate was added in portions, and the mixture was further stirred, and the obtained reaction mixture was poured into a saline solution and extracted with ether. , Washed with saturated saline,
Then, it was dried with anhydrous magnesium sulfate.

The amounts of the chiral ketone compound, the addition time of oxone and sodium bicarbonate, and the stirring time are also shown in Table 1.

[0411] Anhydrous magnesium sulfate was separated by filtration from the washed and dried extract thus obtained, and the solvent was distilled off from the filtrate. To the obtained residue, 9 ml of a mixture of ethyl acetate and n-hexane (1: 8 (volume ratio)) was added, and the mixture was stirred at room temperature for 1 hour.

[0412] The precipitated white powder was collected by filtration and dried under reduced pressure to recover a chiral ketone compound.

On the other hand, the obtained filtrate was subjected to flash column chromatography on silica gel (mobile phase: ethyl acetate:
n-hexane = 1: 8 (volume ratio)).

[0414]

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An optically active phenylglycidic acid ester represented by the formula (wherein R ^x is as defined above) was obtained.

The yield and optical purity of the obtained optically active phenylglycidic acid ester are shown in Table 1. The optical purity was determined by HPLC.

[0417]

[Table 1]

From the results shown in Table 1, Examples 9 to 15 were obtained.
According to the method described above, it can be understood that the optically active phenylglycidic acid ester can be produced in high yield and high optical purity regardless of the type of the ester residue.

Example 16 Trans-4-methoxycinnamic acid methyl ester 961
mg (5.00 mmol) and the formula:

[0420]

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79m of a chiral ketone compound represented by the following formula:
g (0.20 mmol) in 1,2-dimethoxyethane 9
in water and 4.5 ml of water. Oxone (3.074 g, 5.00 mmol) and baking soda (1.302 g, 15.5 mmol) were added to the obtained suspension over 1 hour and 30 minutes, and the mixture was stirred at 22 to 24 ° C. for 2 hours and 30 minutes. A saline solution was added to the reaction mixture, and the mixture was extracted with ether. The obtained extract was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. Extract 31.5 after drying
By HPLC using 546.2 mg of 6 g,
The yield of methyl 3- (4-methoxyphenyl) glycidate was measured, and it was confirmed that the yield was 88.3% and the optical purity of the (2R, 3S) form was 76.8% ee. Was done.

The remaining reaction mixture was concentrated under reduced pressure, and 6.6 mg of 1.042 g of the obtained residue was used to determine the amount of trans-4-methoxycinnamic acid methyl ester by HPLC.
As a result, it was confirmed that only 7.3% remained.

[0423] Isopropyl ether was added to the remaining residue.
5 ml was added, and the mixture was heated to 45 ° C. to dissolve. The solution is cooled to 40 ° C. over 10 minutes with stirring, and the precipitated crystals are collected by filtration. A portion of the obtained precipitated crystal was sampled, and the composition was examined by ¹ H-NMR and HPLC. The precipitated crystal was found to contain 73 mg of a chiral ketone compound and (2R, 3S)
It was confirmed that the mixture was 90.7 mg (98.8% ee of optical purity) of methyl 3- (4-methoxyphenyl) glycidate.

[0424] The filtrate was concentrated under reduced pressure, 10 ml of isopropyl ether was added again to the residue, and the mixture was heated to 40 to 45 ° C to dissolve it. The resulting solution was cooled to 20 ° C. and then to 11 ° C. over 40 minutes and further to 8.5 ° C. over 1 hour and 35 minutes. The precipitated crystals are separated by decantation and washed with cold isopropyl ether to give (2R, 3S) -3- (4-methoxyphenyl)
Glycidic acid methyl ester 587 mg (Yield: 56.
4%, optical purity: 98.5% ee).

[0425] The mother liquor was concentrated under reduced pressure, the residue 265 mg ¹ H
As determined by NMR and HPLC, 6 mg of a chiral ketone compound and racemic trans-3-
It was found that the product consisted of 181.5 mg of (4-methoxyphenyl) glycidic acid methyl ester, and it was confirmed that decomposition of the product and side reaction did not occur in the separation step.

Example 17 Trans-p-methoxycinnamic acid methyl ester 9.6
11 g (50 mmol) and the formula:

[0427]

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The chiral ketone compound 1.0 represented by the following formula:
88 g (2.7 mmol) was dissolved in 1,2-dimethoxyethane (100 ml) at room temperature. Thereafter, 50 ml of distilled water was added to the obtained solution at 20 ° C., and then a mixture of 30.74 g (50 mmol) of oxone and 13.02 g (155 mmol) of sodium bicarbonate was slowly added at the same temperature over 1.5 hours. Was added. After the addition was completed, the mixture was further stirred at the same temperature for 5.5 hours, the obtained reaction mixture was cooled to 0 to 5 ° C, 500 ml of cooled water was added, and the mixture was stirred at the same temperature for 30 minutes.

The precipitated solid was dissolved in 100 ml of chloroform, dried, filtered to remove impurities, and the solvent was distilled off from the filtrate under reduced pressure to obtain a white solid.

The white solid was analyzed by HPLC under the following conditions, and was found to be (2R, 3S) -3- (p
7.-Methoxyphenyl) glycidic acid methyl ester
298 g, estimated to be a mixture of 0.92 g of (2S, 3R) -3- (p-methoxyphenyl) glycidic acid methyl ester, 0.323 g of methyl p-methoxycinnamate and 0.966 g of the chiral ketone compound. Was done.

(HPLC Measurement Conditions) Filler: Chiralcel OD Solvent: n-hexane: isopropyl alcohol (volume ratio) = 10: 1 Flow rate: 1 ml / min Column temperature: 40 ° C. Detection: absorption at 220 nm

By treating the obtained white solid in the same manner as in Example 1, (2R, 3S) -3- (p-methoxyphenyl) glycidic acid methyl ester and the chiral ketone compound can be obtained. did it.

Example 18 Trans-4-methoxycinnamic acid methyl ester 38m
g (0.2 mmol) and the formula:

[0434]

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A chiral ketone compound represented by the following formula: 0.8
mg (0.002 mmol) was dissolved in 3 ml of 1,2-dimethoxyethane. To this solution, 2 ml of a 4.0 × 10 ⁻⁴ M aqueous solution of disodium ethylenediaminetetraacetate was added, and the mixture was stirred at 0 ° C. with vigorous stirring.
12 mg and 260 mg of sodium hydrogen carbonate were divided into three portions and added every 30 minutes.

When the resulting mixture was stirred at the same temperature for 7 hours, p-methoxycinnamic acid methyl ester was no longer detected by thin layer chromatography. After the resulting reaction solution was extracted with diethyl ether, the extract was washed with saturated saline. The aqueous layer after extraction and the washing solution were combined, and extracted again with diethyl ether. The extracts were combined, dried, and the solvent was distilled off.

The residue obtained was purified by silica gel flash column chromatography [solvent: hexane-ethyl acetate (4: 1)] to give (2R, 3S)-
39 mg of 3- (p-methoxyphenyl) glycidic acid methyl ester were obtained.

The obtained (2) was obtained in the same manner as in Example 17.
HPLC analysis of (R, 3S) -3- (p-methoxyphenyl) glycidic acid methyl ester indicated that the product had an optical purity of 63% ee.

Example 19 trans-4-methoxycinnamic acid methyl ester 1.9
22 g (10 mmol) and the formula:

[0440]

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A chiral ketone compound 215 represented by the following formula:
mg (0.5 mmol) in 1,4-dioxane 20 ml
At room temperature. Then, the resulting solution was added with water 10
ml and then at 20 ° C. 6.15 g of oxone
(10 mmol) and 2.60 g of sodium hydrogen carbonate
(31 mmol) was added at 5 minute intervals over 1.5 hours. After completion of the addition, the mixture was stirred at the same temperature for 30 minutes, then heated to 27 ° C. and stirred for 7 hours, and 50 ml of water was added. The reaction mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated.

The obtained residue was treated with H in the same manner as in Example 17.
Analysis by PLC showed that (2R, 3S) -3- (4-
Methoxyphenyl) glycidic acid methyl ester 1.7
84 g (yield: 85.7%, optical purity: 76.4% e
e), 135.7 mg of trans-4-methoxycinnamic acid methyl ester and the chiral ketone compound 21
It was estimated to be 2.1 mg of the mixture.

Example 20 Trans-4-methoxycinnamic acid methyl ester 1.9
22 g (10 mmol) and the formula:

[0444]

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A chiral ketone compound 215 represented by the following formula:
mg (0.5 mmol) in 1,4-dioxane 20 ml
At room temperature. After that, the obtained solution was added at 20 ° C.
At 10 ml of water and 2.21 g of potassium carbonate (16 m
mol)), and then oxone 6.15 at the same temperature.
g (10 mmol) were added at 5 minute intervals over 1.5 hours. After completion of the addition, the mixture was stirred at the same temperature for 30 minutes, and then stirred for 2 minutes.
After heating to 7 ° C. and stirring for 7 hours, 50 ml of water was added.
The reaction mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated. When the obtained residue was analyzed by HPLC in the same manner as in Example 17, it was found that (2R, 3S) -3
1.585 g of-(4-methoxyphenyl) glycidic acid methyl ester (yield: 76.1%, optical purity: 78.
0% ee), was estimated to be a mixture of 341.4 mg of trans-4-methoxycinnamic acid methyl ester and 209.7 mg of the chiral ketone compound.

Reference Example 1 [Synthesis of Chiral Ketone Compound] (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:

[0447]

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After gradually adding 3.13 g of quinidine represented by the 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, 17
21,1670,1584 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 the (−)-formianthraquinonecarboxylic acid in 8 ml of tetrahydrofuran. For 1 hour.

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

[0457]

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89 mg of 1,3-dihydroxyacetone dimer represented by the formula 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:

[0461]

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

The physical 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, chloroform and aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was extracted with chloroform.

After the organic layer was washed 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:

[0468]

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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_Three): Δ 4.21 (d, J = 1)
5 Hz, 2H), 5.59 (d, J = 15 Hz, 2
H), 7.29 (ddd, J = 1.7, 8 Hz, 2
H), 7.46 (ddd, J = 1.7, 7.9 Hz, 2
H), 7.52 (d, J = 9 Hz, 2H), 7.67
(D, J = 9 Hz, 2H), 7.89 (S, 2H),
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.

[0472]

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

The physical 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 1 ml
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, transesterification gave the results shown in Table 2.

[0479]

[Table 2]

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

[0481]

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In a solution of 160 mg (0.48 mmol) of the chiral dicarboxylic acid represented by the formula (6 ml) in tetrahydrofuran is added 0.105 ml (1.20 mmol) of oxalic acid chloride and one drop of dimethylformamide in a nitrogen gas stream 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 at the same temperature overnight.

The solvent was distilled off from the obtained reaction solution, and 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:

[0484]

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

As described above, the styrene derivative (I) represented by the general formula (I) is reacted with the asymmetric oxidizing agent formed from the chiral ketone compound and the oxidizing agent to obtain the styrene derivative (II). It can be seen that the optically active phenyloxirane compound represented by the formula can be obtained with high stereoselectivity and high yield.

Also, as an example of asymmetric oxidation with oxone and a chiral ketone compound, asymmetric epoxidation of trans-stilbene is known [Journal of
American Chemical Society (J. Am. C
hem. Soc. 118, 11311 (1996)
)], Unlike trans-stilbene, which is a simple C2 symmetric compound, the styrene derivative (I), which is the starting compound of the present invention, is a complex compound having no symmetric element, and can control an asymmetric reaction. It can be seen that the optically active phenyloxirane compound can be obtained with a very high optical yield, though it is considered more difficult.

In general, in order to obtain high stereoselectivity in an asymmetric reaction, an extremely low temperature (−78 ° C.)
) In many cases, but the production method of the present invention has the advantage that industrialization is easy because asymmetric oxidation can be performed with high stereoselectivity at around 0 ° C to room temperature.

In the styrene derivative (I), which is a starting compound of the present invention, the electron-withdrawing ester moiety is directly bonded to the double bond, and the asymmetric oxidizing agent formed from the chiral ketone compound and the oxidizing agent. The reaction can be completed in a relatively short time even at a low temperature, even though it is considered that the asymmetric oxidation due to is difficult to proceed.

Further, in the production method of the present invention, since an asymmetric oxidizing agent which is a mild oxidizing agent is used, an optically active phenyloxirane compound having an oxirane ring which can be easily decomposed can be obtained in high yield. .

Further, in the present invention, a chiral ketone compound is used, the chiral ketone compound is oxidized by an oxidizing agent in the reaction system to form an asymmetric oxidizing agent, and the asymmetric oxidizing agent is used in the same reaction system. When the asymmetric oxidation of the styrene derivative (I) existing in the reaction system is performed, the chiral ketone compound generated from the asymmetric oxidizing agent in the asymmetric oxidation reaction is again oxidized by the oxidizing agent in the reaction system, and Since the asymmetric oxidizing agent is regenerated, an asymmetric oxidation reaction can be performed only by using a catalytic amount of a chiral ketone compound. Furthermore, since the chiral ketone compound is a chemically stable compound, it can be reused by collecting it.

[0492]

According to the present invention, an optically active phenyloxirane compound can be obtained in a high yield, and the asymmetric catalyst used in the production thereof can be reused. An excellent effect that a phenyloxirane compound can be produced with high productivity and economy can be obtained.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 9/12 A61P 9/12 C07B 61/00 300 C07B 61/00 300 C07M 7:00 C07M 7:00 (72) Inventor Kusama Mari 2-24-6-105 Tsuji, Urawa City, Saitama Prefecture (72) Inventor Yasuhiko Ozaki 18-18 Ishizu Higashicho, Neyagawa City, Osaka (72) Inventor Tohru Kuroda 9-8-214, Asahigaokacho, Ashiya City, Hyogo Prefecture 72) Inventor Masahiko Seki 4-34-13, Kaida, Nagaokakyo-shi, Kyoto (56) References Reference Table 4-501360 (JP, A) Am. Chem. Soc. (1996), 118, pages 11311-11312 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 301/03 C07D 281/10 CA (STN) REGISTRY (STN)

Claims (25)

(57) [Claims] 1. A compound of the general formula (I): (Wherein ring A is a substituted or unsubstituted benzene ring, R is -C
A group represented by O ₂ R ^q or a group convertible ^thereto , R ^q
Represents an ester residue), wherein an asymmetric oxidizing agent formed from a chiral ketone compound and an oxidizing agent is allowed to act on the styrene derivative (I) represented by the general formula (I)
I): (Wherein, rings A and R are the same as above, and * indicates an asymmetric carbon atom). 2. The chiral ketone compound has the general formula (V): [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 1 -Q-Alk 1 -, (vi) -Q-NR 1 - Alk ² —, (vii) —Alk ³ —NR ¹ —Alk ⁴ — or (viii) —NR ¹ —Alk ⁵ —, Q is a —CO— group or —SO ₂ — group, R ¹ 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 (V). 3. A 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: Formula 5 (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 1 -Q-Alk 1 -, (vi ) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 optical isomer of the ketone compound (VI) represented by the formula: 4. The process according to claim 1, wherein the reaction of the chiral ketone compound with the oxidizing agent and the reaction of the generated asymmetric oxidizing agent on the styrene derivative (I) are carried out in the same reaction system. 5. A compound of the general formula (I): (Wherein ring A is a substituted or unsubstituted benzene ring, R is -C
A group represented by O ₂ R ^q or a group convertible ^thereto , R ^q
Wherein a chiral dioxirane compound is allowed to act on a styrene derivative (I) represented by the following general formula (II): (Wherein, rings A and R are the same as above, and * indicates an asymmetric carbon atom). 6. A chiral dioxirane compound represented by the general formula (III): [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 1 -Q-Alk 1 -, (vi) -Q-NR 1 -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 (III). 7. The chiral dioxirane compound represented by the general formula (IV): [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 1 -Q-Alk 1 -, (vi ) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 method according to claim 5 or 6, which is an optical isomer of the dioxirane compound (IV). 8. A compound of 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: Formula 14 (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 1 -Q-Alk 1 -, (vi ) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q represents a -CO- group or -SO ₂ -group, R ¹ 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] by reacting an optical isomer of a ketone compound (VI) represented by the formula (1) with an oxidizing agent to cause the resulting chiral dioxirane compound (IV) to act on the styrene derivative (I). 7. The method according to any one of the above items. 9. A reaction between an optical isomer of a ketone compound (VI) and an oxidizing agent and a chiral dioxirane compound formed
9. The process according to claim 8, wherein the reaction of (IV) acting on the styrene derivative (I) is carried out in the same reaction system. 10. The styrene derivative (I) is in a trans form, and the optically active phenyloxirane compound (II) is (2)
The process according to any one of claims 1 to 9, which is an (R, 3S) -isomer or a (2S, 3R) -isomer. 11. The styrene derivative (I) is in a trans form, and the chiral ketone compound is represented by the general formula (VI-a): [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 1 -Q-Alk 1 -, (vi ) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 optically active phenyloxirane compound (II) is a (2R, 3S) -isomer. Recipe. 12. The styrene derivative (I) is in a trans form, and the chiral ketone compound is represented by the general formula (VI-b): [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 1 -Q-Alk 1 -, (vi ) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 optically active phenyloxirane compound (II) is a (2S, 3R) -isomer. Recipe. 13. The styrene derivative (I) is in a trans form, and the chiral dioxirane compound is represented by the general formula (IV-
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 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 1 -Q-Alk 1 -, (vi ) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 phenyloxirane compound (II) is a (2R, 3S) -isomer. Production method of optically active phenyloxirane compound (II). 14. The styrene derivative (I) is in a trans form, and the chiral dioxirane compound is represented by the general formula (IV-
b): 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 1 -Q-Alk 1 -, (vi ) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 optically active phenyloxirane compound (II) is a (2S, 3R) -isomer. Recipe. 15. Y is -CO-O-CH_Two-Group, R^a~
R^dBut (a) R^aAnd R^bIs a hydrogen atom, R^cand
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 other3, 4, 7, 8, 9, 11, 1
The production method according to 2, 13, or 14. 16. R ^a and R ^b are each a hydrogen atom, and R ^c and R ^d are bonded to each other. The method according to claim 15, wherein 17. A ketone compound produced by reducing a chiral dioxirane compound from a reaction mixture obtained by reacting a styrene derivative (I) represented by the general formula (I) with a chiral dioxirane compound, and an optical activity The method according to claim 5, wherein the phenyloxirane compound (II) is produced with high purity by a separation method utilizing a difference in solubility in an organic solvent. 18. A ketone compound and an optically active phenyloxirane compound (II) produced by reducing an asymmetric oxidizing agent contained in a reaction mixture and producing each with high purity by a separation method utilizing a difference in solubility in an organic solvent. The method according to claim 1, wherein 19. The ketone compound represented by the general formula (V): [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 1 -Q-Alk 1 -, (vi) -Q-NR 1 - Alk ² —, (vii) —Alk ³ —NR ¹ —Alk ⁴ — or (viii) —NR ¹ —Alk ⁵ —, Q is a —CO— group or —SO ₂ — group, R ¹ 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] is an optical isomer of the ketone compound (V) represented by the following formula:
8. The manufacturing method according to 8. 20. The 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: 33 (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 1 -Q-Alk 1 -, (vi ) -Q-NR ¹ -Alk ^2- , (vii) -Alk ³ -NR ¹ -Alk ⁴ -or (viii) -NR ¹ -Alk ^5- , Q is a -CO- group or -SO ₂ -group, R ¹ 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 is an optical isomer of the ketone compound (VI) represented by the following formula. 21. Ring A is 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, wherein R is -CO ₂ R ^q
( ^Rq represents an ester residue). 22. The method according to claim 21, wherein ring A is a 4-lower alkylphenyl group or a 4-lower alkoxyphenyl group, and ^Rq is a lower alkyl group. 23. The method according to claim 22, wherein ring A is a 4-methoxyphenyl group and ^Rq is a methyl group. 24. The general formula (II): (Wherein ring A is a substituted or unsubstituted benzene ring, R is -C
A group represented by O ₂ R ^q or a group convertible ^thereto , R ^q
Represents an ester residue. * Indicates an asymmetric carbon atom).
From (II) to general formula (VII): (Wherein ring B is a substituted or unsubstituted benzene ring, R ² is a hydrogen atom or a substituted alkyl group, R ³ is a lower alkanoyl group, and rings A and * are the same as described above) In the method for producing a thiazepine derivative or a pharmacologically acceptable salt thereof, the optically active phenyloxirane compound (II) obtained by the production method according to any one of claims 1 to 23 as the optically active phenyloxirane compound (II). ), A method for producing a 1,5-benzothiazepine derivative or a pharmaceutically acceptable salt thereof. 25. The general formula (II): (Wherein ring A is a substituted or unsubstituted benzene ring, R is -C
A group represented by O ₂ R ^q or a group convertible ^thereto , R ^q
Represents an ester residue. * Indicates an asymmetric carbon atom).
From (II) the general formula: (Wherein ring A and ring B represent a substituted or unsubstituted benzene ring, * represents an asymmetric carbon atom) or a salt thereof. A method for producing a nitrocarboxylic acid compound or a salt thereof, comprising using the optically active phenyloxirane compound (II) obtained by any one of the production methods described above.