JP2000026442A - Production of optically active styrene oxide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain the subject compound useful as an intermediate, etc., for producing medicines in high optical purity and yield and in a factory scale by preparing styrene oxide having a larger amount of one of optical isomers in a specific condition and successively optically resolving the styrene oxide by using an asymmetric catalyst. SOLUTION: This optically active styrene oxide expressed by formula V (R1 is H, a halogen, a lower alkyl or the like; R2 and R3 are each H, a lower alkyl or the like; X is a halogen) is produced by ring-closing a phenylhalogenomethylcarbinol expressed by formula II prepared by aseymmetrically reducing a phenyl halogenomethyl ketone expressed by formula I and containing a larger amount of one of optical isomers to obtain a styrene oxide expressed by formula III having a larger amount of one of the optical isomers, and carrying out a kinetic optical resolution using an asymmetric catalyst such as a salen metal catalyst or the like expressed by formula IV (R4 and R4' are each H, methoxy, t-butyl or the like, one of R5 and R6 is H and the other is methyl, phenyl or the like; M is a metal ion; Y is a counter anion).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel method for producing optically active styrene oxides. In detail, styrene oxides obtained by asymmetric reduction of phenylhalogenomethyl ketones, phenylhalogenomethylcarbinols containing one of the optical isomers abundantly, and styrene oxides containing one of the optical isomers abundantly obtained And then performing kinetic optical resolution using an asymmetric catalyst, which relates to a method for producing optically active styrene oxides represented by the following general formula (4).

[0002]

2. Description of the Related Art Optically active styrene oxide derivatives are compounds useful as intermediates in the manufacture of various pharmaceuticals such as drugs for treating diabetes, drugs for treating hyperglycemia, and drugs for preventing and treating obesity. Optically active styrene oxide derivatives, for example,
As a method for producing the R-form m-chlorostyrene oxide, the following method is known. After chlorinating m-chloroacetophenone to chloromethyl-m-chlorophenyl ketone, the resulting mixture is subjected to asymmetric reduction by the action of a CBS catalyst to obtain the corresponding optically active chlorohydrin, which is then treated with a base. A method of ring closure (J.
Med. Chem. , 35 , 3081 (1992)), but the optical purity of the obtained R-form of m-chlorostyrene oxide was not a satisfactory value of 85% ee. Further, there is a method in which a microorganism is allowed to act on bromomethyl-m-chlorophenyl ketone to obtain optically active bromomethyl-m-chlorophenyl carbinol, and this is treated with a base to close the ring (Japanese Patent Application Laid-Open No. 4-218384). Although it is excellent in optical purity, in a process using microorganisms, a dilute solution having a substrate concentration of about 0.5% is used, so that the scale of the apparatus cannot be avoided and is not practical. In addition, a mixture of the S-form and the R-form of phenylhalogenomethylcarbinols is treated with lipase in the presence of a carboxylic acid ester to selectively esterify the S-form, and then the base is actuated to close the R-form. (Japanese Unexamined Patent Publication No. 8-322589), but the range of application is limited by the substrate specificity caused by the use of the enzyme (only the R-form is applicable), and management and operation for preventing inactivation are performed. There was a problem with complexity.

[0003]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a novel method for producing optically active styrene oxides having a high optical purity, which is relatively inexpensive, easy to operate, and can be carried out on a factory scale. To provide.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object, and as a result, have found that phenylhalogenomethylcarbinols, in which one of the optical isomers obtained by asymmetric reduction is abundant, are present. By obtaining styrene oxides with a large amount of one optical isomer and then performing kinetic optical resolution using an asymmetric catalyst, styrene oxides with high optical purity can be easily obtained from relatively inexpensive raw materials. The present inventors have found that they can be manufactured by simple operations, and have completed the present invention.

That is, the present invention relates to (1) general formula (1)

[0006]

Embedded image

Wherein R ¹ is a hydrogen atom, a halogen atom,
Represents a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, and R ² and R ³ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group; Or R ² and R ³ may together form a methylenedioxy group, and X represents a halogen atom. General formula (2) obtained by asymmetric reduction of a phenylhalogenomethyl ketone represented by formula (1), wherein one of the optical isomers is present in a large amount.

[0008]

Embedded image

(Wherein R ¹ , R ² , R ³ and X have the same meanings as described above), and a phenylhalogenomethylcarbinol represented by the formula: General formula (3)

[0010]

Embedded image

(Wherein R ¹ , R ² and R ³ have the same meanings as described above), and are kinetic obtained by using an asymmetric catalyst for the styrene oxide. General formula (4) characterized by performing optical division

[0012]

Embedded image

(Wherein R ¹ , R ² and R ³ have the same meanings as described above), and (2) the asymmetric catalyst has the formula

[0014]

Embedded image

(Wherein R ⁴ and R ⁴ ′ may be the same or different and each represents a hydrogen atom, methoxy, te
rt-butyl, 1-phenylpropyl, or substituted aryl, wherein one of R ⁵ and R ⁶ is a hydrogen atom,
The other is methyl, phenyl, 3,5-dimethylphenyl,
Or two R's each representing 4- (tert-butyl) phenyl or each bonded to a different carbon atom
^{One of the 5} pairs and 2 R ⁶ pairs may together form tetramethylene, the other pair each representing a hydrogen atom, M representing a metal ion, and an ion of the metal ion. When the valence and the number of coordinating atoms of the ligand are different, Y represents a counter anion. When the ionic valence of the metal ion and the number of coordinating atoms of the ligand are the same, Y does not exist. The method for producing optically active styrene oxides of (1) above, which is a salen metal catalyst represented by the formula (1), and (3) the asymmetric reduction of phenylhalogenomethyl ketones, the general formula (5)

[0016]

Embedded image

(Wherein, R ⁷ represents an alkyl group having 1 to ⁷ carbon atoms, an aryl group which may be substituted, or an aralkyl group which may be substituted, and R ⁸ represents a hydrogen atom, a lower alkyl group, Represents an aralkyl group which may be substituted, or R ⁷ and R ⁸ may be combined to form a lower alkylene group, and R ⁹ and R ¹⁰ may be the same or different; Hydrogen atom, carbon number 1
7 represents an alkyl group or an optionally substituted aryl group, or R ⁹ and R ¹⁰ may together form a lower alkylene group. Or R ⁷ and R
⁹ may be taken together to form an unsubstituted, substituted, or fused lower alkylene group of a benzene ring. (1) wherein the reduction is carried out with an asymmetric reducing agent obtained from the optically active amino alcohol and borane represented by the formula (1) or from the optically active amino alcohol, metal borohydride and acid or dialkyl sulfate. And (2) a method for producing optically active styrene oxides.

[0018]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present specification will be described in detail along with a manufacturing process. In addition, in this specification, “one optical isomer is present in a large amount” means that one of the R-form and the S-form is present in an amount of more than 50%.

In the present specification, the terms "lower alkyl group" and "lower alkoxy group" mean, unless otherwise specified.
It has 1 to 4 carbon atoms.

In the asymmetric reduction of the phenylhalogenomethyl ketone of the general formula (1), an asymmetric reducing agent is used.
The asymmetric reducing agent in the present invention is preferably a combination of an optically active amino alcohol and a borane, a combination of an optically active amino alcohol, a metal borohydride and an acid or dialkyl sulfate, and particularly preferably an optically active amino alcohol. It is a combination of a metal borohydride and an acid or dialkyl sulfuric acid. In the above combination, it is also preferable to prepare and use an asymmetric reducing agent after pretreating the optically active amino alcohol with a trialkylboroxine.

The optically active amino alcohol is represented by the formula (5)

[0022]

Embedded image

(Wherein, R ⁷ represents an alkyl group having 1 to ⁷ carbon atoms, an aryl group which may be substituted, or an aralkyl group which may be substituted, and R ⁸ represents a hydrogen atom, a lower alkyl group, Represents an aralkyl group which may be substituted, or R ⁷ and R ⁸ may be combined to form a lower alkylene group, and R ⁹ and R ¹⁰ may be the same or different; Hydrogen atom, carbon number 1
7 represents an alkyl group or an optionally substituted aryl group, or R ⁹ and R ¹⁰ may together form a lower alkylene group, or R ⁷ and R
⁹ may be taken together to form an unsubstituted, substituted, or fused lower alkylene group of a benzene ring. ).

The absolute configuration of the β carbon in the formula (5) is R
Both the body and the S body may be used. When the absolute configuration of the β-carbon is R-form, phenylhalogenomethylcarbinols having a large amount of the R-form in formula (2) are obtained. When the absolute configuration of the β-carbon is S-form, the S-form in formula (2) is obtained. To obtain phenylhalogenomethylcarbinol in which a large amount of is present.

The alkyl group having 1 to ⁷ carbon atoms in R ⁷ may have a cycloalkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, sec.
-Butyl, tert-butyl, pentyl, hexyl, cyclohexylmethyl and the like.

Examples of the optionally substituted aryl group for R ⁷ include aryl groups such as phenyl and naphthyl which may be substituted with lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. For example, phenyl, tolyl, naphthyl and the like can be mentioned.

The optionally substituted aralkyl group for R ⁷ and R ^{8 includes} , for example, an aralkyl group optionally substituted by lower alkyl such as benzyl, phenethyl and p-methylbenzyl.

Examples of the lower alkylene group formed by R ⁷ and R ⁸ together include an alkylene group having 1 to 4 carbon atoms such as methylene, dimethylene, trimethylene and tetramethylene.

The optionally substituted aryl group in R ⁹ and R ¹⁰ includes, for example, phenyl, tolyl, ethylphenyl, propylphenyl, isopropylphenyl,
Butylphenyl, isobutylphenyl, dimethylphenyl, ethylmethylphenyl, diethylphenyl, methylpropylphenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, isopropoxyphenyl, butoxyphenyl, isobutoxyphenyl, dimethoxyphenyl, ethoxymethoxyphenyl, diethoxyphenyl And lower alkyl such as methylmethoxyphenyl, ethoxymethylphenyl and trimethylphenyl, phenyl substituted by lower alkoxy, naphthyl and the like.

As the alkyl group having 1 to 7 carbon atoms for R ⁹ and R ¹⁰ , for example, those similar to the aforementioned R ⁷ can be mentioned.

The lower alkylene group formed by R ⁹ and R ¹⁰ together includes, for example, an alkylene group having 4 to 6 carbon atoms such as tetramethylene, pentamethylene and hexamethylene.

As an unsubstituted, substituted, or lower alkylene group formed by combining R ⁷ and R ⁹ with a benzene ring, an alkylene moiety having 3 to 5 carbon atoms is preferable. , Tetramethylene, pentamethylene, o-phenylenemethylene, o-phenylenedimethylene and the like.

Specific examples of the optically active amino alcohol in the present invention include, for example, optically active norephedrine, 2-amino-1- (2,5-dimethylphenyl)
-1-propanol, 2-amino-1- (2,5-dimethoxyphenyl) -1-propanol, 2-amino-1
-(2,5-diethoxyphenyl) -1-propanol, 2-amino-1- (2,5-dipropoxyphenyl) -1-propanol, 2-amino-1- (2-methoxyphenyl) -1- Propanol, 2-amino-1-
(2-ethoxyphenyl) -1-propanol, 2-amino-1- (2-propoxyphenyl) -1-propanol, 2-amino-1- (2-methylphenyl) -1-
Propanol, 2-amino-1- (2-methoxy-5-
Methylphenyl) -1-propanol, 2-amino-1
-(4-methoxy-2-methylphenyl) -1-propanol, 2-amino-1- (2-ethoxy-5-methylphenyl) -1-propanol, 2-amino-1-
(2,4-dimethylphenyl) -1-propanol, 2
-Amino-1- (2,4,6-trimethylphenyl)-
1-propanol, 2-amino-1- (1-naphthyl)
-1-propanol,

2-amino-1- (2-naphthyl) -1-
Propanol, 2-amino-1,2-diphenylethanol, 2-amino-1,1-diphenyl-1-butanol, 2-amino-1,1-diphenyl-1-pentanol, 2-amino-1,1- Diphenyl-1-propanol, 2-amino-1,1,3-triphenyl-1-propanol, 2-amino-1,1,2-triphenyl-1
-Ethanol, 2-amino-3-methyl-1-butanol, 2-amino-4-methyl-1-pentanol, 2-
Amino-1-propanol, 2-amino-3-phenyl-1-propanol, 2-amino-2-phenyl-1-
Ethanol, 2-aminocyclohexanol, 3-aminoborneol and the like and N-lower alkyl-substituted, N-aralkyl-substituted, 2-pyrrolidinemethanol, α, α-diphenyl-2-pyrrolidinemethanol,
2-piperidinemethanol, α, α-diphenyl-2-
Aziridine methanol, 2-azetidine methanol,
α, α-diphenyl-2-azetidinemethanol and the like.

Some of these are commercially available and are derived from optically active amino acids or Org. C
hem. , 25, 1929 (1960); Am. C
hem. Soc. , 52, 3317 (1930);
Am. Chem. Soc. , 51, 262 (192)
9). Org. Chem. , 11, 390 (194)
6) It can be manufactured according to the method described.

The optically active amino alcohol in the present invention is used per mole of phenylhalogenomethyl ketone.
Usually about 0.005 to 0.5 times, preferably 0.01 to
Used about 0.4 times.

As the borane in the present invention, for example, diborane (B ₂ H ₆ ), tetraborane (B ₄ H ₁₀ ), hexaborane (B ₆ H ₁₀ ), tetrahydrofuran (THF)
Examples include borane complexes, dimethylsulfide borane complexes, catechol borane, and the like.

The borane in the present invention is used usually in an amount of about 0.3 to 2 times, preferably about 0.5 to 1.5 times in terms of boron, based on 1 mol of the phenylhalogenomethyl ketone.

As the metal borohydride in the present invention,
For example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride and the like can be mentioned, and preferred is sodium borohydride.

The metal borohydride in the present invention is used in an amount of usually about 0.3 to 2 times, preferably 0.6 to 1.5 times as much as boron, per mole of phenylhalogenomethyl ketone.
Used about twice.

The acid in the present invention includes, for example, Bronsted acids such as hydrogen chloride, sulfuric acid, acetic acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid, zinc chloride, boron trifluoride, aluminum chloride and aluminum bromide. ,
Lewis acids such as titanium tetrachloride, tin tetrachloride, and tin dichloride are exemplified.

The acid used in the present invention is usually about 0.5 to 2.5 equivalents, preferably 0.1 to 2.5 equivalents, to the metal borohydride.
About 8 to 2.2 equivalents are used.

The alkyl portion of the dialkyl sulfate in the present invention preferably has 1 to 4 carbon atoms, and examples thereof include dimethyl sulfate, diethyl sulfate, and ethyl methyl sulfate.

The dialkyl sulfuric acid used in the present invention is usually used in an amount of about 0.9 to 1.1 times, preferably about 0.95 to 1.05 times 1 mole of the metal borohydride.

The preparation of an asymmetric reducing agent from an optically active amino alcohol and a borane is usually carried out by mixing the two in a solvent. Examples of the solvent include tetrahydrofuran, 1,3-dioxane, 1,4-dioxane,
Ethers such as 1,3-dioxolan, thioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, t-butyl methyl ether,
Aromatics such as benzene, toluene, xylene and chlorobenzene, hydrocarbons such as hexane, heptane and cyclohexane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride, and mixtures thereof. Can be

The solvent is used usually in an amount of about 0.5 to 50 times the weight of the optically active amino alcohol, and the preparation temperature is usually about -20 to 80 ° C, preferably about 0 to 60 ° C.

The preparation of an asymmetric reducing agent from an optically active amino alcohol, a metal borohydride and an acid or dialkyl sulfate is usually carried out in the solvents listed below. Examples of the solvent include ethers such as tetrahydrofuran, 1,4-dioxane, 1,3-dioxolan, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether, sulfides such as dimethyl sulfide and diethyl sulfide, and a single or mixed solvent of these solvents. And a solvent such as benzene, toluene, xylene, chlorobenzene, and 1,2-dichloroethane.

The solvent is used usually in an amount of about 1 to 500 times the weight of the optically active amino alcohol, and the preparation temperature is usually about -20 to 100 ° C, preferably about 0 to 80 ° C.

The preparation of the asymmetric reducing agent from the optically active amino alcohol, the metal borohydride and the acid or dialkyl sulfuric acid is carried out by adding an acid or dialkyl sulfuric acid to a mixture of the optically active amino alcohol, the metal borohydride and the solvent, or The reaction is performed by adding an acid or dialkyl sulfate to a mixture of a metal borohydride and a solvent, and then adding an optically active amino alcohol. In this case, the Lewis acid and the dialkyl sulfuric acid may be added as a mixture with a solvent. In addition, it can also be prepared by adding a mixture of a metal borohydride and a solvent to a mixture of an optically active amino alcohol, an acid and a solvent.

Using the asymmetric reducing agent obtained as described above, asymmetric reduction of phenylhalogenomethyl ketones is performed. As the prepared asymmetric reducing agent, the one obtained by the asymmetric reduction reaction of phenylhalogenomethyl ketones may be used as it is, or may be used after isolation.

The asymmetric reduction of phenylhalogenomethylketones is usually carried out by adding phenylhalogenomethylketones alone or a mixture thereof with a solvent to a mixture of an asymmetric reducing agent and a solvent, or It is performed by adding a mixture of an asymmetric reducing agent and a solvent to a mixture with a solvent.

The phenylhalogenomethyl ketone is represented by the formula (1)

[0053]

Embedded image

(Wherein R ¹ is a hydrogen atom, a halogen atom,
Represents a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, and R ² and R ³ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group; Or R ² and R ³ may together form a methylenedioxy group, and X represents a halogen atom. ).

The halogen atom in R ¹ , R ² and R ³ includes, for example, fluorine, chlorine, bromine and the like.
Preferably they are chlorine and fluorine.

The halogen atom for X includes fluorine, chlorine, bromine and the like, preferably chlorine and bromine.

The lower alkyl group represented by R ¹ , R ² and R ³ has 1 to 5 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Pentyl and the like, preferably having 1 to 3 carbon atoms, such as methyl, ethyl and propyl.

The lower alkoxy group represented by R ¹ , R ² and R ³ has 1 to 5 carbon atoms and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy and the like. And preferably has 1 to 3 carbon atoms, for example, methoxy, ethoxy, propoxy and the like.

The phenylhalogenomethyl ketones in the present invention specifically include 2-bromo-3'-chloroacetophenone and 2-bromo-3 'when X is a bromine atom.
-Bromoacetophenone, 2-bromo-3'-fluoroacetophenone, 2-bromo-3'-methylacetophenone, 2-bromo-3'-methoxyacetophenone,
-Bromo-3'-trifluoromethylacetophenone,
2-bromo-4'-chloroacetophenone, 2-bromo-4'-bromoacetophenone, 2-bromo-4'-methylacetophenone, 2-bromo-4'-methoxyacetophenone, 2-bromo-4'-trifluoromethyl Acetophenone, 2-bromo-4'-fluoroacetophenone, 2-bromo-2'-chloroacetophenone, 2-
Bromo-2'-bromoacetophenone, 2-bromo-
2'-methylacetophenone, 2-bromo-2'-methoxyacetophenone, 2-bromo-2'-trifluoromethylacetophenone, 2-bromo-2'-fluoroacetophenone, 2-bromo-2'-chloro-3'- Methoxyacetophenone, 2-bromo-2'-bromo-3 '
-Methoxyacetophenone, 2-bromo-2'-fluoro-3'-methoxyacetophenone, 2-bromo-3 '
-Methoxy-2'-methylacetophenone, 2-bromo-2 ', 3'-dimethoxyacetophenone, 2-bromo-3'-methoxy-2'-trifluoromethylacetophenone, 2-bromo-2', 3'-dichloro Acetophenone, 2-bromo-2'-bromo-3'-chloroacetophenone, 2-bromo-3'-chloro-2'-fluoroacetophenone, 2-bromo-3'-chloro-2'-methylacetophenone, 2-bromo -3'-chloro-2 '
-Methoxyacetophenone,

2-bromo-3'-chloro-2'-trifluoromethylacetophenone, 2-bromo-2'-bromo-4'-chloroacetophenone, 2-bromo-2 ',
4'-dibromoacetophenone, 2-bromo-2'-bromo-4'-fluoroacetophenone, 2-bromo-
2'-bromo-4'-methylacetophenone, 2-bromo-2'-bromo-4'-methoxyacetophenone, 2
-Bromo-2'-bromo-4'-trifluoromethylacetophenone, 2-bromo-4'-chloro-2'-fluoroacetophenone, 2-bromo-2 ', 4'-difluoroacetophenone, 2-bromo-4' -Bromo-2 '
-Fluoroacetophenone, 2-bromo-2'-fluoro-4'-methylacetophenone, 2-bromo-2'-
Fluoro-4'-methoxyacetophenone, 2-bromo-2'-fluoro-4'-trifluoromethylacetophenone, 2-bromo-4'-chloro-2'-trifluoromethylacetophenone, 2-bromo-4'-bromo −
2'-trifluoromethylacetophenone, 2-bromo-4'-fluoro-2'-trifluoromethylacetophenone, 2-bromo-4'-methyl-2'-trifluoromethylacetophenone, 2-bromo-4'-methoxy -2'-trifluoromethylacetophenone, 2-bromo-2 ', 4'-ditrifluoromethylacetophenone, 2-bromo-4'-chloro-3'-trifluoromethylacetophenone, 2-bromo-4'-bromo- 3 '
-Trifluoromethylacetophenone, 2-bromo-
4'-fluoro-3'-trifluoromethylacetophenone, 2-bromo-4'-methyl-3'-trifluoromethylacetophenone, 2-bromo-4'-methoxy-
3′-trifluoromethylacetophenone, 2-bromo-3 ′, 4′-ditrifluoromethylacetophenone,

2-bromo-5'-bromo-3'-chloroacetophenone, 2-bromo-3 ', 5'-dibromoacetophenone, 2-bromo-5'-bromo-3'-fluoroacetophenone, 2-bromo- 5'-bromo-3 '
-Methylacetophenone, 2-bromo-5'-bromo-
3′-methoxyacetophenone, 2-bromo-3′-bromo-5′-trifluoromethylacetophenone, 2-
Bromo-3'-chloro-5'-trifluoromethylacetophenone, 2-bromo-3'-bromo-5'-trifluoromethylacetophenone, 2-bromo-3'-fluoro-5'-trifluoromethylacetophenone, −
Bromo-3'-methyl-5'-trifluoromethylacetophenone, 2-bromo-3'-methoxy-5'-trifluoromethylacetophenone, 2-bromo-3 ',
5'-dimethoxyacetophenone, 2-bromo-3 ',
5'-ditrifluoromethylacetophenone, 2-bromo-3 ', 5'-dichloroacetophenone, 2-bromo-3', 5'-dibromoacetophenone, 2-bromo-
3 ', 5'-difluoroacetophenone, 2-bromo-
2 ', 6'-dichloroacetophenone, 2-bromo-
2 ′, 4 ′, 6′-trichloroacetophenone, 2-bromo-3 ′, 4 ′, 5′-trichloroacetophenone,
2-bromo-3 ', 4'-methylenedioxyacetophenone and the like. When X is a chlorine atom, those obtained by replacing 2-bromo in the above compound with 2-chloro are exemplified.

As the solvent used in the asymmetric reduction, the same solvents as those used in the step of preparing the asymmetric reducing agent can be used.
The solvent is based on phenylhalogenomethylketones.
Usually, about 0.1 to 20 times by weight, preferably about 1 to 18 times by weight is used.

The amount of the asymmetric reducing agent used in the asymmetric reduction is usually 0.01 to 0. 1 in terms of the optically active amino alcohol used per mole of phenylhalogenomethyl ketone.
It is about 5 times, preferably about 0.02 to 0.4 times.

The reduction temperature is usually about −76 to 100 ° C.,
Preferably it is about 10 to 80 ° C.

The obtained phenylhalogenomethylcarbinols can be isolated by, for example, adding an acid such as hydrochloric acid to the reaction mass to decompose the reducing agent, removing the solvent if necessary, and extracting the solvent with an extraction solvent such as toluene. An aqueous solution of an acid such as hydrochloric acid or hydrochloric acid is added to remove the salt of the optically active amino alcohol and the acid from the aqueous layer, and the solvent can be easily isolated by distilling off the solvent of the separated organic layer. Further, after making the salt of the optically active amino alcohol and the acid removed in the aqueous layer basic, the optically active amino alcohol can be recovered by extracting with an extraction solvent such as toluene and distilling off the solvent.

The isolated phenylhalogenomethylcarbinols can be further purified by subjecting them to purification means such as distillation and various types of chromatography.

Next, the obtained phenylhalogenomethyl carbinols (2)

[0068]

Embedded image

(The definitions of R ¹ , R ² , R ³ and X are the same as those described in detail in the formula (1).) Obtain oxides.

The base used for the ring closure reaction includes, for example, hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide, carbonates of alkali metals such as sodium carbonate and potassium carbonate, sodium methoxide, potassium methoxide, potassium Alkoxides of alkali metals such as -t-butoxide and organic bases such as triethylamine (Or
g. Synth. 1 , 185 (1941); Am.
Chem. Soc. 81 , 2826 (1959), Te
trahedron Letters No. 49,4
963, J.C. Am. Chem. Soc. 81 , 2826
-2829 (1959)).

The base is used in an amount of usually about 1 to 30 times, preferably about 1.2 to 10 times, based on 1 mol of phenylhalogenomethylcarbinol.

Solvents used in the ring closing treatment include, for example, ether solvents such as tetrahydrofuran, diethyl ether, diisopropyl ether and t-butyl methyl ether; aliphatic hydrocarbons such as pentane, hexane and heptane; and aromatic solvents such as benzene, toluene and xylene. Group hydrocarbons, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chlorobenzene, ketones such as acetone, ethyl methyl ketone and isobutyl methyl ketone, water, and mixtures thereof.

The solvent is usually used in an amount of about 0.5 to 50 times, preferably about 2 to 20 times the weight of the phenylhalogenomethylcarbinol.

The reaction temperature depends on the base used,
Usually, it is selected in the range of -10 ° C to the boiling point of the solvent. For example, when 1 to 3N sodium hydroxide is used, the temperature is preferably about 0 to 20 ° C, more preferably about 0 to 10 ° C, and when potassium carbonate is used, it is preferably 30 to 1 ° C.
The temperature is about 00C, more preferably about 40-60C.

After the completion of the reaction, the styrene oxides can be isolated, for example, by distilling off the organic solvent, if necessary, from the reaction mixture, extracting with hexane or the like, and distilling off the solvent.

The isolated styrene oxides are distilled,
It can be purified by various types of chromatography and the like.

Finally, optically active styrene oxides are obtained by subjecting one of the obtained styrene oxides, in which a large number of optical isomers are present, to kinetic optical resolution using water and an asymmetric catalyst.

As the asymmetric catalyst used in the present invention, a salen metal catalyst, a Lewis acid catalyst and the like are effective, and among them, a salen metal catalyst is preferable.

The salen metal catalyst has the formula

[0080]

Embedded image

(Wherein R ⁴ and R ⁴ ′ may be the same or different and each represents a hydrogen atom, methoxy, te
rt-butyl, 1-phenylpropyl, or substituted aryl, wherein one of R ⁵ and R ⁶ is a hydrogen atom,
The other is methyl, phenyl, 3,5-dimethylphenyl,
Or two R's each representing 4- (tert-butyl) phenyl or each bonded to a different carbon atom
^{One of the 5} pairs and 2 R ⁶ pairs may together form tetramethylene, the other pair each representing a hydrogen atom, M representing a metal ion, and an ion of the metal ion. When the valence and the number of coordinating atoms of the ligand are different, Y represents a counter anion. When the ionic valence of the metal ion and the number of coordinating atoms of the ligand are the same, Y does not exist. ).

The substituted aryl in R ⁴ and R ⁴ ′ is defined as an aryl such as phenyl, naphthyl, anthryl, etc., preferably phenyl, naphthyl, etc., which is substituted with 1 to 3, preferably 1 or 2 of the following substituents. Are included. It is preferable that at least one substituent is present at the α-position with respect to the aryl bonding position.

The substituent in the substituted aryl includes phenyl, methoxy, methyl, 3,5-dimethylphenyl and the like, preferably phenyl, methoxy and the like.

Preferred examples of the substituted aryl include 2-phenyl-1-naphthyl and 2-methyl-1-naphthyl.

In the asymmetric catalyst, M represents a metal ion, for example, cobalt, manganese, chromium, titanium, vanadium, iron, nickel, copper and the like, and preferably cobalt and chromium.

In the asymmetric catalyst, when the valence of the metal ion and the number of coordinating atoms of the ligand are different, Y represents a counter anion, and the valence of the metal ion and the number of coordinating atoms of the ligand are the same. Sometimes Y does not exist. That is, when the ionic value of the metal ion is 3 or more, Y represents a counter anion, and when the ionic value of the metal ion is 2, Y does not exist.

Examples of the counter anion include CH ₃ CO ₂ ⁻ , PF ₆ ⁻ , Cl ⁻ , PhCO ₂ ^{− and the} like, preferably CH ₃ CO ₂ ⁻ , PhCO ₂ ^−.
And so on.

As a preferred example of the salen metal catalyst in the present invention, (R, R) -N, N'-bis (3,5-di-
tert-butylsalicylidene) -1,2-cyclohexanediaminocobalt, (R, R) -N, N′-bis (3,5-di-tert-butylsalicylidene) -1,
2-diphenyl-1,2-ethanediaminocobalt and the like.

The amount of water used for optical resolution is 0.001 to 50 mol times, preferably 0.005 to 10 mol times, relative to styrene oxides.

The amount of the asymmetric catalyst used for optical resolution is 0.001 to 10 mol times, preferably 0.01 to 1.0 mol times, relative to styrene oxides.

The temperature at the time of optical division is -10 to 100 ° C.
Preferably it is 0-50 degreeC.

The kinetic resolution in the present invention means that one of the enantiomers is converted to styrene oxide by utilizing the difference in the reaction rate between the enantiomers of styrene oxide (R-styrene oxides and S-styrene oxides). After leaving unreacted and changing the other enantiomer to a compound other than styrene oxides, the optically active styrene oxide left unreacted is separated from compounds other than styrene oxides generated from the other enantiomer and obtained. That is. The end of the reaction is determined by analyzing the optical purity of the styrene oxides over time using an analysis using an optically active HPLC column and confirming that the styrene oxide has reached a predetermined optical purity.

The obtained optically active styrene oxides can be isolated, for example, as follows. Water and an organic solvent are added to a reaction solution containing optically active styrene oxides that has reached a predetermined optical purity, and liquid separation is performed. The aqueous layer is extracted again with an organic solvent, and the organic layers are combined and washed with water.
Dry with a desiccant such as magnesium sulfate. By separating the drying agent and concentrating the filtrate, the residue obtained is distilled under reduced pressure, whereby optically active styrene oxides can be obtained as a fraction. In addition, the product can be isolated by fractionation by column chromatography or the like.

Examples of the organic solvent used for isolation include toluene, xylene, diethyl ether, t-butyl methyl ether, 1,2-dichloroethane and the like.

The optical purity of the optically active styrene oxides can be measured, for example, by high performance liquid chromatography having an optically active column. The optical purity of the optically active styrene oxides obtained in the present invention is 90 to 90.
100% ee. “100% ee” means that one enantiomer was not detected analytically.

A method for producing a phenylhalogenomethylketone of the general formula (1) as a raw material, for example, a bromomethylphenylketone in which X is bromine is described below, but is not limited thereto.

The production of the phenylhalogenomethylketones of the general formula (1) can be carried out in an alcoholic solvent by the formula

[0098]

Embedded image

(In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) The reaction is usually carried out by dropping bromine into a mixture of an acetophenone and an alcoholic solvent. In addition, in the bromination reaction of dialkyl ketone, it is said that dropping is not preferable and it is necessary to add them all at once (Organic Synthesis, V
I, 194 (1988)), and in the present invention, dropping is preferable.

As the acetophenones, specifically,
3'-chloroacetophenone, 3'-bromoacetophenone, 3'-fluoroacetophenone, 3'-methylacetophenone, 3'-methoxyacetophenone, 3'-
Trifluoromethylacetophenone, 4′-chloroacetophenone, 4′-bromoacetophenone, 4′-fluoroacetophenone, 4′-methylacetophenone,
4'-methoxyacetophenone, 4'-trifluoromethylacetophenone, 2'-chloroacetophenone,
2′-bromoacetophenone, 2′-fluoroacetophenone, 2′-methylacetophenone, 2′-methoxyacetophenone, 2′-trifluoromethylacetophenone, 2′-chloro-3′-methoxyacetophenone,
2'-bromo-3'-methoxyacetophenone, 2'-
Fluoro-3′-methoxyacetophenone, 3′-methoxy-2′-methylacetophenone, 2 ′, 3′-dimethoxyacetophenone, 3′-methoxy-2′-trifluoromethylacetophenone, 2 ′, 3′-dichloroacetophenone, 2′-bromo-3′-chloroacetophenone, 3′-chloro-2′-fluoroacetophenone,
3'-chloro-2'-methylacetophenone, 3'-chloro-2'-methoxyacetophenone, 3'-chloro-
2′-trifluoromethylacetophenone, 2′-bromo-4′-chloroacetophenone, 2 ′, 4′-dibromoacetophenone, 2′-bromo-4′-fluoroacetophenone, 2′-bromo-4′-methylacetophenone, 2'-bromo-4'-methoxyacetophenone,
2'-bromo-4'-trifluoromethylacetophenone,

4'-chloro-2'-fluoroacetophenone, 2 ', 4'-difluoroacetophenone, 4'-
Bromo-2'-fluoroacetophenone, 2'-fluoro-4'-methylacetophenone, 2'-fluoro-
4'-methoxyacetophenone, 2'-fluoro-4 '
-Trifluoromethylacetophenone, 4'-chloro-
2'-trifluoromethylacetophenone, 4'-bromo-2'-trifluoromethylacetophenone, 4'-
Fluoro-2'-trifluoromethylacetophenone,
4'-methyl-2'-trifluoromethylacetophenone, 4'-methoxy-2'-trifluoromethylacetophenone, 2 ', 4'-bis (trifluoromethyl) acetophenone, 4'-chloro-3'-trifluoro Methylacetophenone, 4'-bromo-3'-trifluoromethylacetophenone, 4'-fluoro-3'-trifluoromethylacetophenone, 3'-trifluoromethyl-4'-methylacetophenone, 3'-trifluoromethyl-4 '-Methoxyacetophenone, 3', 4'-
Bis (trifluoromethyl) acetophenone, 5′-bromo-3′-chloroacetophenone, 3 ′, 5′-dibromoacetophenone, 5′-bromo-3′-fluoroacetophenone, 5′-bromo-3′-methylacetophenone, 5'-bromo-3'-methoxyacetophenone,
5'-bromo-3'-trifluoromethylacetophenone,

3'-chloro-5'-trifluoromethylacetophenone, 3'-bromo-5'-trifluoromethylacetophenone, 3'-fluoro-5'-trifluoromethylacetophenone, 3'-methyl-5'- Trifluoromethylacetophenone, 3'-methoxy-5 '
-Trifluoromethylacetophenone, 3 ', 5'-dimethoxyacetophenone, 3', 5'-ditrifluoromethylacetophenone, 3 ', 5'-dichloroacetophenone, 3', 5'-dibromoacetophenone, 3 ',
5'-difluoroacetophenone, 2 ', 6'-dichloroacetophenone, 2', 4 ', 6'-trichloroacetophenone, 3', 4 ', 5'-trichloroacetophenone, 3', 4'-methylenedioxyacetophenone, etc. Is mentioned.

As bromine, commercially available bromine can be used as it is. It is preferable to use 0.8 to 0.99 times of bromine with respect to 1 mol of acetophenones. This is because if it is less than 0.8 times, the yield decreases, and if it exceeds 0.99 times, a dibromo compound is by-produced.

Examples of the alcohol-based solvent include lower alcohols such as methanol, ethanol and propanol. Methanol is preferred. As the alcohol-based solvent, a commercially available one may be used as it is, and it is preferable to use it after drying with a desiccant such as Molecular Sieve 4A.

The alcoholic solvent is usually used in an amount of about 0.5 to 20 times by weight, preferably about 1.5 to 10 times by weight, based on acetophenones.

The reaction temperature is preferably in the range of 30 to 45 ° C. This is because if the temperature is lower than 30 ° C., it takes time to complete the reaction, and if the temperature exceeds 45 ° C., a by-product is generated.
The bromination reaction produces a ketal, which can be hydrolyzed by adding approximately the same amount of water as the alcoholic solvent. The temperature at this time is 30 to 45 ° C. In the case of a dialkyl ketone, hydrolysis is performed by adding concentrated sulfuric acid, but this reaction is not necessary in this reaction and the reaction proceeds.

The resulting bromomethylphenyl ketones can be isolated by adding water equal to or more than the weight of the acetophenones after completion of the reaction, cooling, and collecting the precipitated crystals by filtration. The obtained target product can be further purified by recrystallization from hexane, heptane, isopropanol or the like, if necessary.

[0108]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. The optical purity described is the optically active HPL
This is a value measured by the C column.

Example 1 500 ml equipped with a thermometer, stirrer and condenser
The four-necked flask was purged with nitrogen, and 2.06 g (54.45 mmol) of sodium borohydride, (R) -α, α-
656 mg of diphenyl-2-pyrrolidinemethanol
(2.59 mmol) and tetrahydrofuran 152
After charging g, the temperature was raised to 57 ° C. Next, 6.86 g (54.41 mmol) of dimethyl sulfate was added dropwise at 57-58 ° C over 2 hours, and the mixture was kept at the same temperature for 3 hours. Further, 20 g of 2-bromo-3'-chloroacetophenone
(86.36 mmol) in tetrahydrofuran 50
g at 57-58 ° C over 100 minutes.
Incubated for hours.

After cooling to 5 ° C., 30% hydrochloric acid 30.59
g was added dropwise at 20 ° C. or lower while paying attention to foaming. Further, 16 g of methanol was added, and the mixture was kept at 40 ° C. for 1 hour. Then, t-butyl methyl ether 105 ml, water 56 ml
Was added and stirred, and the organic layer was separated. 19 ml of t-butyl methyl ether was added to the aqueous layer, and the mixture was extracted again. The organic layers were combined and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 20.10 g of (R)-
2-Bromo-1- (3-chlorophenyl) ethanol (yield: 99.7%, optical purity: 95.5% ee) was obtained.

A 300 ml four-necked flask equipped with a thermometer, a stirrer, and a condenser was purged with nitrogen, and 18 g (77.09 mmol) of (R) -2-bromo-1- (3-chlorophenyl) ethanol obtained above and t. -Butyl methyl ether (100.3 g) was charged and cooled to 3 ° C. 132.2 g of 8% aqueous sodium hydroxide solution
The mixture was added dropwise at 0 ° C. over 2 hours, stirred at the same temperature for 3 hours, and then the organic layer was separated. Next, the organic layer was washed twice with 97.2 g of a 1% aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. This was concentrated under reduced pressure to obtain (R) -m-chlorostyrene oxide (yield: (R) -2-bromo-
99. against 1- (3-chlorophenyl) ethanol.
0%). The optical purity was 95.8% ee.

Next, this m-methylene having an optical purity of 95.8% ee
11 g of chlorostyrene oxide (7.16 mmol
l), water 129 mg, and (R, R) -N, N'-bis (3,5-di-tert-butylsalicylidene)-
341 mg of 1,2-cyclohexanediaminocobalt
(0.50 mmol) in a reaction tube purged with nitrogen,
Stirred at room temperature for 24 hours. 22 ml of water and 44 ml of t-butyl methyl ether were added, and the mixture was stirred and the organic layer was separated. Further, the obtained aqueous layer was extracted with 22 ml of t-butyl methyl ether. 11m water combined with organic layer
, dried over magnesium sulfate, filtered, and distilled under reduced pressure to obtain (R) -m-chlorostyrene oxide (yield: 61.4% based on m-chlorostyrene oxide having an optical purity of 95.8% ee). I got Optical purity is 9
It was 9.5% ee.

[0113]

According to the present invention, optically active styrene oxides having a high optical purity can be obtained by a production method which is relatively inexpensive, easy to operate, and can be carried out on a factory scale. Thus, an R-form styrene oxide derivative, which is a compound useful as an intermediate for the production of various pharmaceuticals such as a therapeutic agent for diabetes, a therapeutic agent for hyperglycemia, an agent for preventing and treating obesity, and the like, can be provided in a state of high optical purity.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07B 61/00 300 C07B 61/00 300 C07M 7:00 F term (Reference) 4C048 AA01 BB02 BB04 CC01 UU01 UU03 XX02 4G069 AA06 BA21A BA21B BA27A BA27B BA36C BC58B BC67B BE13A BE13B CB35 CB57 DA02 4H006 AA02 AC41 AC81 AC83 BE23

Claims (3)

[Claims] 1. A compound of the general formula (1) (Wherein, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group, and R ² and R ³ may be the same or different, and each represents a hydrogen atom, a halogen atom, Represents a lower alkyl group, a lower alkoxy group, or a trifluoromethyl group,
Alternatively, R ² and R ³ may form a methylenedioxy group together, and X represents a halogen atom. )
Which is obtained by asymmetric reduction of a phenylhalogenomethylketone represented by the general formula (2), wherein one of the optical isomers is present in a large amount. (Wherein R ¹ , R ² , R ³ and X have the same meanings as described above), and a ring closing treatment is performed on the phenylhalogenomethylcarbinol represented by the general formula ( 3) (In the formula, R ¹ , R ² and R ³ are as defined above.)
After obtaining a styrene oxide represented by the formula, kinetic optical resolution is performed on the styrene oxide using an asymmetric catalyst. (In the formula, R ¹ , R ² and R ³ are as defined above.)
A method for producing an optically active styrene oxide represented by the formula: 2. An asymmetric catalyst having the formula: (Wherein, R ⁴ and R ⁴ ′ may be the same or different and each represent a hydrogen atom, methoxy, tert-butyl, 1-phenylpropyl, or substituted aryl, and one of R ⁵ and R ⁶ is a hydrogen atom And the other is methyl, phenyl, 3,5-dimethylphenyl, or 4
- (tert-butyl) or a phenyl, or a different one of the pairs of the pair of pairs and two R ⁶ two R ⁵ are each bonded to a carbon atom together form a tetramethylene, The other pair may each represent a hydrogen atom, M represents a metal ion, Y represents a counter anion when the valence of the metal ion and the number of coordinating atoms of the ligand are different, and the ionic valence of the metal ion And when the number of coordinating atoms of the ligand is the same, Y does not exist. 2. The method for producing optically active styrene oxides according to claim 1, wherein the catalyst is a salen metal catalyst represented by the formula: 3. When asymmetric reduction of phenylhalogenomethyl ketones is carried out, general formula (5) is used. (Wherein, R ⁷ represents an alkyl group having 1 to ⁷ carbon atoms, an optionally substituted aryl group, or an optionally substituted aralkyl group, and R ⁸ represents a hydrogen atom, a lower alkyl group, or a substituted May represent an aralkyl group, or R ⁷ and R ⁸ may be combined to form a lower alkylene group; R ⁹ and R ¹⁰ may be the same or different; Represents an alkyl group having 1 to 7 carbon atoms, or an aryl group which may be substituted,
Alternatively, R ⁹ and R ¹⁰ may be combined to form a lower alkylene group. Alternatively, R ⁷ and R ⁹ may be combined to form a lower alkylene group which is unsubstituted, substituted, or fused with a benzene ring. ) Or an asymmetric reducing agent obtained from the optically active amino alcohol and borane, or from the optically active amino alcohol, a metal borohydride and an acid or dialkyl sulfate. 3. The method for producing an optically active styrene oxide according to 2.