WO2001019777A1

WO2001019777A1 - α-KETO ESTERS AND PROCESSES FOR THE PREPARATION THEREOF

Info

Publication number: WO2001019777A1
Application number: PCT/JP2000/006301
Authority: WO
Inventors: Makoto Yamashita; Toshiaki Nagata
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 1999-09-16
Filing date: 2000-09-14
Publication date: 2001-03-22
Also published as: AU7313200A

Abstract

Compounds represented by general formulae (I), (IV) and (V) or salts thereof, useful as intermediates for the synthesis of drugs; and processes for the preparation of the compounds or the salts wherein R and R' are each a hydrocarbon group.

Description

Description α-Ketoester and its production

The present invention provides a method for producing an oxazolidinedion derivative or a salt thereof, which has a blood sugar and blood lipid lowering effect and is useful as a therapeutic agent for diabetes and the like, and an important raw material intermediate in the course of the process. Background Art on Ketoesters and Their Production

EP-A 0 6 1 2 7 4 3 and Ε Ρ—AO 7 10 6 5 9 describe oxazolidinedione derivatives or their salts that are important as pharmaceuticals such as antidiabetic drugs, and their production methods. ing. These methods use an ester compound (eg, EP-A0) in which a hydroxyl group on a benzene ring of an ester compound (a compound represented by the following formula (II) or a salt thereof) is substituted with an expensive aromatic alkyl group. (A compound represented by the formula (IX-6) or a salt thereof) of 71059 is used as a starting compound.

Japanese Patent Application Laid-Open Nos. H10-12026 and H10-1262022 disclose a keketoester which is an alkyloxy substituted with a substituent on a benzene ring. No disclosure is made of α-ketoester in which the above substituent is a hydroxy group.

It is desired to provide an industrially advantageous method for producing an oxazolidinedione derivative or the like useful as a therapeutic agent for diabetes, an advantageous synthetic intermediate therefor, and a method for producing the same. Disclosure of the invention

The present inventors have conducted intensive studies to solve the above problems, and as a result, for the first time, synthesized a novel α-ketoester (a compound represented by the following formula (I) or a salt thereof), When used as an intermediate for the synthesis of various drugs such as therapeutic agents, it is possible to unexpectedly obtain the desired product by using high-yield, high-purity and inexpensive raw materials. As a result, they found that an industrially advantageous production method could be provided, and based on these findings, completed the present invention.

That is, the present invention

1) Equation (I)

[Wherein, R represents a hydrocarbon group. ] Or a salt thereof;

2) The compound according to the above 1), wherein R is an alkyl group having 1 to 4 carbon atoms;

3) The compound according to the above 1), wherein R is a methyl group or an ethyl group;

4) 5- (4-hydroxyphenyl) -ethyl 2-oxopentanoate or a salt thereof;

5) methyl 5- (4-hydroxyphenyl) -1-oxopentanoate or a salt thereof;

6) Equation (II)

[Wherein, R ′ represents a hydrocarbon group. And a salt thereof and formula (III): R'OOC-COOR [wherein, R represents a hydrocarbon group; R "represents a hydrogen atom or a hydrocarbon group.] Formula (I) characterized in that the ester, its salt or its reactive derivative is condensed and then subjected to a decarboxylation reaction.

[Wherein, R is as defined above. 7) A process for producing a compound represented by the formula (IV)

[Wherein, R and R ′ represent the same or different hydrocarbon groups. Wherein the compound represented by the formula (I) or a salt thereof is subjected to a decarboxylation reaction.

[Wherein, R is as defined above. 8) Method for producing compound or salt thereof represented by formula (IV)

C00R '

[Wherein, R and R ′ are the same or different and represent a hydrocarbon group. ] Or a salt thereof;

9) The compound according to the above 8), wherein R and R ′ are a methyl group or an ethyl group; 10) a compound of the formula (I)

[Wherein, R represents a hydrocarbon group. Wherein the compound represented by the formula (I) or a salt thereof is subjected to a reduction reaction:

[Wherein, R is as defined above. 11) A method for producing a compound represented by the formula (V)

[Wherein, R represents a hydrocarbon group. ] Or a salt thereof

12) The compound as described in 11) above, wherein R is a methyl group or an ethyl group.

13) an optically active form of the compound described in 11) above;

14) Equation (II)

[Wherein, R ′ represents a hydrocarbon group. And a salt thereof and a compound of the formula (III): R'OOC-COOR wherein R is a hydrocarbon group; R "is a hydrogen atom or a hydrocarbon group Is shown. And a salt or a reactive derivative thereof represented by the formula (IV)

[The symbols in the formula are as defined above. To produce a compound represented by the formula (I)

[Wherein, R is as defined above. To produce a compound represented by the formula (V):

[Wherein, R is as defined above. To produce a compound represented by the formula (VI)

Rb

I

Rjr (Y) ^ — (CH ₂ ) n— CH-Q

Wherein the R a is an optionally substituted heterocyclic group or an optionally substituted carbon hydrocarbon radical, a R b is a hydrogen atom or a flicking ₄ alkyl group, Y one CO-, -CH

(OH) — or — NRi ² — (Ri ² represents an optionally substituted alkyl group), m represents 0 or 1, n represents 0, 1 or 2, and Q represents a leaving group. With a compound represented by the formula (VII)

[The symbols in the formula are as defined above. Or a salt thereof, which is hydrolyzed to give a compound of the formula (VIII) Ra- (YV ~ (CH ₂ ) _n

[The symbols in the formula are as defined above. Or a salt thereof, which is represented by the formula (IX): XCOORc wherein X represents a halogen atom, R c represents a hydrogen atom or a _4- alkyl group. ] And ammonia with the compound represented by the formula (X)

R OCOORc

Ra- iY ^-CH n -CH-0 ~-V-CH ₂ CH ₂ CH ₂ -CH-CONH _∑

[The symbols in the formula are as defined above. Or a salt thereof, and subjecting the compound to a ring closure reaction,

[The symbols in the formula are as defined above. ] A method for producing a compound represented by the formula

15) Ethyl (R) -2-hydroxy-5- [4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl] pentanoate or a salt thereof;

16) sodium (R) -2-hydroxy-5- [4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl] pentanoate or a salt thereof; And so on. In the above formula, examples of the hydrocarbon group represented by R or R ′ include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, and an aromatic-aliphatic hydrocarbon group. Can be

As the aliphatic hydrocarbon group, 1 to carbon atoms: L5 linear or branched aliphatic hydrocarbon group such as alkyl group, C ₂ - _{1 5} alkenyl group, C ₂ - _{1 5} alkynyl group And the like.

Preferred examples of the alkyl group include an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and Ethylpropyl, Examples include hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, and decyl. It is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or an ethyl group.

Preferable examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl (allyl), 2-methyl-1-propenyl. , 2-methyl_2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- Pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.

Preferable examples of the alkynyl group include alkynyl groups having 2 to 10 carbon atoms such as ethynyl, 1-propynyl, 2-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.

The alicyclic hydrocarbon group, 3 carbon: 12 saturated or alicyclic carbon hydrocarbon radical of unsaturated, e.g., C 3 ^ ₂ cycloalkyl group, C ₂ cycloalkenyl group, C ₅ - _{1 2} A cycloalkadienyl group;

Preferable examples of the cycloalkyl group include a cycloalkyl group having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [ 2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, and the like. Preferable examples of the cycloalkenyl group include cycloalkenyl groups having 3 to 10 carbon atoms, such as 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, and 2-cyclohexene-11. —Yl, 3-cyclohexene-1 f1 and the like.

Preferred examples of the cycloalkadienyl group include cycloalkyl having 5 to 10 carbon atoms. Lukadienyl groups include, for example, 2,4-cyclopentene-1-yl, 2,4-cyclohexene-1-yl, 2,5-cyclohexene-1-yl and the like. Examples of the aromatic hydrocarbon group include monocyclic or condensed polycyclic aromatic hydrocarbons having 6 to 16 carbon atoms (e.g., aryl groups and the like), for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, Biphenyl is preferred. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

Examples of the aromatic monoaliphatic hydrocarbon group include phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl and 3-phenylpropyl, and naphthylalkyl having 11 to 13 carbon atoms. And, for example, α-naphthylmethyl, 1-naphthylethyl and the like.

The hydrocarbon group represented by R or R 'is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably methyl or ethyl.

Among the compounds represented by the formula (I) or salts thereof, the most preferred is 5- (4-hydroxyphenyl) -12-oxopentanoate or a salt thereof, or 5- (4-hydroxyphenyl) _ Methyl 2-oxopentanoate or a salt thereof.

Hereinafter, the compound of the present invention represented by the formula (I) or a salt thereof (hereinafter sometimes referred to as compound (I). In the following description of the production method, when the compound is simply referred to as a compound, For example, the compound (II) means a compound represented by the formula (II) or a salt thereof.

Law

(I)

[Wherein each symbol has the same meaning as described above. ]

Compound (I) is obtained by combining compound (Π) with a compound which can be produced by a method known per se. (III): R'OOC-COOR wherein each symbol is as defined above. The compound (IV) is obtained by condensing an oxalate, a salt thereof or a reactive derivative thereof represented by the formula (1), followed by decarboxylation by heating or the like.

Examples of the hydrocarbon group represented by R "include the same as the hydrocarbon group represented by R. R" is preferably an alkyl group having 1 to 4 carbon atoms, more preferably Et al. R and R "may be the same or different, but are preferably the same.

Examples of the reactive derivative of the oxalate represented by the formula (III) (particularly when R "is a hydrogen atom) include, for example, acid anhydride, acid halide (acid chloride, acid bromide), imidazolide or mixed Acid anhydrides (eg, anhydrides with methyl carbonate, anhydrides with ethyl carbonate, etc.) are examples. Specific examples thereof include, for example, a formula: QaOC-COOR [where Q _a is desorbed A group (eg, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc., and R is as defined above.) And the like.

The reaction of the compound (II) with the oxalate represented by the formula (III), a salt thereof or a reactive derivative thereof is advantageously performed in a suitable solvent in the presence of a base.

Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; and acetylene, diisopropyl ether, dioxane, and tetrahydrofuran. Ethers; halogenated hydrocarbons such as formaldehyde, dichloromethane, and 1,1,2,2-tetrachloroethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide; dimethyl And sulfoxides such as sulfoxide. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1- to L00-fold (v / w), preferably 1- to 20-fold (vZw), relative to compound (Π). The solvent is preferably an alcohol such as ethanol.

Examples of the base include metal alkoxides such as sodium ethoxide, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide. Can be The amount of the base to be used is 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (II). The base is preferably potassium tert-butoxide.

The amount of the oxalate represented by the formula (in) to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound ι).

The reaction temperature is usually from −50 ° C. to 150 °, preferably from 110 ° C. (: up to 100 ° C.) The reaction time is generally from 0.5 to 50 hours, preferably from 1 to 50 ° C. The compound (IV) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound (IV) may be used in the next reaction as it is in the reaction mixture.

Compound (IV) is a novel compound, and in particular, a compound in which R and R 'are ethyl groups is useful as a synthetic intermediate.

Compound (I) can be produced by subjecting compound (IV) to a decarboxylation reaction. This decarboxylation reaction is usually carried out by heating in a mixed solvent of water and a polar solvent such as hydrated dimethylformamide or hydrated dimethyl sulfoxide in the presence or absence of sodium chloride or lithium chloride.

The amount of sodium chloride or lithium chloride to be used is generally 0 to 5 molar equivalents, preferably 0 to 2 molar equivalents, relative to compound (IV). The reaction temperature is usually 50 to 150, preferably 80 to 130. The reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.

The compound (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. B method

CH3COCOOH

(X I I)

Esterification

(X I I I)

[The symbols in the formula are as defined above. ]

In this method, first, 4-hydroxyphenylacetaldehyde and pyruvic acid are condensed to produce compound (XII). This reaction is performed in a solvent in the presence of a base.

Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl ether, dioxane, tetrahydrofuran and the like. Ethers; amides such as Ν, Ν-dimethylformamide; sulfoxides such as dimethylsulfoxide; and esters such as acetic acid. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1- to 100-fold (vZw), preferably 1- to 20-fold (vZw) the amount of 4-hydroxyphenylacetaldehyde.

Examples of the base include alkali metal salts such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide; amines such as pyridine, triethylamine, N, N-dimethylaniline; sodium hydride; Metal hydrides such as potassium hydride; metal alkoxides such as sodium ethoxide, sodium methoxide, sodium tert-butoxide, and potassium tert-butoxide. The amount of the base to be used is generally 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 4-hydroxyphenylacetaldehyde. The amount of pyruvic acid to be used is generally 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 4-hydroxyphenylacetaldehyde.

This reaction is usually carried out at 150: to 150, preferably at _10 ° C to 100. It is. The reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours. Then, the compound (XII) is subjected to an esterification reaction to produce a compound (XIII). This esterification reaction can be carried out by a method known per se, for example, compound (XII) and alcohols (R OH) [R has the same meaning as described above. Is directly reacted in the presence of an acid to form an ester or a reactive derivative of compound (XII), for example, an acid anhydride, an acid halide (an acid chloride, an acid bromide), an imidazolide or a mixed acid anhydride (eg, For example, a method of appropriately reacting an anhydride with methyl carbonic acid, an anhydride with ethyl carbonic acid, etc.) with an alcohol (ROH) is used. The amount of the alcohol (R〇H) to be used is generally 1 to 100 molar equivalents, preferably 1 to 30 molar equivalents, relative to compound (XII).

Then, the compound (XIII) is subjected to a reduction reaction to produce a compound (I). This reduction reaction can be performed by a method known per se. Examples of the reduction reaction include reduction with a metal hydride, reduction with a metal hydride complex, reduction with diborane and substituted borane, catalytic hydrogenation, and the like.

That is, the reduction reaction is performed by treating compound (XIII) with a reducing agent in an organic solvent that does not affect the reaction. Examples of the reducing agent include alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.); metal hydride complex compounds such as lithium aluminum hydride; metal hydrides such as sodium hydride; organotin compounds ( Metal and metal salts such as nickel compounds and zinc compounds; catalytic reducing agents using a transition metal catalyst such as palladium, platinum, rhodium, ruthenium and iridium and hydrogen; and diborane. The amount of the reducing agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XIII).

Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, diisopropyl ether, dioxane, and the like. Ethers such as tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide. These solvents are two kinds The above may be mixed and used at an appropriate ratio. The amount of the solvent to be used is generally 1- to 100-fold (vZw), preferably 1- to 20-fold (vZw), relative to compound (XIII).

The reaction temperature is usually from −20 ° C. to 150 ° C., preferably from 0 ° C. to 100 ° C. The reaction time is generally 0.5 to 24 hours, preferably 1 to 12 hours.

The compound (I) thus obtained can be isolated and purified by a known separation and purification means such as concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. -Compounds (XII) and (XIII) may be isolated and purified by known separation and purification means, or may be used as a reaction mixture in the next reaction.

C method

(XV I)

[Wherein, R ² represents an alkyl group having 1 to 4 carbon atoms. ]

Examples of the alkyl group having 1 to 4 carbon atoms represented by R ² include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

In this method, first, 4-hydroxyphenylpropionaldehyde is condensed with hydantoin or phosphate (XIV) to produce compound (XV). Where phosphate ester (XIV) is the It is produced by brominating hydantoin and then reacting with a trialkyl phosphite according to the method described in Strey, Vol. 56, p. 6977, 1991.

This condensation reaction is performed in a solvent in the presence of a base.

Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl ether, dioxane, tetrahydrofuran and the like. Ethers; esters such as ethyl acetate and methyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide; dimethyl Sulfoxides such as sulfoxide; carboxylic acids such as acetic acid; These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent used is usually 1 to 100 times (v Zw) with respect to 4-hydroxyphenylpropionaldehyde, preferably:! 110 times (v Zw).

Examples of the base include metal salts such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, hydroxide hydroxide and the like; amines such as pyridine, triethylamine, and Ν, Ν-dimethylaniline; hydrogen Metal hydrides such as sodium hydride and potassium hydride; metal alkoxides such as sodium ethoxide, sodium methoxide, sodium tert-butoxide, and potassium tert-butoxide. The amount of the base to be used is generally 0.1 to 5 molar equivalents, preferably 0.5 to 2 molar equivalents, relative to 4-hydroxyphenylpropionaldehyde.

The amount of hydantoin or compound (XIV) to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to 4-hydroxyphenylpropionaldehyde.

The reaction temperature is generally 0: to 150, preferably 10 to 60 :. The reaction time is generally 5 to 50 hours, preferably 1 to 24 hours.

Then, the compound (XV) is subjected to a hydrolysis reaction to produce a compound (XVI). This hydrolysis reaction is carried out in a water-containing solvent in the presence of potassium hydroxide or sodium hydroxide. Performed in the presence of a base. Examples of the solvent to be used include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran. Ethers of halogen; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachlorobenzene; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide And the like. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1- to 100-fold (v / w), preferably 1- to 10-fold (v / w), relative to compound (XV).

The amount of the strong base to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XV).

Then, the compound (XVI) is subjected to an esterification reaction to produce a compound (I). This reaction is carried out in the same manner as in the esterification reaction in Method B.

The compound (I) thus obtained can be isolated and purified by a known separation and purification means such as concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compounds (XV) and (XVI) may be isolated and purified by known separation and purification means, or may be used as a reaction mixture in the next reaction.

D method

(XV I I) Halogenated

(XV I 1 1)

[Wherein X _a represents a halogen atom. ]

X _a is fluorine, chlorine, bromine, a halogen atom such as iodine. Of these, chlorine and bromine are preferred.

In this method, first, 4-hydroxyphenylpropionaldehyde is reduced To produce a compound (XVII). The reduction reaction is performed in the same manner as the reduction reaction in the above-mentioned Method B. Then, the compound (XVHI) can be produced by subjecting the compound (XVII) to a halogenation reaction known per se (eg, chlorination with thionyl chloride, bromination with phosphorus tribromide, etc.).

Further, the compound (χνιπ) is subjected to a Grignard reaction (for example, the method described in Synthesis Communications, Vol. 11, p. 943, 1981) to produce the compound (I). Can be.

In the present method, as the solvent, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as getyl ether, diisopropyl ether, dioxane and tetrahydrofuran are used. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1 to 100 times (v Zw), preferably 1 to 20 times (v / w) based on 4-hydroxyphenylpropionaldehyde.

The reaction temperature is usually from 150 ° C. to 150, preferably from −20 to 100. The reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours. The compound (I) thus obtained can be isolated and purified by a known separation and purification means such as concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compounds (XVII) and (XVIII) may be isolated and purified by known separation and purification means, or may be used as a reaction mixture in the next reaction.

E method

[Wherein, R ³ and R ⁴ are the same or different hydrocarbon groups; other symbols are as defined above. ] Examples of the hydrocarbon group represented by R ³ or R ⁴ include the same as the hydrocarbon group represented by R, preferably an alkyl group having 1 to 4 carbon atoms. In this method, 4-hydroxyphenylbutyronitrile and sulfide (XIX) are subjected to a condensation reaction to produce compound (XX), and then compound (XX) is treated with copper chloride to give compound (I). ) To manufacture.

The condensation reaction is performed in the same manner as the condensation reaction in the above-mentioned Method B. Next, the reaction between compound (XX) and copper chloride is carried out according to a method known per se (for example, the method described in Tetrahedron Res., Pp. 375, 1978).

Solvents used in this method include alcohols such as methanol, ethanol, n-propanolyl, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl ether, dioxane And ethers such as tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane, and 1,1,2,2-tetrachloromethane; amides such as N, N-dimethylformamide. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1 to 100 times (v Zw), preferably 1 to 20 times (v Zw), relative to compound (XX).

The reaction temperature is usually from 120 to 150 :, preferably from 0 t to 100. The reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.

The compound (XX) may be isolated and purified by a known separation and purification means, or may be used as a reaction mixture in the next reaction.

Compound (II) used in Method A and 4-hydroxyphenylbutyronitrile used in Method E can be produced from Compound (XXI) according to Method F. F method

(XXI) (XXII I)

(XXI) (XI la)

(XVI I la) (XXV)

(XXVI) (lla)

[Wherein, R ⁵ represents an alkyl group having 1 to 4 carbon atoms, R ⁷ represents a hydrogen atom, a substituted or unsubstituted silyl group, an alkyl group which may be substituted, or a cycloalkyl having 3 to 8 carbon atoms. an alkyl group, Q _b is a leaving group, and other symbols are as defined above. As the alkyl group having 1 to 4 carbon atoms represented by R ^5, for example methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- heptyl, etc. tert- butyl.

Examples of the optionally substituted silyl group represented by R ⁷ include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like.

Examples of the optionally substituted alkyl group represented by R ⁷ include, for example, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl , Methylthiomethyl, phenylthiomethyl, phenacyl, cyclopropylmethyl, tert-butyl, benzyl, nitrobenzyl, 2,6-dimethylbenzyl, 4-methoxybenzyl, 2,6-dichlorobenzyl, 9-anthrylmethyl, 4-1 Picolyl, trityl and the like.

Examples of the cycloalkyl group having 3 to 8 carbon atoms represented by R ⁷ include, for example, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

In the cycloalkyl group, one to three (preferably one) of carbon atoms as ring-constituting atoms may be substituted with an oxygen atom or a sulfur atom, and examples thereof include tetrahydrofuryl and tetrahydrofuryl. Vilanyl and the like.

The leaving group represented by Q _b, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), methanesulfonyloxy O carboxymethyl, benzenesulfonyl O carboxymethyl, p- toluene sulfonyl O carboxymethyl and the like. '

In this method, first, compound (XXI) is reacted with compound (XXII) to produce compound (XXIII). This reaction is performed in a suitable solvent in the presence of a base according to a conventional method.

Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl ether, dioxane, tetrahydrofuran and the like. Ethers of halogen; halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane; esters such as ethyl acetate; acetic acid; Ν, Ν-dimethylformamide Amides; sulfoxides such as dimethyl sulfoxide; and the like. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1- to L00-fold (vZw), preferably 1- to 20-fold (vZw), relative to compound (XXI).

Examples of the base include alkali metal salts such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide; amines such as pyridine, triethylamine, N, N_dimethylaniline; sodium hydride; Metal hydrides such as potassium hydride; metal alkoxides such as sodium ethoxide, sodium methoxide, sodium tert-butoxide, and potassium tert-butoxide. The amount of these bases to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XXI). The amount of compound (II) to be used is generally 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (XXI). You.

The reaction temperature is usually from −50 ° C. to 150 ° C., preferably from −10 ° C. to 100 ° C. The reaction time is generally 0.5 to 30 hours, preferably 1 to 15 hours. Then, compound (XXIV) is produced by subjecting compound (II) to a reduction reaction. This reduction reaction is carried out according to a conventional method in a solvent, in the presence of a catalyst, in a hydrogen atmosphere of 0.1 to 5.1 MPa.

Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; getyl ether, diisopropyl ether, dioxane, tetrahydrofuran and the like. Ethers; halogenated hydrocarbons such as chloroform, dichloromethane, and 1,1,2,2-tetrachloromethane; esters such as ethyl acetate; acetic acid; N, N-dimethylformamide; Amides. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1- to 100-fold (v Zw), preferably 1- to 20-fold (v / w), relative to compound (XXIII).

Examples of the catalyst include metals such as nickel compounds; transition metal catalysts such as palladium, platinum, rhodium, ruthenium, and iridium.

The reaction temperature is usually 0 to 150, preferably 10 to 120 ° C. The reaction time is generally 0.5 to 100 hours, preferably 1 to 24 hours. .

The compound (XXIV) thus obtained is further subjected to a reduction reaction to produce a compound (XVIIa). This reduction reaction can be performed by a method known per se. As such a method, for example, reduction with a metal hydride, reduction with a metal hydride complex compound, reduction with diborane and substituted borane, and the like are used.

That is, the reduction reaction is carried out by treating compound (XXIV) with a reducing agent in an organic solvent that does not affect the reaction.

Examples of the reducing agent include alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.), metal hydrogen complex such as lithium aluminum hydride, diborane, etc., and among them, diisobutylaluminum hydrideゥ Is preferred. The amount of the reducing agent to be used is generally 1-10 mol equivalents, preferably 1-5 mol equivalents, relative to compound (XXIV).

Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; and getyl ether and diisopropyl alcohol. Ethers such as ter, dioxane, and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloromethane; amides such as Ν, Ν-dimethylformamide; Is mentioned. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1- to L00-fold (v / w), preferably 1- to 20-fold (v / w), relative to compound (XXIV).

The reaction temperature is usually from 120 to 150, preferably from 0 to 100. The reaction time is generally 0.5 to 24 hours, preferably 1 to 12 hours.

Compound (XVIIa) are prepared by methods known per se, for example chlorinated by chloride Chioniru, phosphorus tribromide bromination or methanesulphonyl chloride according to Ri by the mesylation by, Q _b is C l of each formula (XVIIIa), B r Or 化合物 a compound of SO ₂ CH ₃ can be produced.

The compound (XXV) thus obtained is reacted with potassium cyanide or sodium cyanide in an appropriate solvent to produce a compound (XXV).

Examples of the solvent include alcohols such as methanol, ethanol and n-propanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diisopropyl ether, dioxane and tetrahydrofuran; Halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane; amides such as N, N-dimethylformamide; sulfoxides such as dimethylsulfoxide; ketones such as acetone and 2-butaneone And the like. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1- to 100-fold (v / w), preferably 1- to 20-fold (v / w), relative to compound (XVIIIa). The amount of potassium cyanide or sodium cyanide to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XVIIIa).

The reaction temperature is generally 0 to 150 ° (: preferably 20 to 120 ° C.) The reaction time is generally 0.5 to 30 hours, preferably 1 to 15 hours. is there.

Next, compound (XXVI) is produced by subjecting compound (XXV) to a hydrolysis reaction. This hydrolysis reaction is carried out in a water-containing solvent in the presence of an acid or a base, preferably in the presence of a mineral acid such as hydrochloric acid, sulfuric acid or nitric acid.

Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, diisopropyl ether, siloxane, and tetrahydrofuran. Ethers such as chloroform, halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane and the like; esters such as ethyl acetate; acetic acid; amides such as N, N-dimethylformamide And sulfoxides such as dimethyl sulfoxide. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1- to 100-fold (v Zw), preferably 1- to 20-fold (v Zw) with respect to compound (XXV). Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid, and examples of the base include potassium hydroxide or sodium hydroxide. The amount of these acids or bases to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XXV).

Compound (Ila) is produced by subjecting compound (XXVI) to an esterification reaction. This reaction is carried out in the same manner as in the esterification reaction in Method B.

Compound (II) can be produced by subjecting compound (Ila) thus obtained to a deprotection reaction. The deprotection reaction is performed according to a method known per se. For example, when R ⁷ of compound (Ila) is benzyl, compound (II) is produced by treating in the same manner as in the reduction reaction (catalytic hydrogenation reaction) of compound (XIII) in method B.

Furthermore, 4-hydroxyphenylbutyronitrile can be produced by subjecting compound (XXV) to a deprotection reaction. The compound (II) and 4-hydroxyphenylbutyrate obtained in this manner can be isolated by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. It can be purified. The compounds (XXIII), (XXIV), (XVIIa), (XVIIIa), (XXV). (XXVI) and (Ila) may be isolated and purified by known separation and purification means, or The mixture may be used in the next reaction.

Compound (II) mentioned in Method A can also be produced from Compound (XXVI) according to Method G.

G method

(M b) (H e)

——-(I I)

[In the formula, R ⁸ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; other symbols are as defined above. ]

The alkyl group having 1 to 4 carbon atoms represented by R ^8, for example methyl, Echiru, n- propyl, isopropyl, n- butyl, isobutyl, sec- butyl, tert- butyl.

In this method, a compound (化合物 νπ) and a succinic anhydride or a compound (χχνιπ) are first subjected to a Friedel-Crafts reaction to produce a compound (XXIX).

This reaction is carried out in a solvent in the presence of a Lewis acid according to a conventional method.

Examples of the Lewis acid include aluminum chloride, titanium tetrachloride, antimony chloride, tin tetrachloride, zinc chloride, and iron chloride. Of these, aluminum chloride is preferred. Examples of the solvent include aromatic hydrocarbons such as nitrobenzene, benzene, toluene, and xylene; ethers such as getyl ether, diisopropyl ether, dioxane, tetrahydrofuran, and anisol; chloroform, dichloromethane; Halogenated hydrocarbons such as 1,1,2,2-tetrachlorobenzene; carbon disulfide; These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The solvent is preferably a halogenated hydrocarbon such as dichloromethane and anisol. The amount of the solvent to be used is generally 1- to 100-fold (v / w), preferably 1- to 20-fold (vZw), relative to compound (XXVII).

The amount of succinic anhydride or compound (XXVIII) to be used is generally 5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (XXVII). The amount of the Lewis acid to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XXVII).

The reaction temperature is from 120 ° C to 150 ° C, preferably from 0 to 100 ° C. The reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.

Then, the compound (XXIX) is subjected to a reduction reaction to produce a compound (lib). This reaction can be performed by a method known per se. Examples of such a method include the method described in Organic Reactions, Vol. 4, p. 378, pp. 1948 (eg, reduction by the Oluf Kissner reaction), Organic Reactions, Vol. 1, p. , 1942 (eg, reduction by Clementen reaction), reduction with metal hydride complex, reduction with diborane and substituted borane, reduction with tritylsilane, catalytic hydrogenation, and the like.

That is, the reduction reaction is carried out by treating compound (XXIX) with a reducing agent in a solvent that does not affect the reaction.

Examples of the reducing agent include hydrazine under basic conditions, zinc amalgam under acidic conditions; alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.), and metals such as diisobutylaluminum hydride. Hydrogen complex compounds; metal hydrides such as sodium hydride; organotin compounds (triphenyltin hydride etc.); metals and metal salts such as nickel compounds and zinc compounds; transitions such as palladium, platinum, rhodium, ruthenium and iridium Using metal catalyst and hydrogen Contact reducing agent and diborane. The amount of the reducing agent to be used is generally 1-10 molar equivalents, preferably 1-5 molar equivalents, relative to compound (XXIX). Examples of the solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; and methyl ether, diisopropyl alcohol. Ethers such as ter, dioxane, and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane; amides such as Ν, Ν-dimethylformamide; water And the like. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1- to L00-fold (v / w) relative to the compound (XXIX), preferably:! Up to 20 times (v / w).

The reaction temperature is usually from −20 to 200, preferably from 0 t: to 100. The reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.

Then, the compound (lib) is subjected to a deprotection reaction to produce the compound (lie).

The case where R ⁷ of the compound (lib) is a methyl group or an isopropyl group will be described below.

A compound (lie) is produced by subjecting a compound (lib) in which R ⁷ is a methyl group to a demethylation reaction. The demethylation reaction is carried out in an aqueous solvent in the presence of an acid (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid) and under heating. The reaction temperature is usually 0 to 200: preferably 50 to 150. The reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.

The demethylation reaction can also be performed by reacting with an alkylmercaptan (eg, ethyl mercaptan, dodecamercaptan, etc.) in a solvent in the presence of aluminum chloride or titanium tetrachloride. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran; chloroform, dichloromethane, 1,1,2,2. —Halogenated hydrocarbons such as tetrachloroethane and the like. These solvents may be used by mixing two or more kinds in an appropriate ratio. May be used. The amount of the solvent to be used is generally 1 to 100 times (V / w), preferably 1 to 20 times (Vnow), relative to the compound (lib).

The amount of aluminum chloride or titanium tetrachloride to be used is generally 1 to 20 molar equivalents, preferably 5 to 10 equivalents, relative to compound (lib).

The reaction temperature is usually -80 "C-100: preferably-50 ° C-50. The reaction time is usually 5-50 hours, preferably 1-24 hours. .

The compound (lie) is produced by subjecting the compound (lib) in which R ⁷ is an isopropyl group to a deisopropylation reaction. The deisopropylation reaction is performed by treating with a solvent such as aluminum chloride, titanium tetrachloride, titanium trichloride, boron trichloride, or silicon tetrachloride.

Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane, and 1,1,2,2-tetrachlorobenzene; nitriles such as acetonitrile. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1 to 100 times (v Zw), preferably 1 to 20 times (v Zw), relative to the compound (lib). The amount of aluminum chloride, titanium tetrachloride, titanium trichloride, boron trichloride, or manganese tetrachloride to be used is generally 1 to 20 molar equivalents, preferably 1 to 6 molar equivalents, relative to compound (lib). .

The reaction temperature is usually from 180 to 100, preferably from 150 to 8 Ot :. The reaction time is generally 0.5 to 50 hours, preferably 1 to 24 hours.

The compound (lie) in which R ⁸ is a hydrogen atom is subjected to an esterification reaction to produce a compound (II). Further, the compound (lie) in which R ⁸ is an alkyl group having 1 to 4 carbon atoms is subjected to a transesterification reaction, if necessary, to produce a compound (II). These reactions are carried out in the same manner as the esterification reaction in Method B.

The compound (Π) thus obtained can be isolated and purified by a known separation and purification means such as concentration, (2) concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compounds (XXIX), (lib) and (lie) may be isolated and purified by known separation and purification means, or may be used as a reaction mixture in the next reaction. 4-Hydroxyphenylpropionaldehyde used in Method C and Method D can be produced from compound (XXIVa) according to Method H.

H method

(XX I Va) (XV I I) Oxidation

[The symbols in the formula are as defined above. ]

In this method, first, compound (XXIVa) is subjected to a reduction reaction to produce compound (XVII). This reaction is performed in the same manner as in the reduction reaction in the above-mentioned Method F. Then, the compound (XVII) is subjected to an oxidation reaction to produce 4-hydroxyphenylpropionaldehyde. This reaction is performed according to a known oxidation reaction. Such reactions include, for example, Jones oxidation consisting of chromium oxide-pyridine sulphate, Collins oxidation using a chromium oxide pyridine complex, oxidation with pyridinium dichromate, and oxidation with pyridinium dichromate; Oxidation with activated dimethyl sulfoxide (activated DMSO), oxidation with oxoammonium salts, and the like. Of these, oxidation with activated DMSO is preferred.

Oxidation with activated DMSO is performed, for example, in a solvent in the presence of DMSO and an electrophilic reagent.

Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran; chromate form, dichloromethane, 1,1,2, Halogenated hydrocarbons such as 2-tetrachloroethane; amines such as pyridine; amides such as Ν, Ν-dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be used as a mixture of two or more at an appropriate ratio. The amount of the solvent to be used is generally 1 to 100 times (v / w), preferably 1 to 20 times (v / v), relative to compound (XVII). The 4-hydroxyphenylpropionaldehyde thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. .

The compound (XVII) may be isolated and purified by a known separation and purification means, or may be used as a reaction mixture in the next reaction.

4-Hydroxyphenylpropionaldehyde used in Method C and Method D can be produced, for example, by Method I. '

(XX I I l a) vat oxidation

(XXX)

(XXX I)

[The symbols in the formula are as defined above. ]

In this method, first, 4-hydroxybenzaldehyde is reacted with compound (II) to produce compound (XXIIIa). This reaction is carried out in the same manner as in the reaction of compound (XXI) with compound (XXII) in the above-mentioned Method F.

Then, the compound (XXIIIa) is subjected to a reduction reaction to produce the compound (XXX). This reaction is carried out in the same manner as in the reduction reaction of compound (XXIV) in the above-mentioned Method F.

Then, compound (XXX) is subjected to an oxidation reaction to produce compound (XXXI). This reaction can be performed by a method known per se. Examples of such a method include oxidation with manganese dioxide, oxidation with chromic acid, and oxidation with dimethyl sulfoxide.

That is, the oxidation reaction is performed by treating compound (XXX) with an oxidizing agent in an organic solvent that does not affect the reaction. As oxidizing agents, Chromic anhydride or the like is used. Of these, manganese dioxide is preferred. The amount of the oxidizing agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XXX).

Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran; chromatoform, dichloromethane, 1,1,2,2-tetra Halogenated hydrocarbons such as chlorobenzene; sulfoxides such as dimethyl sulfoxide; and the like. These solvents may be used by mixing two or more kinds at an appropriate ratio. The amount of the solvent to be used is generally 1 to 100 times (V / w), preferably 1 to 20 times (v Zw), relative to compound (XXX).

Then, the compound (XXXI) is subjected to a reduction reaction to produce 4-hydroxyphenylpropionaldehyde.

This reaction is performed in the same manner as in the reduction reaction of compound (XXIII) in the above-mentioned Method F.

The 4-hydroxyphenylpropionaldehyde thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. .

The compounds (XXIIIa), (XXX), and (XXXI) may be isolated and purified by a known separation and purification method, or may be used as a reaction mixture in the next reaction. Each compound (including compounds (1), (11), (III) and (V), etc.) in the above-mentioned Method A to Method I may form an appropriate salt as long as the reaction is not hindered. . Such salts include suitable salts with inorganic acids, organic acids, inorganic bases or organic bases.

Suitable examples of salts with inorganic or organic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, Examples include salts with malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferable examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt.

Preferred examples of salts of organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine. Salts with min and the like.

Further, the compound (I) can be prepared by introducing an aromatic alkyl group into a hydroxyl group on the benzene ring E by a method known per se to obtain a compound as described in JP-A-10-120621 and JP-A-10-120. After synthesizing an α-ketoester compound or a salt thereof described in 62 as a starting compound, JP-A-10-12062 and JP-A-10-120

After subjecting to the asymmetric reduction described in 62, furthermore, Ε Ρ— A O 61 27 34 3 and EP

A oxazolidinedione derivative or a salt thereof can be derived according to the method described in AO7106959, and is useful as an intermediate for synthesizing the oxazolidinedione derivative or a salt thereof.

Further, by subjecting compound (I) or a salt thereof to a reduction reaction, formula (V)

Rb

Rs- CY ^ — (CH ₂ ) n— CH-Q

[Wherein, R a represents an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group, R b represents a hydrogen atom or a C i _ ₄ alkyl group, and Y represents —CO—,- CH

(OH) — or — NR ¹² — (R ¹² represents an optionally substituted alkyl group), m represents 0 or 1, n represents 0, 1 or 2, and Q represents a leaving group. With a compound represented by the formula (VII) Rb OH

Ra- (Y¾- (CH ₂ ) _n — CH-O- -CH ₂ CH ₂ CH ₂ -CH-COOR

[The symbols in the formula are as defined above. To produce a compound represented by the formula (VIII)

[The symbols in the formula are as defined above. ] To produce a compound represented by, this formula (IX): XCOORc [wherein, X is a halogen atom, R c denotes a hydrogen atom or 〇 ₄ alkyl group. ] And ammonia with the compound represented by the formula (X)

R OCOORc

a- (Y-(CH ₂ ) _n one CH-0 ~ ( ⁷ > — CH ₂ CH ₂ CH CH-CONH ₂

[The symbols in the formula are as defined above. To produce a compound represented by the formula (XI)

Rr-0

[The symbols in the formula are as defined above. ] Or a salt thereof can be produced.

In the above formula, the heterocyclic group in the “optionally substituted heterocyclic group” represented by R a includes, as a ring-constituting atom, a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom. Examples thereof include a 5- to 7-membered cyclic or fused ring group having 1 to 4 atoms. Examples of the condensed ring include a condensed ring of such a 5- to 7-membered heterocyclic ring, a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring or a 5-membered ring containing 1 sulfur atom. Can be

Specific examples of the heterocyclic group include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl Dinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl , 4-thiazolyl, 5-thiazolyl, 2-xoxazolyl, 4-oxoxazolyl, 5-xoxazolyl, 1,2,4-oxoxadiazo-l-u 5-yl, 1,2,4-triazo-l-u 3 1, 2, 3 — triazo- 4 yl, tetrazo 1-5-yl, benzimidazole 2-yl, indole 3-yl, 1 H-indazolu 3, 1 H-pyro mouth [2,3—b] pyrazine-1 2-yl, 1 H-pyro mouth [2,3-b] pyridine-1 6-yl, 1 H-imidazo [4,5-b] pyridine-1 2-yl, 1 H-imidazo [4,5-c] Jin one 2 - I le, 1 H - imidazo [4, 5-b] pyrazine one 2 - I le, benzopyranyl, Jihidoroben Zopiraniru and the like. The heterocyclic group is preferably a pyridyl, oxazolyl or thiazolyl group.

Examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” for Ra include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbon group, and an araliphatic group. Aromatic hydrocarbon groups and aromatic hydrocarbon groups. The number of carbon atoms in these hydrocarbon groups is preferably 1 to 14.

As the aliphatic hydrocarbon group, an aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferable. Examples of the aliphatic hydrocarbon group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, hexyl and isohexyl. C1-8 saturated aliphatic hydrocarbon groups such as xyl, heptyl and octyl (eg, alkyl groups, etc.); for example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-1pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2 , 4-hexagenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl 1, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2, 4 —Hexazinyl, 5-hexynyl, 1-heptynyl, 1-octynyl and other unsaturated aliphatic hydrocarbon groups having 2 to 8 carbon atoms (eg, alkenyl, alkadienyl, alkynyl, alkadinyl, etc.) No.

As the alicyclic hydrocarbon group, an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferable. Examples of the alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl (eg, cycloalkyl group) and 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl And an unsaturated alicyclic hydrocarbon group having 5 to 7 carbon atoms (eg, cycloalkenyl group, cycloalkadienyl group, etc.), such as 2,4-cyclohepphenylenyl.

Examples of the alicyclic monoaliphatic hydrocarbon group include those in which the above alicyclic hydrocarbon group is bonded to an aliphatic hydrocarbon group (eg, a cycloalkyl-alkyl group, a cycloalkenyl monoalkyl group, etc.). Among them, an alicyclic monoaliphatic hydrocarbon group having 4 to 9 carbon atoms is preferable. Examples of the alicyclic monoaliphatic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclo Hexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl and the like.

The number of carbon atoms in the araliphatic hydrocarbon group To 13 araliphatic hydrocarbon groups (eg, aralkyl groups, etc.) are preferred. Examples of the araliphatic hydrocarbon group include phenylalkyl having 7 to 9 carbon atoms, such as benzyl, phenyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and 1-phenylpropyl. Examples thereof include naphthylalkyl having 11 to 13 carbon atoms, such as methyl, hynaphthylethyl, 3-naphthylmethyl, and β-naphthylethyl. As the aromatic hydrocarbon group, an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, aryl group, etc.) is preferable. Examples of the aromatic hydrocarbon group include phenyl, naph Chill (α-naphthyl, / 3-naphthyl) and the like.

The hydrocarbon group and the heterocyclic group represented by Ra may have 1 to 5, preferably 1 to 3 substituents at any substitutable positions. Examples of the substituent include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic complex ring group, a non-aromatic heterocyclic group, a halogen atom, a nitro group, and a substituent. Good amino group, optionally substituted acyl group, optionally substituted hydroxyl group, optionally substituted thiol group, optionally esterified carboxyl group, amidino group, sorbamoyl group, Examples include a sulfamoyl group, a sulfo group, a cyano group, an azide group, and a nitroso group.

Examples of the aliphatic hydrocarbon group include a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, such as an alkyl group, an alkenyl group, and an alkynyl group. Preferred examples of the alkyl group include an alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert. .-Pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, Decyl and the like.

Preferable examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms, for example, vinyl, aryl, isopropyl, 1-propenyl, 2-methyl-1-probenyl, 1-butenyl, 2-butenyl , 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-1hexenyl, Examples include 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

Preferred examples of the alkynyl group include alkynyl groups having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,

3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,

5 monohexynyl and the like. Examples of the alicyclic hydrocarbon group include a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group.

Preferable examples of the cycloalkyl group include a cycloalkyl group having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2 2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] noel, bicyclo [4.3.1] decyl.

Preferable examples of the cycloalkenyl group include cycloalkenyl groups having 3 to 10 carbon atoms, for example, 2-cyclopentene-11-yl, 3-cyclopentene-11-yl, 2-cyclohexene-11-yl. And 3-cyclohexene-11%.

Preferable examples of the cycloalkadienyl group include cycloalkadienyl groups having 4 to 10 carbon atoms, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadiene-1-yl, 2 , 5-cyclohexadiene-1-yl and the like.

Preferable examples of the aryl group include an aryl group having 6 to 14 carbon atoms, such as phenyl, naphthyl (1-naphthyl, 2-naphthyl), anthryl, phenanthryl, and acenaphthylenyl.

Preferred examples of the aromatic heterocyclic group include, for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 3,4-oxaziazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, Aromatic monocyclic heterocyclic groups such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; for example, benzofuranyl, isobenzofuranyl, benzo [b] phenyl, indolyl, isoindolinyl, 1H-indazolyl, benzimidazolyl, benzozo Xazolyl, 1,2— 1 H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, a-carbolinyl, 3-carbolinyl, acarporinyl, akridinyl, phenoxazinyl, phenoxazinyl , Phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyro-port [l, 2-b] pyridazinyl, birazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1, 5-a] Pyridyl, imidazo [1,2-b] Pyridazinyl, imidazo [1,2-a] Pyrimidinyl, 1,2,4-triazolo [4,3-a] Pyridyl, 1,2,4-triazolo [ 4,3-b] Aromatic condensed compound such as pyridazinyl And a cyclic group.

Preferable examples of the non-aromatic heterocyclic group include, for example, oxilanyl, azetidinyl, oxenyl, cesyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydroviranyl, morpholinyl, thiomorpholin, piradizinyl, pyrrolidino, piperidino , Morpholino, and thiomorpholino.

Examples of halogen atoms also include fluorine, chlorine, bromine and iodine. In the amino group which may be substituted, the substituted amino group includes an N-monosubstituted amino group and an N, N-disubstituted amino group. Examples of the substituent amino group, for example, ₁₀ alkyl group, C ₂ - ₁₀ alkenyl group, C ₂ - ₁₀ Al Kiniru group,, C ₃ -. A cycloalkyl group, an aromatic group (eg, phenyl), a heterocyclic group or. An amino group having one or two substituents (e.g., alkanoyl, benzoyl, nicotinyl) as a substituent (e.g., methylamino, dimethylamino, ethylamino, getylamino, dibutylamino, diarylamino, cyclohexylamino, phenylamino, N —Methyl-1-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinylamino, etc.).

Examples of the acyl group in the optionally substituted acyl group include, for example, an acyl group having 1 to 13 carbon atoms, for example, an alkanol group having 1 to 10 carbon atoms, and 3 to 10 carbon atoms. And a cycloalkanoyl group having 4 to 10 carbon atoms, a cycloalkenoyl group having 4 to 10 carbon atoms, and an aromatic carbonyl group having 6 to 12 carbon atoms.

Preferred examples of the alkanoyl group having 1 to 10 carbon atoms include, for example, formyl, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, and octanol. Preferable examples of the alkenoyl group having 3 to 10 carbon atoms include, for example, acryloyl, methacryloyl, crotonyl, isocrotonyl and the like.

Preferable examples of the cycloalkanoyl group having 4 to 10 carbon atoms include cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl and the like.

Preferable examples of the cycloalkenoyl group having 4 to 10 carbon atoms include 2-cyclohexenecarbonyl.

Preferable examples of the aromatic carbonyl group having 6 to 12 carbon atoms include benzoyl, naphthoyl, nicotinol and the like.

Examples of the substituent in the substituted acyl group include an alkyl group having 1 to 3 carbon atoms, for example, an alkoxy group having 1 to 3 carbon atoms, a halogen atom (eg, chlorine, fluorine, bromine, etc.), a nitro group, and a hydroxyl group. And an amino group.

In the optionally substituted hydroxyl group, examples of the substituted hydroxyl group include an alkoxy group, a cycloalkyloxy group, an alkenyloxy group, a cycloalkenyloxy group, an aralkyloxy group, an acyloxy group, and an aryloxy group. And the like.

Preferred examples of the alkoxy group include an alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neope And benzyloxy, hexyloxy, heptyloxy, nonyloxy and the like.

Preferable examples of the cycloalkyloxy group include a cycloalkyloxy group having 3 to 10 carbon atoms, such as cyclobutoxy, cyclopentyloxy, and cyclohexyl. Roxy and the like.

Preferable examples of the alkenyloxy group include alkenyloxy groups having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, and 3-hexenyloxy.

Preferable examples of the cycloalkenyloxy group include a cycloalkenyloxy group having 3 to 10 carbon atoms, such as 2-cyclopentenyloxy and 2-cyclohexenyloxy. '

A preferred example of an aralkyloxy group is carbon number? ~ 10 aralkyloxy groups, for example fenir 二. ^ 4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.) and the like.

Preferable examples of the acyloxy group include an acyloxy group having 2 to 13 carbon atoms, and more preferably an alkanoyloxy group having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isoptyryloxy) Etc.).

Preferred examples of the aryloxy group include an aryloxy group having 6 to 14 carbon atoms, such as phenoxy and naphthyloxy. The aryloxy group may have one or two substituents, and examples of such a substituent include a halogen atom (eg, chlorine, fluorine, bromine, etc.). Examples of the substituted aryloxy group include 4-chlorophenoxy and the like. In the thiol group which may be substituted, examples of the substituted thiol group include an alkylthio group, a cycloalkylthio group, an alkenylthio group, a cycloalkenylthio group, an aralkylthio group, an acylthio group, and an arylthio group.

Preferable examples of the alkylthio group include an alkylthio group having 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, tert.-butylthio, pentylthio, and isobenzylthio. , Neopentylthio, hexylthio, heptylthio, nonylthio and the like.

Preferred examples of the cycloalkylthio group include cycloalkyl having 3 to 10 carbon atoms. Ruthio group, for example, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.

Preferable examples of the alkenylthio group include a alkenylthio group having 2 to 10 carbon atoms, such as allylthio, crotylthio, 2-pentenylthio, and 3-hexenylthio.

Preferable examples of the cycloalkenylthio group include a cycloalkenylthio group having 3 to 10 carbon atoms, for example, 2-cyclopentenylthio, 2-cyclohexenylthio and the like.

Preferred examples of the aralkylthio group include carbon number? ~ 1 0 Ararukiruchio group, for example phenylene Lou C i _ ₄ alkylthio (e.g., benzylthio, Fuenechiruchio, etc.) and the like.

Preferable examples of the acylthio group include an acylthio group having 2 to 13 carbon atoms, more preferably an alkanolthio group having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.).

Preferred examples of the arylthio group include an arylthio group having 6 to 14 carbon atoms, such as phenylthio and naphthylthio. The arylthio group may have one or two substituents, and such substituents include, for example, nitrogen, and a halogen atom (eg, chlorine, fluorine, bromine, etc.). Examples of the substituted arylthio group include 4-chlorophenylthio and the like.

Examples of the carboxyl group which may be esterified include an alkoxyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group and the like.

Preferable examples of the alkoxycarbonyl group include an alkoxy group having 2 to 5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxy group, butoxycarbonyl and the like.

Preferable examples of the aralkyloxycarbonyl group include an aralkyloxycarbonyl group having 8 to 10 carbon atoms, such as benzyloxycarbonyl. Preferred examples of the aryloxycarbonyl group include an aryloxycarbonyl group having 7 to 15 carbon atoms, such as phenoxycarbonyl and p-tolyloxycarbonyl. Bonyl and the like.

The substituent in the hydrocarbon group and the heterocyclic group represented by R is preferably an alkyl group having 1 to 10 carbon atoms, an aromatic heterocyclic group, or an aryl group having 6 to 14 carbon atoms, more preferably Alkyl, frill, chenyl, phenyl and naphthyl.

The substituents on the hydrocarbon group and the heterocyclic group represented by Ra are more appropriate when they are an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group. May have one or more, preferably 1 to 3, such substituents. Examples of such a substituent include an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, An alkynyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 14 carbon atoms, an aromatic heterocyclic group (eg, chenyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non- aromatic Hajime Tamaki (e.g., tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperazino, etc.), Ararukiru group, an amino group of 7 carbon atoms 9, N-mono- ₄ alkylamino, N, N-di - C i _ ₄ alkylamino group, § Shiruamino group having 2 to 8 carbon atoms (e.g., Asechiruamino, propionyl Rua Mino, etc. Benzoiruamino), amidino group, alkano Ashiru group (e.g., 2 to 8 carbon atoms of 2 to 8 carbon atoms ), N-mono- _4- alkyl rubamoyl group, N, N-di- _4- alkyl rubamoyl group, sulfamoyl group, N-mono-alkylsulfamoyl group, N, N-diC i _ ₄ alkylsulfamoyl group, propyloxyl group, alkoxycarbonyl group having 2 to 8 carbon atoms, hydroxyl group, alkoxy group having 1 to 4 carbon atoms, alkenyloxy group having 2 to 5 carbon atoms, carbon number 3 7 to 7 cycloalkyloxy groups, C7 to C9 aralkyloxy groups, C6 to C14 aryloxy groups, mercapto groups, C1 to C4 alkylthio groups, C7 to C7 9 aralkylthio groups, 6 to 14 carbon atoms aralkylthio groups, sulfo groups, cyano groups, azido groups, nitro groups, nitroso groups, halogen atoms and the like.

Ra is preferably an optionally substituted heterocyclic group. R a is more preferably 0 Bok ₃ alkyl, furyl, thienyl, from phenyl and naphthyl Pyridyl, oxazolyl or thiazolyl which may have 1 to 3 substituents selected. Ra is particularly preferably 5-methyl-2-phenyl-1,3-thiazol-4-yl, 5-methyl-2-phenyl-1,3-oxazolu-1-yl or the like.

Examples of the alkyl group represented by R b and R c include those exemplified above for R ² .

R b is preferably a hydrogen atom. '

Y is - CO-, one CH (OH) - or - NRi2_ a indicates (Ri2 is an alkyl group which may be substituted), preferably _CH (OH) one or - - NRi ^2.

In the “optionally substituted alkyl group” represented by Ri ² , examples of the alkyl group include the C i _ ₄ alkyl groups exemplified as R ² above. The alkyl group may have 1 to 3 substituents. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine), C ^ ₄ alkoxy (eg, Methoxy, ethoxy, propoxy, butoxy, t.-butoxy), hydroxy, nitro, dimethyl (eg, formyl, acetyl, propionyl) and the like.

m and n are preferably 0.

As the leaving group for Q, leaving groups exemplified for the aforementioned Q _a. Of these, a halogen atom is preferable, and chlorine is particularly preferable.

■ Preferable examples of compound (VI) include 4- (chloromethyl) -1-methyl-2-phenyl-1,3-xazole, 4- (chloromethyl) -15-methyl-2-phenyl — 1, 3-thiazol and the like.

Examples of the halogen atom represented by X include fluorine, chlorine, bromine, and iodine. Of these, chlorine and bromine are preferred.

R c is preferably methyl or ethyl, and more preferably ethyl.

Preferable examples of the compound (IX) include methyl chlorocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate, isopropyl chlorocarbonate, methyl bromocarbonate, bromocarbon Ethyl acid, propyl bromocarbonate, isopropyl bromocarbonate, butyl bromocarbonate and the like. Of these, ethyl chlorocarbonate is preferred.

The compounds (V), (VII), (VIII), (X) and (XI) are preferably optically active forms.

Preferred examples of compound (VII) or a salt thereof include 2-hydroxy-5- [4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl] pentyl Ethyl acid or its salt, sodium 2-hydroxy-5- [4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl] pentenoate or And salts thereof. In particular, ethyl (R) -2-hydroxy-5- [4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenylyl] pentanoate or a salt thereof ,

Sodium (R) -2-hydroxy-5- [4-[(5-methyl-2-phenylyl-1,3,3-thiazol-4-yl) methoxy] phenyl] pentanoate or a salt thereof is preferred.

Examples of the salts of the compounds (V), (VI), (VII), (VIII), (X), and (XI) include those exemplified as the salts of each compound used in Method A and the like.

In the process for producing compound (XI) described in detail below, compound (1), (V), (VI), (VII), (VIII) (X) as a raw material and compound (XI) as a target compound are It may be used as a salt as described above.

The reduction reaction of compound (I) can be carried out in the same manner as in the reduction reaction of compound (XIII) in the above-mentioned Method B.

Further, an optically active compound of the compound (V) can be produced by subjecting the compound (I) to an asymmetric reduction reaction.

Here, as the asymmetric reduction reaction, for example, a method using baker's yeast (eg,

A method using a chiral catalyst such as a ruthenium-phosphine complex (eg, Japanese Patent Application Laid-Open No. H10-12026, Japanese Patent Application Laid-Open No. H10-12062), etc. ) And the like. Among them, it is preferable to use a chiral catalyst such as a ruthenium-phosphine complex.

In particular, the method J and the method K described in detail below are preferable because the desired optically active substance can be obtained easily with high yield and high purity.

J method Compound (I) is represented by the formula (XXXII): [RuWMClkJ ιΧ ^

Wherein W is an optically active tertiary phosphine; M is Zn, Al, Ti or Sn; Χΐ is N (C ₂ H ₅ ) ₃ , HN (C ₂ H ₅ ) ₂ , H ₂ N (C ₂ H ₅ ), CH ₃ CO ₂ or a halogen atom; when X is N (C ₂ H ₅ ) ₃ , HN (C ₂ H ₅ ) 2 or H ₂ N (C ₂ H ₅ ), 1 Is 2 and h is 1 and k is 4 when M is Zn, k is 5 when M is A1, k is 6 when M is Ti or Sn; and Χΐ is CH ₃ C0 ₂ or a halogen atom, 1 is 1, h is 2, and k is 2 'when M is Zn, k is 3 when M is A1, k when M is Ti or Sn Is 4. By subjecting the compound to a hydrogenation reaction in the presence of the compound represented by the formula (I), an optically active form of the compound (V) can be produced.

The optically active tertiary phosphine represented by W is represented by the general formula (XXXIV)

[In the formula, ring G represents a benzene ring which may be hydrogenated, and R ⁹ , Rio and each represent a hydrogen atom or a C _1-4 alkyl group which may be the same or different. And an optically active form of the compound represented by the formula:

As the C _1-4 alkyl group represented by R ⁹ , Rio and R ¹¹ , the same as the above-mentioned alkyl group having 1 to 4 carbon atoms represented by R ² can be used.

Specific examples of compound (XXXIV) include 2,2'-bis (diphenylphosphino) -Ι, Ι-binaphthyl; 2,2'-bis (di- (Ρ-tolyl) phosphino) -Ι, Γ -Binaphthyl; 2,2'-bis (di- (3,5-dimethylphenyl) phosphino) -Ι, Γ-binaphthyl; 2,2'-bis (diphenylphosphino) -5,5 ', 6,6' , 7,7 ', 8,8'-octane hydro-Ι, Γ-binaphthyl and the like.

Compound (XXXIV) is particularly preferably a compound in which ring G is a benzene ring and R ⁹ , Rio and Rii are hydrogen atoms, that is, 2,2′-bis (diphenylphosphino) -Ι, Γ- Binaphthyl and 2,2'-bis (di- (p-tolylyl) phosphino) -1,1'-binaphthyl.

The optically active tertiary phosphine represented by W has optical isomers of (R) and (S), which can be appropriately selected depending on the absolute configuration of the target compound. That is, to obtain the (R) -form target compound, use the (R) optically active tertiary phosphine.To obtain the (S) -form target compound, use the (S) optical compound. Active tertiary phosphine may be used.

In the formula (XXXII), examples of the halogen atom represented by Χΐ include fluorine, chlorine, bromine, and iodine, with chlorine being preferred.

As preferable examples of compound (ΧΧΧΠ) is, W compound (XXXIV), the ring G is a benzene ring, R9, Riq and RU are hydrogen atoms, M is Ti, X ¹ is N (C ₂ H ₅₎ ₃ or chlorine When X ¹ is N (C ₂ H ₅ ) ₃ , 1 is 2, h is 1, k force is 6, and when Xi is chlorine, 1 is 1, h is 2, and k is 4. Is mentioned.

The compound (ΧΧΧΠ) is particularly preferably bis [ruthenium [2,2′-bis (diphenylphosphino) -Ι, Γ-binaphthyl] hexaclo-titanium] triethylamine. Compound (XXXII) can be produced by a method known per se, for example, a method described in JP-A-64-68387, JP-A-3-255090, JP-A-4-139140, or a method analogous thereto.

In particular, the compound (XXXII) in which Xi is a halogen atom has the formula (ΧΧΧΙΠ):

Wherein, X ² is a halogen atom; T is optionally substituted benzene, a Asetoni Bok drills or; W is an optically active tertiary phosphine; Z is a halogen atom, C] 0 _4, Indicate PF ₆ , BPh ₄ , BF ₄ ;

When T is benzene which may have a substituent, p, q and r are 1; when T is acetonitrile, when p is 1 q is 2 and r is 1 When p is 0, q is 4 and r is 2. ] And a Lewis acid.

In the formula (ΧΧΧΙΠ), as the halogen atom represented by X ² or z, those similar to the halogen atom represented by χι are used.

In the formula (XXXIII), the position in benzene which may have a substituent represented by The substituent d ₄ alkyl, d ₄ alkoxy, C ₂ -.. Include ₅ alkoxycarbonyl and eight necked Gen atoms.

Here, as the d. _4-alkyl, the same alkyl of 1 to 4 carbon atoms represented by R ² is used.

Examples of d.4 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, tert.-butoxy and the like.

C ₂ - The ₅ alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, cycloalkenyl, propoxy force Ruponiru, isopropoxycarbonyl, butoxycarbonyl two Le, isobutoxycarbonyl, sec- butoxide deer Lupo alkenyl, tert- butoxycarbonyl sulfonyl, and the like.

As the halogen atom, those similar to the halogen atom represented by the above Χΐ are used.

Preferable examples of the benzene which may have a substituent represented by Τ include benzene, toluene, xylene, trimethylbenzene, hexamethylbenzene, ethylbenzene, tert.-butylbenzene, P-cymene, cumene And methyl benzoate, methyl benzoate, benzoyl, methyl anisol, benzene benzene, dichlorobenzene, trichlorobenzene, bromobenzene, fluorobenzene, and the like.

Preferred examples of the compound (ΧΧΧΠΙ) include a compound in which T is benzene; W is a compound (XXXIV); ring G is a benzene ring; R ⁹ , R ^10, and R ¹¹ are hydrogen atoms; And the like.

The compound (ΧΧΧΙΠ) is particularly preferably ruthenium chromatobenzene [2,2′-bis (diphenylphosphino) -Ι, Γ-binaphthyl] chloride.

Compound (ΧΧΧΙΠ) can be prepared by a method known per se, for example, JP-A-2-191289 and JP-A-3-191289.

255090, a method described in JP-A-4-139140, or the like, or a method analogous thereto.

Examples of the Lewis acid include Lewis acids containing M (Zn, Al, Ti or Sn) in Formula (XXXII), such as titanium tetrachloride, tin tetrachloride, zinc chloride, and aluminum chloride. I can do it. The Lewis acid is preferably titanium tetrachloride.

The reaction between compound (ΧΧΧΙΠ) and a Lewis acid is usually performed in an organic solvent. The organic solvent may be any as long as it does not inhibit the reaction. Specific examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, diisopropyl ether, tert.-butyl methyl ether, dioxane, and the like. Ethers such as tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,1,2,2-tetrachlorobenzene; These organic solvents may be used as a mixture of two or more kinds at an appropriate ratio. The organic solvent is preferably a halogenated hydrocarbon such as dichloromethane. The amount of the organic solvent to be used is generally 1 to 100 times (v Zw), preferably 1 to 500 times (v Zw), relative to compound (XXXIII).

The reaction temperature is usually from −20 to: I30 :, preferably from 0 to 50 t :.

The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The amount of the Lewis acid to be used is generally 0 :! to 5 moles, preferably 0.5 to 2 moles, relative to compound (II).

The compound (XXXII) in which X ¹ is a halogen atom thus obtained can be purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, and the like. Further, a reaction solution containing the compound (XXXIII) and a Lewis acid may be used as the compound (II) in the reduction reaction of the compound (I).

The hydrogenation reaction of compound (I) is carried out by a method known per se in an organic solvent under a hydrogen pressure of usually 0.01 to: 2 MPa, preferably 0.01 to 5 MPa. This reaction is preferably performed in an inert gas such as argon or helium.

The organic solvent may be any as long as it does not inhibit the reaction. Specific examples thereof include alcohols such as methanol, ethanol, n.-propanol and isopropanol; aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as getyl ether, diisopropyl ether, tert.-butyl methyl ether, dioxane, tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, chloroform, 1,1,2,2-tetrachloroethane, etc. Esters such as ethyl acetate and isopropyl acetate; acetic acid; and amides such as N, N-dimethylformamide. These organic solvents may be used by mixing two or more kinds thereof at an appropriate ratio. Organic solvent Is preferably an alcohol, and more preferably an alcohol having the same alkyl group as R in compound (I) (eg, ethanol and the like). Further, it is preferable to use the degassed and dehydrated organic solvent. The amount of the organic solvent to be used is generally 1- to 1000-fold (v Zw), preferably 1- to 500-fold (v / w), relative to compound (I).

The reaction temperature is usually 0 to 150 ° C, preferably 5 to: 120 ° λ, and more preferably 10 to 80. '

The reaction time is generally 0.5 to: 100 hours, preferably 1 to 50 hours, more preferably 5 to 30 hours.

The compound (V) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

κ¾

By subjecting compound (I) to a hydrogenation reaction in the presence of compound (II) and a protonic acid, an optically active form of compound (V) can be produced.

Examples of the protic acid include methanesulfonic acid, (-)-camphor-10-sulfonic acid, (+)-camphor-10-sulfonic acid, (+)-3-bromocampha-8-sulfonic acid, sulfuric acid, and Ρ- Toluenesulfonic acid, perchloric acid (including silver (I) perchlorate), tetrafluoroboric acid (including silver (I) tetrafluoroborate), phosphoric acid, benzoic acid, hexafluorophosphate Acids (including silver (I) hexafluorophosphate). The protonic acid is preferably (-)-camphor-10-sulfonic acid, (+)-camphor-10-sulfonic acid, p.toluenesulfonic acid, sulfuric acid, perchloric acid and the like. Protic acids may be used as a mixture of two or more kinds at an appropriate ratio. The amount of the protonic acid to be used is generally 0.1 to 100,000-fold mol, preferably 0.5 to 100-fold mol, relative to compound (XXXIII).

The hydrogenation reaction of compound (I) is carried out in the same manner as in the above-mentioned Method J.

Compound (V) is a novel compound, especially a compound in which R is an ethyl group. Things are useful.

The reaction between compound (V) and compound (VI) is carried out, for example, in the presence of a base in a suitable solvent.

Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium hydrogen carbonate; amines such as pyridine, triethylamine, Ν, Ν-dimethylaniline; potassium hydride, sodium hydride, and the like. Metal hydrides; alkali metal alkoxides such as sodium ethoxide, sodium methoxy ', potassium tert.-butoxide and the like. Of these, alkali metal salts such as potassium carbonate are preferred. The amount of the base to be used is preferably 1 to 5 molar equivalents relative to compound (V).

Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; ketones such as acetone and 2-butanone; Ν, Ν-dimethylformamide and the like. Amides; sulfoxides such as dimethyl sulfoxide; and halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The solvent is preferably an amide such as Ν, Ν-dimethylformamide.

The amount of compound (VI) to be used is generally 1 to 5 molar equivalents, relative to compound (V). The reaction temperature is usually from 150 to 150, preferably from -10 to 100.

The reaction time is generally 0.5 hour to 30 hours, preferably 1 hour to 10 hours. The compound (VII) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. In addition, compound (VII) may be used in the next reaction as a reaction mixture.

The compound (VI) used in the above reaction can be produced according to a method known per se.

Then, the compound (νιπ) can be produced by subjecting the compound evil) to a hydrolysis reaction. This reaction is carried out in the same manner as in the hydrolysis reaction of compound (XV) in the above-mentioned Method C.

The compound (VIII) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Further, the compound (νιπ) may be used in the next reaction as a reaction mixture.

Furthermore, a salt (eg, sodium salt, potassium salt) formed between a compound (νιπ) and a base (eg, sodium hydroxide, potassium hydroxide) used in a hydrolysis reaction may be used in the next reaction. Good.

Then, compound (VIII) is reacted with compound (IX) and ammonia to produce compound (X). This reaction is carried out according to a method known per se, for example, a method described in JP-A-10-182623. This reaction is performed, for example, in an organic solvent in the presence of a base.

Examples of the organic solvent include ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran; esters such as ethyl acetate; ketones such as acetone and methyl ethyl ketone; chloroform, dichloromethane; -Halogenated hydrocarbons such as -dichloroethane and 1,1,2,2-tetrachloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; amines such as pyridine; Ν, Ν-dimethylformamide And amides such as dimethylacetamide; nitriles such as acetonitrile. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The solvent is preferably an ester such as ethyl acetate.

Examples of the base include amines such as pyridine, triethylamine, tri-η-butylamine, 1,8-diazabicyclo [5.4.0] indes-7-ene (DBU), and 4-dimethylaminopyridine. Of these, triethylamine and the like are preferred. The amount of these bases to be used is preferably 2 to 10 equivalents to compound (VIII).

In this reaction, ammonia is usually used as an aqueous solution. The concentration of ammonia in the aqueous solution is, for example, 5 to 20%. The amount of compound (IX) to be used is generally 1 to 5 molar equivalents, relative to compound (VIII). The reaction temperature is usually from −60 to 100 ° (preferably, from −20 ° C. to 50. The reaction time is usually from about 0.5 to 30 hours, preferably from 1 to 10 hours. The compound (X) thus obtained should be isolated and purified by known separation and purification means, for example, concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. The compound (X) may be used as a reaction mixture in the next reaction.

Next, compound (XI) can be produced by subjecting compound (X) to a ring closure reaction. This reaction is carried out according to a method known per se, for example, a method described in JP-A-10-182623. This reaction is carried out, for example, in an organic solvent in the presence of a base.

Examples of the organic solvent include alcohols such as methanol, ethanol, propanol, and isopropanol; ethers such as getyl ether, diisopropyl ether, dioxane, and tetrahydrofuran; esters such as ethyl acetate; and acetone and methyl ethyl ketone. Ketones; halogenated hydrocarbons such as formaldehyde, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane; aromatic hydrocarbons such as benzene, toluene, and xylene Amines such as pyridine; amides such as Ν, Ν-dimethylformamide and dimethylacetamide; nitriles such as acetonitrile. These solvents may be used as a mixture of two or more kinds at an appropriate ratio. The solvent is preferably a nitrile such as acetonitrile.

Examples of the base include metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium ethoxide, sodium methoxide and potassium tert.-butoxide; pyridine, triethylamine, tri-n-butylamine, Examples thereof include amines such as 8-diazabicyclo [5.4.0] penta-7-ene (DBU) and 4-dimethylaminopyridine. Of these, amines such as 1,8-diazabicyclo [5.4.0] pendase-7-ene (DBU) are preferred. The amount of the base to be used is preferably 1 to 10 equivalents to compound (X).

The reaction temperature is usually from −50 to 100, preferably from 130 to 50. The reaction time is usually 10 minutes to 20 hours, preferably 0.5 hours to 10 hours.

The compound (XI) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The thus-obtained compound (XI) or a salt thereof has an excellent pharmaceutical effect (eg, a blood glucose and blood lipid lowering effect). For example, the method described in EP-A-612, 743, etc. Therefore it can be used. -Best mode for carrying out the invention

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

In the following Reference Examples and Examples, room temperature indicates 1 to 30 ° C. When a mixed solvent is used, the solvent ratio indicates a volume ratio.

In the examples, methanol and ethanol used in the asymmetric reduction reaction were refluxed, distilled and further degassed in the presence of magnesium methoxide or magnesium ethoxide. A commercially available anhydrous solvent was degassed and used as necessary. In other reactions, a commercially available dehydrated solvent was used as necessary.

The optical purity of the optically active substance was evaluated by the enantiomeric excess (% e.e.). The enantiomeric excess was determined by the following formula using high performance liquid chromatography under the following conditions.

Enantiomeric excess (% 6.) = 100 [(1)-(S)] / [(R) + (S)]

[Where (R) and (S) indicate the absolute configuration of the enantiomers and the area of each enantiomer in high performance liquid chromatography]

(High performance liquid chromatography conditions)

Column: CHIRALPAK AD (Daicel Chemical Industries, Ltd.) (particle size 10 β m; column diameter: 4.6 mm; column length: 250 mm)

Mobile phase: n-hexane / isopropanol = 80/20 (v / v) or 90/10 (v / v)

Flow rate: 0.5 or l.Oml / min Temperature: 35 or room temperature

Detection: UV 210nm or 277nm

Reference example 1

4- (4-Methoxyphenyl)-4-year-old 'noph'tanic acid

371.2 g (2.78 mol) of anhydrous aluminum chloride was added to 600 ml of shirk DD methane, followed by ice cooling. Next, 200 ml (l.86 mol) of aniline was added dropwise, and anhydrous anhydride was added in 202.0 g (2.04 mol) in two portions (102 g, 100 g), followed by stirring at room temperature for 2.5 hours. . To another container, 2 L of 4N monohydrochloric acid solution and 1 L of ethyl acetate were added, and the reaction solution was added under ice cooling. The precipitated crystals were collected by filtration and washed four times with 1 L of water. The crystals were recrystallized from 2.6 L of acetone-water (4: 6). Dry under reduced pressure at 50 for 10 hours or more.350.7 g of the title compound as white crystals

(90.8%).

Melting point: 146-148

iH-NMR (300 MHz, DMSO-d ₆ ) ppm; 12 · 09 (1Η, bs), 7.96 (2H, d), 7.04 (2H, d), 3.85 (3H, s), 3.19 (2H, t), 2.56 (2H, t).

Reference example 2

Production of 4- (4-toxylphenyl) phthalic acid

One liter of talent-Toclef. To the mixture were added 120 g (576 mmol) of 4- (4-methoxyphenyl) -4-butyroxoptonic acid, 600 ml of THF-7 (1: 1), 0.565 g (5.8 mmol) of concentrated sulfuric acid, and 6.0 g of 10% Pd-C. The reaction was carried out at an internal temperature of 50 ° C and a hydrogen pressure of 0.86 lMPa for 7 hours. 576 ml of 1N-NaOH solution was added to the reaction solution, and the catalyst Pd-C was filtered off and washed with 174 ml of water. The filtrate and the washing solution were combined, and THF was distilled off. 560 ml of a 1N-HC1 solution was added dropwise to the concentrated residue to adjust the pH to 4, thereby precipitating crystals. The crystals were collected by filtration and washed three times with 240 ml of water. Dry under reduced pressure at 40 for 10 hours or more.104.07 g of the title compound as white crystals

(93.0%).

Melting point: 58-60

_{-ΝΜΙΙ (300ΜΗζ, CDC1 3) ppm} ; 7.09 (2H, dt), 6.83 (2H, dt), 3.78 (3H, s), 2.62 (2H, t), 2.36 (2H, t), 1.98-1 · 88 (2Η, m). Reference example 3

Production of 4- (4-hydroxyphenyl) "tanic acid

100 g (0.515 mol) of 4- (4-methoxyphenyl) butanoic acid and 450 ml of 48% hydrobromic acid were reacted at 100 ° C. for 6 hours. 300 ml of water was added dropwise to the reaction solution to precipitate crystals, and the crystals were collected by filtration. After drying under reduced pressure at 40 for 10 hours or more, 89.50 g (96.5%) of the title compound was obtained as almost white crystals.

Melting point: 112 ~: I13:

Ή-paint R (300MHz, DMSO-d ₆ ) ppm; 11 · 99 (1Η, bs), 9.12 (1H, s), 6.96 (2H, dd),

6.67 (2H, dt), 2.46 (2H, t), 2.18 (2H, t), 1.78-1.68 (2H, m).

Reference example 4

Manufacture of 4- (4-human 'roxyphenyl) ethyl phthalate

4-(4-Hyd D xyphenyl) phthalic acid 89.0 g (0.494 mol), EtOH 267 ml, 35% hydrochloric acid

5.15 g (49.4 mmol) were mixed and reacted at 50 ° C for 5 hours. To the reaction solution was added dropwise to 5% NaHCO ₃ water, and adjusted to pH 7. After evaporating the solvent under reduced pressure, 89 ml of water and 267 ml of ethyl acetate were added to the remaining oily substance, and the mixture was extracted. The aqueous layer was separated, and the ethyl acetate layer was washed with 89 ml of 2% aqueous NaCl. The ethyl acetate extract was concentrated under reduced pressure to give 97.65 g (94.9%) of the title compound as a pale yellow oil.

_{iH-NMR (300MHz, CDC1 3} ) ppm; 7.02 (2H, dd), 6.75 (2H, dd), 5.46 (1H, s),

4.13 (2H, q), 2.57 (2H, t), 2.31 (2H, t), 1.91 (2H, m), 1.25 (3H, t).

Reference example 5

Preparation of 4- (4-hydroxyphenyl) methyl phthalate

A mixture of 8.5 g (48 mmol) of 4- (4-hydroxyphenyl) phthalic acid, 50 ml of methanol and 0.12 ml of concentrated sulfuric acid was reacted at room temperature overnight. Was added dropwise saturated NaHCO ₃ water, the reaction mixture was adjusted to pH 8. After evaporating the solvent under reduced pressure, 50 ml of water and 100 ml of ethyl acetate were added to the residual oily substance, and the mixture was extracted. The aqueous layer was separated, and the ethyl acetate layer was washed with 50 ml of water and 50 ml of saturated saline. The ethyl acetate extract was concentrated under reduced pressure to obtain 8.7 g of the title compound as a pale yellow oil.

iH-NMR (300 MHz, CDCI3) ppm; 7.04 (2H, m), 6.75 (2H, m), 5.11 (lH, s), 3.67 (3H, s), 2.57 (2H, t), 2.32 (2H, t) ), 1.91 (2H, m). Example 1

To 5- (4-hydroxyphenyl) -2-oxo. Manufacture of ethyl ethyl tannate

225 ml of ethanol, 150 g (0.72 mol) of 4- (4-human '□ xyphenyl) ethyl butyrate, and 293.5 ml (2.16 mol) of dimethyl oxalate were mixed and adjusted to 5 ° C. or lower. To this solution, 242.5 g (2.16 mol) of tert-butoxy or dimethyl was added in three portions (60.63 g, 60.63 g, 121.24 g) under ice cooling. After the addition was completed, the reaction was carried out by stirring at 48 for 4 hours. The reaction was cooled to room temperature. The amount of 900 ml of 1N hydrochloric acid was reduced to 5 or less in another container, and then the reaction solution was added. 150 ml of 1N hydrochloric acid and 900 ml of toluene were added to the reaction vessel, and the mixture was washed. At room temperature, 6N hydrochloric acid was added dropwise to adjust the pH to 5.5. The aqueous layer was separated, and the organic layer was washed three times with 450 ml of 5% aqueous NaCl. The organic layer was concentrated under reduced pressure, and 440 ml of DMSO and 44 ml of deionized water were added to the residue. Thereafter, the mixture was heated and reacted at an internal temperature of 115 to 120 for 7 hours. The reaction solution was cooled, 880 ml of ethyl acetate was added, and 440 ml of 5% aqueous NaCl was added dropwise. The aqueous layer was separated and washed once with acetate Echiru layer with 5% NaHCO ₃ water 440 ml, 5% NaCl water 440 ml, 10% NaCl water 440 ml. The ethyl acetate layer was concentrated to 477 g under reduced pressure, and then 367 ml of n-hexane and 146.6 g of silica gel were added. After stirring at room temperature for 30 minutes, the silica gel was removed by filtration and washed with 733 ml of ethyl acetate: n-hexane (1: 1). The combined filtrates were concentrated to 293 g under reduced pressure. 268 ml of _n- hexane was added dropwise to the concentrated solution, and then seed crystals were inoculated and stirred at room temperature for 1.5 hours. After confirming the crystallization, 710 ml of n-hexane was further added dropwise over 1 hour, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled with ice water and aged at 5 or less for 2 hours. The precipitated crystals were collected by filtration and washed with 440 ml of ethyl acetate: _n- hexane (1: 8). The mixture was dried under reduced pressure at 30 for 10 hours or more to give 113.94 g (69%) of the title compound as pale brown crystals.

Melting point: 54-56t:

iH-NMR (300 MHz, CDCls) pm; 7.02 (2H, dd), 6.75 (2H, tt), 4.93 (1H, s), 4.29 (2H, q), 2.83 (2H, t), 2.59 (2H, t) ), 1.93 (2H, m), 1.35 (3H, t).

Example 2

5-(4-Hydroxyphenyl)-to 2-Okiri. Production of methyl tantanate

8 ml of methanol, 4 g of methyl 4- (4-hydroxyphenyl) phthalate and 9.7 g of methyl oxalate were mixed. To this solution was added 9.2 g of tert-hydroxy; After addition is complete, And reacted with stirring for 5.5 hours. The reaction was cooled to room temperature. The pH was adjusted to 3 with 14 ml of 2N hydrochloric acid. The aqueous layer was separated, the organic layer was washed with saturated saline, and the organic layer was concentrated under reduced pressure. To the residue were added 32 ml of DMS0 and 3.2 ml of city water, and the mixture was heated and reacted at an internal temperature of 115 to 120 for 6 hours. The reaction solution was cooled to an internal temperature of 10: and ethyl ethyl acetate (100 ml) was added, and then water (60 ml) was added dropwise. The aqueous layer was separated, and the ethyl acetate layer was washed once with water and saturated saline. After the ethyl acetate layer was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution with ethyl acetate-II. Hexane), and the effective fraction was concentrated to obtain 0.39 g of the title compound as crystals. .

H-band R (300MHz, CDCls) pm; 7.09 (2H, m), 6.84 (2H, m), 3.91 (lH, s), 3.79 (3H, s), 2.84 (2H, t), 2.61 (2H, t), 1.94 (2H, m).

Reference example 6

Production of 4-benzyloxy-3-methoxyketyl ethyl

420 g (1.73 mol) of 4-benzyloxy-3-methoxybenzaldehyde and 428.2 g (1.91 mol) of ethyl phosphonoacetate were added to 1.7 L of N, N-dimethylformamide. Under 10 or less, 232.9 g (2.08 mol) of potassium tert-butoxide was added, followed by stirring at room temperature for 0.5 hour. Ice water was added, extracted with ethyl acetate, and washed with water. After concentration under reduced pressure, crystallization from diisopropyl ether and _n- hexane, filtration and drying under reduced pressure gave 455 g (yield 84.0%) of the title compound.

Melting point: 67

! H-NMROOOMHz, CDCI3) ppm: 1.33 (3H, t), 3.91 (3H, s), 4.26 (2H, q),

5.19 (2H, s), 6.30 (lH, d), 6.9-6.8 (lH, m), 7.0 (2H, m), 7.3-7.5 (5H, m), 9.84 (lH, d).

Production of 3- (4-benzyloxy-3-methoxyphenyl) propanol

187.4 g (0.6 mol) of 4-benzyloxy-3-methoxyquenyl ethyl ester was added to 1.7 L of tetrahydrofuran. Sodium borohydride under nitrogen stream

126.1 g (3.00 mol) were added. While heating and refluxing, 400 ml of methanol was added dropwise over 1.5 hours, and the mixture was heated and refluxed for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to a half volume, and city water and ethyl acetate were added for extraction. The organic layer was washed with water and concentrated under reduced pressure to an appropriate amount. Then, diisopropyl ether was added dropwise, and the precipitated crystals were collected by filtration. Dry under reduced pressure, 133.2 g (81.5% yield) of the title compound was obtained.

Melting point: 76

_{iH-NMR (300MHz, CDC1 3} ) ppm: 1.65 (lH, brs), 1.81-1.90 (2H, m), 2.63 (2H, t), 3.65 (2H, t), 3.86 (3H, s), 5.11 ( 2H, s), 6.64-7.44 (8H, m).

Reference Example 8

Preparation of l- (4-benzyloxy-3-methoxyphenyl) -3-methansulfonyloxypropane

Suspension of 382.8 g (1.41 mol) of 3- (4-benzyloxy-3-methoxyphenyl) propanol and 202 g (2.0 mol) of triethylamine in 2.0 L of ethyl acetate, 195.0 g (1.7 mol) of methanesulfonyl chloride at 10 to 15 Was added dropwise over 1 hour. Then, the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. After washing the organic layer with water, it was concentrated under reduced pressure to an appropriate amount. Then, diisopropyl ether was added dropwise, and the precipitated crystals were collected by filtration. Drying under reduced pressure gave 348.2 g (yield 70.7%) of the title compound. Melting point: 86 ~ 87

iH-NMR (300MHz, CDCI3) ppm: 2.05 (2H, dd), 2.69 (2H, t), 2.99 (3H, s), 3.89 (3H, s), 4.22 (2H, t), 5.13 (2H, s ), 6.6-6.8 (3H, m), 7.3-7.5 (5H, m).

Reference Example 9

Preparation of l- (4-benzyloxy-3-methoxyphenyl) -3-cyanopropane

175 g (0.5 mol) of 1_ (4-benzyloxy-3-methoxyphenyl) -3-methanesulfonyloxypropane and 29.5 g (0.6 mol) of powdered sodium cyanate were suspended in 900 ml of Ν, Ν-dimethylformamide. After cooling, the mixture was cooled, poured into cold water and extracted with ethyl acetate. After washing with water, the mixture was concentrated under reduced pressure to an appropriate amount. Then, diisopropyl ether was added dropwise, and the precipitated crystals were collected by filtration. Drying afforded 131.7 g (93.7% yield) of the title compound.

Melting point: 78-79 ° C

_{Ή-ΝΜϋ (300ΜΗζ, CDC1 3} ) ppm: 2.05 (2H, dd), 2.30 (2H, t), 2.71 (2H, t),

3.88 (3H, s), 5.13 (2H, s), 6.6-6.8 (3H, m), 7.3-7.5 (5H, m).

Reference Example 10

Production of ethyl 4- (4-hydroxy-3-methoxyphenyl) butanoate 10.1 kg (37.0 mol) of l- (4-benzyloxy-3-methoxyphenyl) -3-cyanopropane was added to 40 L of ethanol, and 5 to 6 equivalents of hydrogen chloride gas were blown at 15 ° C or lower. The mixture was gradually heated and refluxed for 3 hours. After the completion of the reaction, the solvent was concentrated under reduced pressure to half the volume, and ethyl acetate and water were added for extraction. Further, the organic layer was washed with saturated saline. After concentration under reduced pressure, 8.55 kg (85.3%) of an oily substance of the title compound was obtained. _{iH-NMR (300MHz, CDC1 3} ) ppm: 1.25 (3H, t), 1.94 (2H, dd), 2.31 (2H, t),

2.58 (2H, t), 3.88 (3H, s), 4.13 (2H, q), 5.52 (lH, s), 6.7-6.8 (3, m).

Reference Example 11

Preparation of ethyl ethyl 5- (4-hydroxy-3-methoxyphenyl) -2-oxopentanoate

760 mg (3.19 mmol) of ethyl 4- (4-hydroxy-3-methoxyphenyl) butanoate, 1.3 ml (9.57 mmol) of getyl oxalate, and 1.3 ml of ethanol were mixed. After cooling with ice, 1.40 g (9.57 mmol) of potassium tert-butoxide was added little by little. After the addition was completed, the mixture was stirred at 50 t: for 3 hours. After adjusting the pH to 3 with 1N hydrochloric acid, ethyl acetate and city water were added for extraction. The organic layer was washed with saturated saline and concentrated under reduced pressure. To the residue were added 3 ml of dimethyl sulfoxide and 0.3 ml of water, and the mixture was heated at 120 for 6 hours. After cooling, ethyl acetate and 5% saline were added for extraction. The organic layer was concentrated under reduced pressure, and purified by silica gel column chromatography (eluted with ethyl acetate: n-hexane) to obtain 523 mg (yield: 61.7%) of the title compound.

iH-NMR (300MHz, CDCI3) ppm: 1.36 (3H, t), 1.95 (2H, dt), 2.59 (2H, t),

2.84 (2H, t), 3.88 (3H, s), 4.29 (2H, q), 5.48 (lH, s), 6.6-6.9 (3H, m).

Reference example 1 2

Production of methyl (2R) -5- (4-benzyloxyphenyl) -2-hydroxypentanoate

8.5 mg (0.00800 mmol) of compound C and 500 mg (1.60 mniol) of methyl 5- (4-benzyloxyphenyl) -2-oxopentanoate were placed in a 120 ml autoclave, sufficiently purged with argon, and then degassed with ethanol 10 ml. And catalytically reduced at a hydrogen pressure of 1 MPa or less at 50 for 24 hours. The enantiomeric excess of the title compound in the obtained reaction solution was 93.8% ee ((R) form was obtained).

Reference Example 1 3

Preparation of (2R) -5- (4-benzyloxyphenyl) -2-hydroxypentyl ethyl fuinate In a 120 ml autoclave, put 8.1 mg (0.00766 mmol) of compound C and 500 rng (1.532 nmol) of ethyl 5- (4-oxophenyl) -2-oxopentanoate, sufficiently purge with argon, and then add 10 ml of degassed ethanol. Hydrogen pressure IMPa or lower, 5 (contact reduction with TC for 24 hours.) The enantiomer excess of the title compound in the obtained reaction solution was 88.8 ° / oee ((R) -isomer was obtained).

Ή-paint R (300Mz, CDCl ₃ ) ppm: 1.28 (3H, t), 1.68-1.78 (4H, m), 2.59 (2H, t), 2.50-2.75 (2H, m), 2.5-3.0 ( lH _! brs), 4.17-4.22 (lH, m), 4.17-4.20 (lH), 4.23 (2H, q), 5.04 (2H, s), 6.89 (2H, d), 7.09 (2H, d) _; 7.31 -7.45 (5H, m), IR (neat): 3507, 1731 cm- ^1. Reference example 1 4

Preparation of (2R) -5- (4-[(5-methyl-2-phenyl-1,3-thiazolyl-4-yl) methoxy] phenyl) -2-ethylethyl-2-hydroxypentanoate

In a 120 ml autoclave, 12.55 mg (0.01182 mmol) of compound C and 5- (4- (5R)-(3- {4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) After 500 mg (2.363 mmol) of ethyl methoxy] phenyl) -2-oxopentanoate was added, and sufficiently purged with argon, 10 ml of degassed ethanol was added, and the mixture was subjected to catalytic reduction at a hydrogen pressure of IMPa or less and 50 for 24 hours. The enantiomeric excess of the title compound in the obtained reaction solution was 85.4% ee ((R) form was obtained).

iH-NMR (300 Mz, CDCl ₃ ) ppm: 1.28 (3H, t), 1.64-1.84 (4H, m), 2.3-2.9 (lH, brs), 2.52 (3H, s), 2.59 (lH, q ) ₎ 4.15-4.19 (lH, m) _! 4.22 (2H, q), 5.15 (2H, s), 6.96 (2H, d), 7.10 (2H, d), 7.38-7.42 (3H, m), 7.88- 7.91 (2H, m), IR (neat) level: 3500,1736 cm ¹ .

Reference example 1 5

Of (2R) -5- (4-hydroxy-3-methoxyphenyl) -2-hydroxypentanoate

In a 120 ml autoclave, add 2.0 mg (0.001878 mmol) of compound C and 100 mg (0.3755 mmol) of ethyl 5- (4-hydroxy-3-methoxyphenyl) -2-oxopenate, and sufficiently purge with argon. After that, 2 ml of degassed ethanol was added, and the mixture was catalytically reduced at a hydrogen pressure of less than IMPa and 50 ^ for 24 hours. The enantiomeric excess of the title compound in the obtained reaction solution was 88.7% e.e. ((R) form was obtained).

-Image R (300 MHz, CDCl ₃ ) ppm: 1.28 (3H, t), 1.64-1.83 (4H, m), 2,54-2.60 (2H, m ), 2.80 (lH, brs), 3.87 (3H, s), 4.2 (lH, m), 4.23 (2H, q) _! 5.52 (lH, brs) _; 6.67 (lH _J d), 6.68 (lH, s) , 6.82 (lH, d)

Reference Example 1 6-

Ethyl (2R) -5- (4-hydroxy-3-methoxyphenyl) -2-hydroxypentanoate

In a 120 ml autoclave, put 1.9 mg (0.001878 mmol) of compound E and 0 mg (0.3755 mmol) of 5- (4-hydroxy-3-methoxyphenyl) -2-oxopentyl ethyl benzoate, and sufficiently purge with argon. Then, 2 ml of degassed ethanol was added, and the mixture was catalytically reduced at a hydrogen pressure of 1 MPa or less at 50 for 24 hours. The enantiomeric excess of the title compound in the obtained reaction solution was 91.3% e.e. ((S) form was obtained).

Reference Example 1 7

Production of (2R) -5- [4- [2- (2-furyl) -5-methylyl-4-oxazolylmethoxy] -3-methoxyphenyl] -2-hydroxypentanoate

In a 120 ml autoclave, 12.1 mg (0.058486 mniol) of compound C and (2R) -5- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxyphenyl 1.0 g (2.339 mmol) of ethyl 2-oxopentanoate was added, and after sufficiently purging with argon, 20 ml of degassed ethanol was added, and the mixture was catalytically reduced at a hydrogen pressure of IMPa or less and 50 for 24 hours. The enantiomer excess of the title compound in the obtained reaction solution was 83.6% e.e. ((R) form was obtained).

Reference Example 1 8

Production of (2R) -5- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxyphenyl] -2-hydroxypentanoate

In a 120 ml autoclave, 12.4 mg (0.058486 imnol) of compound E and (2R) -5- [4- [2- (2-furyl) -5-methyl-4-oxazolylmethoxy] -3-methoxyphenyl 1.0 g (2.339 mmol) of ethyl 2-oxopentanoate was added, and after sufficiently purging with argon, 20 ml of degassed ethanol was added, and the mixture was subjected to contact reduction under a hydrogen pressure of 1 MPa or less and 50 for 24 hours. The enantiomeric excess of the title compound in the obtained reaction solution was 84.0% e.e. ((S) form was obtained).

Example 3 Production of ethyl (R) -5- (4-hydroxyphenyl) -2-hydroxypentanoate (hereinafter abbreviated as compound A)

(R)-(+)-2,2'_bis (diphenylphosphino) -Ι, Γ-binaphthyl ((R) -BINAP) 10.0 g (16.0 mmol) and bis [ruthenium benzene Dichloride] ([Ru (benzene) Cl ₂ ] 2) 3.65 g (7.3 mmol)

(150 ml) and dichloromethane (150 ml) were added, and the mixture was stirred at 50 for 2.5 hours. After the completion of the reaction, the reaction solution is cooled, the solvent is distilled off under reduced pressure, and the residue is dried to dryness. Dark brown brown ruthenium chlorobenzene [2,2'-bis (diphenylphosphino) -1,1'-binaphthyl ] Chloride [RuCl (benzene) ((R) -BINAP)] Cl (hereinafter abbreviated as compound B) (14.5 g) was obtained. Put 14.4 g (14.6 mmol) of compound B in a 500 ml Schlenk tube purged with argon, sufficiently purge with argon, and then add 300 ml of dichloromethane and titanium tetrachloride.

1.60 ml (14.6 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the mixture was distilled off under reduced pressure to obtain a dark green solid (hereinafter abbreviated as compound C) (17.7 g).

200 g (846.5 mmol) of ethyl 5- (4-hydroxyphenyl) -2-oxopentanoate (hereinafter abbreviated as compound A ') and 1.87 g (1.69 mmol) of compound C were placed in a 1 L-autoclave, and sufficiently argon was added. After the replacement, 600 ml of dehydrated ethanol in which argon had been passed was added, and the mixture was reduced under a hydrogen pressure of 4 to 5 MPa and 50 t for 24 hours. The resulting reaction solution (89-91% ee (R) form is obtained) is concentrated under reduced pressure, the residue is dissolved in 500 ml of toluene, crystallized, and 171.3 g of substantially pure title compound (compound A) ( The yield was 84.9%) (a series of operations were performed in an inert gas). The enantiomeric excess was 96-99% ee. Ή-NMR (300 MHz, CDCl ₃ ) ppm: 1.28 (3H, t), 1.60-1.84 (4H, m), 2.53- 2.60 (2H, m), 2.90 (lH, d), 4.19 (lH, m), 4.31 (2H, d), 5.37 (2H, d), 7.01 (2H, d), 13C-NMR (75MHz, CDCl 3) ppm: 14.6, 27.1, 34.2, 35.0, 62.2, 70.9, 115.6, 129.8, 134.2, 154.3, 175.7,

IR (KBr, cm-i) SEO: 3675, 3424, 1720

[a] D ¹⁹ —1.22 ° (c 0.00490, MeOH)

Elemental analysis (as C ₁₃ H ₁₈ 0 ₄₎

Calculated: C: 65.53, H: 7.61, 0: 24.86; Measurements: C: 65.63, H: 7.73

mp 69.5-71.

Example 4

Production of Compound A

97 g (410.6 mmol) of Compound A 'and Compound C in 1 L-autoclave

After adding 1.45 g (1.37 mmol) and sufficiently purging with argon, 485 ml of dehydrated ethanol through which argon was passed was added, and the mixture was reduced at a hydrogen pressure of 0.9 to 1.0 MPa and 50 for 24 hours. The resulting reaction solution (90% e.e. (R) form was obtained) was concentrated under reduced pressure, and the residue was dissolved in 500 ml of toluene to obtain 103.9 g of the title compound (Compound A).

Example 5

Production of Compound A

Bis [(S) -2,2'_bis (diphenylphosphino) -Ι, Γ-binaphthyl] triethylamine (Ru ₂ Cl ₄ ((S) -BINAP) ₂ NEt ₃ ) 500 mg (0.3 mmol) was placed in a 50-ml Schlenk tube, sufficiently purged with argon, added with 20 ml of dichloromethane and 0.07 ml (0.6 mmol) of titanium tetrachloride, and stirred at room temperature for 3 hours. After the reaction is completed, dichloromethane is distilled off under reduced pressure, and the residue is evaporated to dryness to obtain bis [ruthenium [(S) -2,2,2-bis (diphenylphosphino) -Ι, Γ-pinaphthyl] hexa. Chlorotitanium] triethylamine ([Ru ((S) -BINAP) TiCl ₆ ] ₂ NEt ₃ ) (hereinafter abbreviated as compound E) was obtained as a dark green solid.

In a 120 ml autoclave, add the above dark green solid (compound

E) 5.48 mg (0.0053 mmol) and Compound A '250 mg (1.06 mmol) were added, and after sufficient argon substitution, 5 ml of degassed ethanol was added, and the mixture was catalytically reduced at 50 under a hydrogen pressure of 1 MPa or less for 24 hours. . The enantiomer excess of the target compound in the obtained reaction solution was 91.8% ee ((S) -isomer was obtained).

Example 6

Production of Compound A

1.39 g of (R)-(+)-2,2'_bis (di- (p-tolyl) phosphino) -1,1'-binaphthyl ((R) -tol-BINAP) in a 100 ml Schlenk tube purged with argon (2.05 mmol) and bis [ruthenium benzene dichloride l ([Ru (benzene) Cl ₂ ] 2) 0.466 g (0.931 mmol) Then, toluene (15 ml) and dichloromethane (15 ml) were added, and the mixture was stirred at 50 for 2.5 hours. After completion of the reaction, the reaction solution was cooled, the solvent was distilled off under reduced pressure, and the residue was evaporated to dryness. The dark brown brown ruthenium chlorobenzene [2,2'-bis (di- (P-tolylyl) phosphino) -Ι, [Γ-Binaphthyl] cupride [RuCl (benzene) ((R) -tol-BINAP)] Cl (hereinafter abbreviated as compound F) was obtained. After sufficiently replacing the Schlenk tube with argon, 300 ml of dichloromethane and 0.20 ml (1.86 mmol) of titanium tetrachloride were added to the compound F, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, dichloromethane was distilled off under reduced pressure, and the residue was dried to obtain a dark green solid (hereinafter, abbreviated as compound G).

Compound G 11.8 mg (0.0105 mmol) in a 120 ml autoclave _; Compound A '

After 500 mg (2.12 mmol) was added and the atmosphere was sufficiently replaced with argon, 10 ml of degassed ethanol was added, and the mixture was subjected to catalytic reduction at a hydrogen pressure of IMPa or less and 50 for 24 hours. The enantiomeric excess of the target compound in the obtained reaction solution was 88.8% e.e. ((R) form was obtained).

Example 7

Production of Compound A

In a 120 ml autoclave, add 9.2 mg (0.0105 mmol) of compound B, (R)-(-)-camphorsulfuronic acid (the amount used is described below), and 500 mg (2.12 mmol) of compound A ', and sufficiently replace with argon. After the reaction, 10 ml of degassed ethanol was added, and the mixture was subjected to catalytic reduction at a hydrogen pressure of IMPa or lower at 50 at 24 hours. The enantiomer excess of the target substance in the obtained reaction solution was measured.

The amount of (R)-(-)-camphorsulfonic acid used is 0.0mg (0.0000mmol),

For 2.5 mg (0.0108 mmol), 4.9 (0.0211 mmol), 9.8 (0.0422 mmol), 24.6 (0.106 mmol), 123 mg (0.529 mniol), and 246 mg (1.06 mmol), the enantiomeric excess is 83.8 each. , 88.3, 89.0, 91.1-91.3. 91.2, 86.6, 82.5% ee ((R) form was obtained). Example 8

Production of Compound A

In a 120 ml autoclave, put 9.2 mg (0.0105 mmol) of compound B, 8.1 mg (0.0105 mniol) of p-toluenesulfonate, and 500 mg (2.12 mmol) of compound A ', sufficiently purge with argon, and then degas. Then, the mixture was subjected to catalytic reduction at a hydrogen pressure of IMPa or lower at, 5 (T for 24 hours. The enantiomeric excess of the target compound in the obtained reaction solution was It was 91.5% ee.

Example 9

Production of Compound A

Compound B 9.2 mg (0.0105 mmol), phosphoric acid in a 120 ml autoclave

After 6.0 mg (0.0612 mmol) and 500 mg (2.12 mmol) of compound A 'were added, and sufficiently purged with argon, 10 ml of degassed ethanol was added, and the mixture was subjected to catalytic reduction at a hydrogen pressure of IMPa or less and 50 t: for 24 hours. The enantiomeric excess of the target compound in the obtained reaction solution was 85.2% e.e. ((R) -isomer was obtained).

Example 10

Production of Compound A

Compound B 9.2 mg (0.0105 mmol) in a 120 ml autoclave, benzoic acid

After 5.2 mg (0.0423 mmol) and 500 mg (2.12 mmol) of compound A 'were added, and sufficiently purged with argon, 10 ml of degassed ethanol was added, and the mixture was subjected to catalytic reduction under a hydrogen pressure of 1 MPa or less and 50 "for 24 hours. Enantiomeric excess of the desired product in the reaction solution

79.7% e.e. ((R) form was obtained).

Example 1 1

Production of Compound A

In a 120 ml autoclave, put 9.2 mg (0.0105 mmol) of compound B, 2.4 mg (0.0105 mmol) of silver (I) monohydrate, and 500 mg (2.12 mmol) of compound A 'and sufficiently purge with argon. 10 ml of degassed ethanol was added, and the mixture was catalytically reduced at a hydrogen pressure of 1 MPa or less at 50 for 24 hours. The enantiomeric excess of the target compound in the obtained reaction solution was 58.9% e.e. ((R) form was obtained).

Example 1 2

Production of Compound A

Compound B 9.2 mg (0.0105 mmol), (R)-(-)-Camphorsulfuric acid 9.8 mg (0.0423imnol), Silver perchlorate (I) monohydrate 2.4 mg (0.0105 mmol) in 120 ml autoclave Compound A '(500 mg, 2.12 mmol) was added, and the atmosphere was sufficiently purged with argon. Then, 10 ml of degassed ethanol was added, and the mixture was catalytically reduced at a hydrogen pressure of 1 MPa or less at 50 at 24 hours for 24 hours. The enantiomer excess of the target compound in the obtained reaction solution is 89.8% ee ((R) form is obtained). I got it.

Example 13

Production of Compound A

Compound B 9.2 mg (0.0105 mmol), silver tetrafluoroborate (I) 2.1 mg (0.0105 nmol), and compound A '500 mg (2.12 nimol) were placed in a 120 ml autoclave, sufficiently purged with argon, and then degassed with ethanol 10 ml. , And catalytically reduced at a hydrogen pressure of 1 MPa or less at 50 for 24 hours. The enantiomer excess of the target compound in the obtained reaction solution is

84.5% e.e. ((R) form was obtained).

Example 14

Production of Compound A

Compound B 9.2 mg (0.0105 mmol), (R)-(-)-Camphorsulfuric acid 9.8 mg (0.0423 mmol), silver tetrafluoroborate (I) in 120 ml autoclave

After 2.1 mg (0.0105 mmol) and 500 mg (2.12 mmol) of compound A 'were added, and sufficiently purged with argon, 10 ml of degassed ethanol was added, and the mixture was catalytically reduced at a hydrogen pressure of 1 MPa or less at 50 for 24 hours. The enantiomer excess of the target compound in the obtained reaction solution is

89.8% e.e. ((R) form was obtained).

Example 15

Production of Compound A

Add 9.2 mg (0.0105 mmol) of compound B, 2.7 mg (0.0105 mmol) of silver (I) hexafluorophosphate, and 500 mg (2.12 mmol) of compound A 'in a 120 ml autoclave, perform sufficient argon substitution, and then degas. 10 ml of ethanol was added, and the mixture was catalytically reduced at a hydrogen pressure of 1 MPa or less at 50 t: for 24 hours. The enantiomer excess of the target compound in the obtained reaction solution was 85.7% e.e. ((R) form was obtained).

Example 16

Production of Compound A

Compound B 9.2 mg (0.0105 mmol), (R)-(-)-Camphorsulfuric acid 9.8 mg (0.0423 mmol), silver hexafluorophosphate (I) in a 120 ml autoclave

2.7 mg (0.0105 mmol) ₍ Compound A '500 mg (2.12 mmol) is added, and the atmosphere is sufficiently purged with argon, then 10 ml of degassed ethanol is added, and the hydrogen pressure is 1 MPa or less. Catalytic reduction was performed for 24 hours. The enantiomer excess of the target compound in the obtained reaction solution is

89.1% e.e. ((R) form was obtained).

Example 17

Production of Compound A

[(R) -2,2, -Bis (diphenylphosphino) -Ι, Γ-pinaphthyl] ruthenium diacetate Ru (OAc) ₂ [(R) -binap] 6.6 mg (0.00783 mmol) in a 120 ml autoclave Then, 370 _mg (1.57 mmol) of Compound A 'was added, and the atmosphere was sufficiently purged with argon. Then, 7.4 ml of degassed ethanol was added, and the mixture was catalytically reduced at 50 or less at a hydrogen pressure of 1 MPa or less for 24 hours. The enantiomer excess of the target compound (Compound A) in the obtained reaction solution was 29.9% ee (9% of the (R) form was obtained).

Example 18

Production of Compound A

120ml O (prepared in the same preparation as above compounds B) one Tokurepu in benzene [(described hereinafter) optically active phosphorus ligand] base Ruteniumukuroro chloride ^{[RuCl (benzene) (P A} P)] Cl (0.0105 nmiol) and 500 mg (2.12 mmol) of compound A 'were added, and after sufficient argon substitution, 10 ml of degassed ethanol was added, and the mixture was catalytically reduced at a hydrogen pressure of 1 MPa or less at 50 at 24 hours. The enantiomer excess of the target substance in the obtained reaction solution was measured.

As optically active phosphorus ligands (Ρ ^Λ Ρ), (R, R) -Me-DuPHOS, (S, S) -DIOP, (S, S) -BDPP, BPPM, (R) (S) -JOSIPHOS, (R) (S) -BPPFA, (R) (S) -BPPFOH, (R) (S) -PPFA, (R, R) -NORPHOS, (R) -PROPHOS, CARBOPHOS, (S) -NMDPP, ( When S) -QUINAP and BCPM (PPM) are used, the enantiomeric excess is 60 (R), 33 (R), 73 (R), 11 (R), 10 (S), 16 (S), respectively. , 10 (S), 10 (S), 79 (R), 38 (R), 3 (R), 4 (R), 32 (S), 6 (R)% ee.

Example 19

Production of methyl (R) -5- (4-hydroxyphenyl) -2-hydroxypentanoate

In a 120 ml autoclave, 9.3 mg (0.00877 mmol) of compound C and 390 mg (1.75 mmol) of methyl 5- (4-hydroxyphenyl) -2-oxopenate were sufficiently substituted with argon, and then degassed. Add 7.8 ml of ethanol, hydrogen pressure lMPa Thereafter, catalytic reduction was performed at 50 ° C for 24 hours. The enantiomeric excess of the target compound in the obtained reaction solution was 95.0% ee ((R) -isomer was obtained).

Example 20

(R) — 2 —Hydroxy— 5— {4-[(5 —Methyl— 2 —Fenyl 1, 3 —Thiazol-4-yl) methoxy] phenyl} Preparation of ethyl pentanoate

620 g (2.60 mol) of (R) -1-hydroxy-1-5- (4-hydroxyphenyl) pentanoate, 4- (chloromethyl) -5-methyl-2-phenyl-1,3-thiazole A mixture of 640 g (2.86 mol), 539.0 g (3.90 mol) of potassium carbonate and 3.1 L of dimethylformamide was stirred at 60 for 6 hours. After cooling the reaction solution to 15, 3 L of ethyl acetate was added, and then, at 15 to 25, 4.96 L of water was added, followed by separation and extraction. The organic layer was washed twice with 4.34 L of 5% saline. After concentrating the organic layer to 2 kg, methanol (3.1 L) was added, and the mixture was concentrated under reduced pressure to 2.14 kg to obtain the title compound as a brown methanol solution. When this solution was quantified by HPLC, the actual content of the title compound was 954.4 g, the yield was 87.9%, and the optical purity was 97.3% ee.

Ή-NMR (300MHz, CDCl3) ppm: 1.28 (3H, t), 1.64-1.84 (4H, m), 2.3-

2.9 (lH, brs), 2.52 (3H, s), 2.59 (2H, q), 4.22 (2H, q), 5.15 (2H, s), 6.96 (2H, d), 7.10 (2H, d), 7.38 -7.42 (3H, m), 7.88-7.91 (2H, m)

IR (neat) ^-!: 3500, 1736

Example 2 1

(R) — 2-Hydroxy-5— {4 -— ((5—Methyl-2—phenyl-1,3-thiazol-4-yl) methoxy] phenyl} sodium pentanoate

(R) 12-Hydroxy_5_ {4-([5-Methyl-12-fluoro-1,3-thiazo-1-yl-4-methoxy) methoxy] phenyl} Ethyl pentanoate in methanol 2.14 kg (pure amount: 954 g) was dissolved in 3.72 L of methanol. To the resulting solution, 2.48 L of 2N sodium hydroxide was added dropwise at 39 to 47, stirred at 40 for 1 hour, and then left at 25 at 1 hour. The crystals were collected by suction filtration, and washed with 1.24 L of cold water and 1.86 L of toluene. The obtained crystals were dried under reduced pressure at 50: to give the title compound as pale yellow crystals. 954.8 g, 96.7% yield, 97.3% optical purity

-NMR (300MHz, DMSO-d ₆ ) ppm: 1.31-1.38 (lH, m), 1.53-1.64i3H, m), 2.46-2.50 (5H, m), 3.45 (lH, t), 4.30 (lH, brs), 5.09 (2H, s), 6.95 (2H, d),

7.09 (2H, d), 7.45-7.52 (3H, m), 7.86-7.89 (2H, m)

Example 22

(R) — 2-ethoxycarbonyloxy— 5-{{4-[(5-methyl-2-phenyl-1,3-thiazolyl-41-yl) methoxy] phenyl} pentanoic acid amide Manufacture

(R) —2-Hydroxy-5_ {4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl} Sodium pentanoate 905.4 g (2.16 mol) in acetic acid Suspended in 10.9 L of ethyl acetate and cooled to —5 :. To the resulting suspension was added dropwise 619 ml (6.48 mol) of ethyl ethyl carbonate at the same temperature, and 331 ml (2.38 mol) of triethylamine was added dropwise over 35 minutes, followed by stirring for 1 hour. Then, 485 ml (7.13 mol) of 25% ammonia water was added dropwise over 1 hour, and the mixture was stirred at 0 for 30 minutes. The reaction solution was stirred at room temperature for 30 minutes, water (4.53 L) was added, and the mixture was heated and dissolved at 40. The organic layer was separated, washed with 10% saline, and added with activated carbon (trade name: Shirasagi A) 90.5 g at 40 and stirred for 20 minutes. The activated carbon was filtered off by Millipore and washed with 2.72 L of ethyl acetate heated to 40. The filtrate was concentrated to 4.98 kg and stirred at room temperature to precipitate crystals. The obtained crystals were washed with 4.53 L of diisopropyl ether and dried under reduced pressure to give the title compound. 868.5g, yield 88.5%, optical purity 99.5% ee

Ή-NMR (300MHz, CDCl ₃ ) ppm: 1.32 (3H, t), 1.69-1.76 (2H, m), 1.88-

1.95 (2H, m), 2.52 (3H, s), 2.59 (2H, q), 4.23 (2H, q), 5.08 (lH, m), 5.14 (2H, s), 5.69 (lH, brs), 6.13 (lH, brs), 6.95 (2H, d), 7.08 (2H, d), 7.26-7.44 (3H, m), 7.87- 7.91 (2H, m)

Example 2 3

(R) — 5— [3— [4— [(5-Methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl} propyl] 1-1,3-oxazolidine— 2 Manufacture of 4-dione

(R) — 2-Ethoxycarbonyloxy 5 _ {4-[(5-Methyl-12-phenyl-1,3-thiazol-4-yl) methoxy] phenyl} pentanoic acid 861 g of amide was suspended in 6.03 L of acetonitrile, and 412 mL of 1,8-diazabicyclo [5.4.0] pande-7-ene (DBU) was added dropwise at 19 to 21. After stirring the resulting mixture at 25 ° C for 2 hours, 4.31 L of water was added, and 1.72 L of 2N hydrochloric acid was added dropwise over 30 minutes to precipitate crystals at pH 1.2 (seed crystals at pH 8). Is added). The crystallization liquid was allowed to stand at 25 t: for 1 hour, and filtered. The residue was washed once with 4.3 L of acetonitrile-water (1: 2) and twice with 4.3 L of water, and dried under reduced pressure at 50 to give crude crystals (741.8 g, yield 95.8%, optical purity 99.6% ee). Obtained. The crude crystals were dissolved at 70 in 8.89 L of ethanol-water (85:15). Activated carbon (trade name: Shirasagi A) 37 g was added to the resulting solution, and the mixture was stirred for 15 minutes. After filtering off the activated carbon under pressure, the filtrate was washed with 2.22 L of 70% ethanol / water (85:15), cooled slowly, and stirred at 40 for 1 hour to precipitate crystals. The crystallized solution was cooled with ice from 40 to 0 ~ 5 ^ over 1.5 hours, and left still for 1 hour. The crystals were collected by filtration, washed with 2.22 L of ethanol, and dried under reduced pressure at 50 to give the title compound. 659.9g, yield 83.9%, optical purity 99.9% ee

_{Ή-NMR (300MHz, CDC1 3} ) ppm: 1.71-1.87 (3H, m), 1.95-2.01 (lH, m),

2,51 (3H, s), 2.59 (2H, t), 4.76 (lH, m), 5.13 (2H, s), 6.95 (2H, d), 7.07 (2H, d), 7.37-7.44 (3H, m), 7.85-7.89 (2H, m), 8.72 (lH, brs),

Example 24

(R) —2-Hydroxy-5— {4— [(5-Methyl-2-phenyl-1,3-thiazole-4-yl) methoxy] phenyl} Preparation of ethyl pentanoate (R) 1 2 -Hydroxy-5- (4-hydroxyphenyl) pentanoic acid 15.0 g, 4- (chloromethyl) -15-methyl-12-phenyl-1,1,3-thiazol 15.5 g, Carbonic acid A mixture of 13.1 g of potassium and 75 mL of dimethylformamide was stirred with 6 O: for 3 hours. After cooling the reaction solution to 15, 73 mL of ethyl acetate and 12 OmL of water were added and stirred. The organic layer was separated and washed twice with 105 mL of 5% saline. After the organic layer was concentrated under reduced pressure, 75 mL of methanol was added, and the mixture was concentrated again to obtain the title compound as a brown oil (27.6 g). Example 25

(R) —2-Hydroxy-5- {4 -— [(5-Methyl-1-phenyl-1,3-thiazole-4-yl) methoxy] phenyl} Preparation of sodium pentanoate (R) —2-Hydroxy-5— {4-[(5-Methyl-2-phenyl-1-, 3-thiazol-4-yl) methoxy] phenyl} ethyl pentanoate 27.

To a mixture of 6 g and 12 OmL of methanol, 6 OmL of 2N sodium hydroxide was added dropwise at 40 ° C, and reacted at the same temperature for 1 hour. After the reaction solution was cooled to room temperature, it was allowed to stand at room temperature for 1 hour. The crystals were collected by filtration and washed once with 3 OmL of cold water and twice with 45 mL of toluene. The obtained crystals were dried under reduced pressure to give the title compound as pale yellow crystals 21.

Obtained as 7 g.

Example 26 "(R) -12-ethoxycarponyloxy-5- {4-([5-methyl-2-phenyl-1,3-thiazole-4-yl) methoxy] phenyl} pentanoic acid Manufacture of mid

(R) -2-hydroxy-1-5- (4-[(5-methyl-1-phenyl-1,3-thiazol-4-yl) methoxy] phenyl] sodium pentanoate 20.1 g and ethyl acetate To about 228 mL of the mixture, 14.7 g of ethyl chlorocarbonate and 5.04 g of triethylamine were successively added dropwise at about 15 and reacted at the same temperature for 3 hours. To the reaction solution, 10.2 mL of 25% ammonia water was added dropwise at the same temperature, and reacted at the same temperature for 30 minutes. The reaction solution was heated to room temperature and reacted at room temperature for 1 hour. Then, 95 mL of water was added, and the mixture was heated to around 40 to dissolve the crystals. After separating the aqueous layer, the ethyl acetate layer was washed with 48 mL of 10% saline. Activated carbon (1.9 g) was added to the ethyl acetate layer, and the mixture was stirred at 40 for 30 minutes. Then, the activated carbon was filtered off while hot and washed with 57 mL of ethyl acetate. The filtrate was concentrated under reduced pressure, and ethyl acetate was added to the residue to make the total amount 104.5 g. Then, the mixture was heated at 30 and 285 mL of isopropyl ether was added dropwise. After leaving the mixture at 3 for 1 hour, the crystals were filtered and washed with 95 mL of isopropyl ether. The crystals were dried under reduced pressure to give the title compound as white crystals (17.9 g). (Yield 84.0%)

Example 27

(R) —5— [3— [4— [(5-Methyl-2-phenyl-1, 3-thiazole-4_yl) methoxy] phenyl] propyl] — 1,3-oxazolidin-1,2 4—Manufacture of Zeon (R) — 2-ethoxycarbonyloxy— 5- {4-— [(5-methyl-2-phenyl-1,3-thiazol-4-propyl) methoxy] phenyl} pentanoic acid amide 16.6 g and acetonitrile To 161 mL of the suspension, 7.9 mL of DBU was added dropwise at room temperature, and reacted at room temperature for 2 hours. After adding 83 mL of water to the reaction solution at the same temperature, 33 mL of 2N hydrochloric acid was added dropwise to precipitate crystals. After allowing to stand at room temperature for 1 hour, the crystals were filtered and washed once with 83 mL of acetonitrile-monohydrate solution (1: 2) and twice with 83 mL of water. The crystals were dried under reduced pressure to obtain 14.2 g of white crude crystals of the title compound. (Yield 91.9%) ―

A mixture of 13.4 g of the crude crystals and a mixture of methanol-denatured ethanol and purified water (85:15) (156 mL) was heated to 70 to dissolve the crystals. To the resulting solution was added 0.65 g of activated carbon, and after stirring for 15 minutes, the activated carbon was filtered off while hot and washed with 39 mL of a mixture of hot methanol-denatured ethanol and purified water (85:15). After the filtrate was reheated to 70 ° C, crystals were deposited while cooling slowly. After standing for 1 hour under ice cooling, the crystals were filtered and washed with cold methanol-denatured ethanol. The crystals were dried under reduced pressure to obtain 12.6 g of white pure crystals of the title compound. (Yield 93.8) Industrial applicability

The peak ketoester of the present invention, that is, the compound (I) or a salt thereof is useful as an intermediate for synthesizing various drugs such as an oxazolidinedione derivative or a salt thereof, such as an antidiabetic agent. This is an industrially advantageous production method that can obtain the target product at high efficiency, high purity and low cost.

Claims

The scope of the claims

1. Formula (I)

[Wherein, R represents a hydrocarbon group. ] The compound represented by these, or its salt.

2. The compound according to claim 1, wherein R is an alkyl group having 1 to 4 carbon atoms.

3. The compound according to claim 1, wherein R is a methyl group or an ethyl group.

4.5- (4-Hydroxyphenyl) ethyl 2-oxopentanoate or a salt thereof.

5.5- (4-Hydroxyphenyl) methyl 2-oxopentanoate or a salt thereof.

6. Equation (II)

[Wherein, R ′ represents a hydrocarbon group. And a salt thereof and formula (III): R'OOC-COOR [wherein, R represents a hydrocarbon group; R "represents a hydrogen atom or a hydrocarbon group.] Formula (I) "characterized by condensing an ester, a salt thereof or a reactive derivative thereof, followed by a decarboxylation reaction.

[Wherein, R is as defined above. ] The manufacturing method of the compound represented by these, or its salt.

7. Equation (IV)

H0- -CH „CH ₂ CH ₂ -C0-C00R [Wherein, R is as defined above. ] The manufacturing method of the compound represented by these, or its salt.

8. Equation (IV)

C00R '

[Wherein, R and R ′ are the same or different and represent a hydrocarbon group. ] The compound represented by these, or its salt.

9. The compound according to claim 8, wherein R and R 'are a methyl group or an ethyl group.

1 0. Equation (I)

1 1. Equation (V)

12. The compound according to claim 11, wherein R is a methyl group or an ethyl group.

13. An optically active form of the compound according to claim 11.

1 4. Equation (II)

[Wherein, R ′ represents a hydrocarbon group. And a salt thereof and a formula (ΠΙ): R'OOC-COOR [wherein, R represents a hydrocarbon group; R "represents a hydrogen atom or a hydrocarbon group.] Condensed with an ester, a salt thereof or a reactive derivative thereof to obtain the formula αν)

[Wherein, R is as defined above. To produce a compound represented by the formula (V)

Rb

Ra ^ Y ^ — (CH ₂ ) n— CH-Q

[Wherein, R a represents an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group, R b represents a hydrogen atom or a dialkyl group, Y represents one CO—, —CH

(OH) —or—NRi ² — (Ri ² represents an alkyl group which may be substituted), m represents 0 or 1, n represents ◦, 1 or 2, and Q represents a leaving group. With a compound represented by the formula (VII)

[The symbols in the formula are as defined above. ] Or a salt thereof, which is hydrolyzed to give a compound of formula (ΥΙΠ)

R Y (CHJ 2

[The symbols in the formula are as defined above. To produce a compound represented by the formula: or a salt thereof, which is represented by the formula (IX): XCOORc wherein X is a halogen atom, and R c is a hydrogen atom Or a C ^ alkyl group. With the compound of formula (X) Ra- (YV- (CH „) _n

Rb

Ra- (CH ₂ ) _n -CH-0 0

[The symbols in the formula are as defined above. ] Or a salt thereof.

1 5. Ethyl (R) -2-hydroxy-5- [4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl] pentanoate or a salt thereof.

1 6. Sodium (R) -2-hydroxy-5- [4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] phenyl] pentanoate or a salt thereof.