JPH07228574A - Optically active azole derivative, its production and use thereof - Google Patents

Abstract

PURPOSE:To obtain an optically active azole derivative in high yield and short time using short steps by reacting a specific triazolone compound with a specific triazole compound. CONSTITUTION:This optically active azole derivative expressed by formula III is produced by reacting (A) a compound of formula I (R<1> is an aliphatic hydrocarbon group, an aromatic hydrocarbon group, etc., which may have substituents; Y and Z are different from each other and selected from N and methine which may have a lower alkyl as a substituent) with (B) a compound of formula II [Ar is a halogenated phenyl; R<2> is a lower alkyl or a (substituted) phenyl; (R) shows the steric configuration] in an inert solvent such as dimethylformamide preferably in the presence of a base such as an alkali metal carbonate or an alkali metal bicarbonate. An example of the azole derivative is the derivative of formula IV.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active azole derivative useful as a therapeutic agent for fungal diseases (antimycotic disease), a method for producing the same and uses thereof.

[0002]

European Patent Publication No. 567982 describes a method for producing an optically active azole derivative having a triazolone group by reacting a triazolone derivative with an oxirane triazole derivative in the presence of sodium hydride.

[0003]

There is a demand for an industrial production method by which an optically active azole derivative can be obtained in a short time, a short process, a high yield and a high purity.

[0004]

The present invention provides (1) general formula [I]

[Chemical 8]

[In the formula, R ¹ represents an aliphatic or aromatic hydrocarbon group which may have a substituent, or an aromatic heterocyclic group which may have a substituent, and Y and Z represent Differently represent a methine group which may be substituted with a nitrogen atom or a lower alkyl group] or a salt thereof and a general formula [II
I]

[0006]

[Chemical 9]

[Wherein Ar represents a halogenated phenyl group,
R ² is a lower alkyl group or an optionally substituted phenyl group, and (R) represents a steric configuration] to produce a compound of the general formula [IV]

[0008]

[Chemical 10]

[Wherein each symbol has the same meaning as described above]
A method of producing a compound represented by the general formula [IV] or a salt thereof, which comprises obtaining a compound represented by the formula: or a salt thereof, (2) a general formula [I]

[0010]

[Chemical 11]

[Wherein R ¹ represents an aliphatic or aromatic hydrocarbon group which may have a substituent, or an aromatic heterocyclic group which may have a substituent, and Y and Z are Differently represent a methine group which may be substituted with a nitrogen atom or a lower alkyl group] or a salt thereof and a general formula [I
I]

[0012]

[Chemical 12]

[Wherein Ar represents a halogenated phenyl group,
(R) and (S) each have a steric configuration] in the presence of an alkali metal carbonate to give a compound represented by the general formula [IV]

[0014]

[Chemical 13]

[Wherein each symbol has the same meaning as described above]
A method for producing a compound represented by the general formula [IV] or a salt thereof, which comprises obtaining a compound represented by the formula [IV]

[0016]

[Chemical 14]

[Wherein R ¹ represents an aliphatic or aromatic hydrocarbon group which may have a substituent, or an aromatic heterocyclic group which may have a substituent, and Y and Z are Or a methine group which may be substituted with a nitrogen atom or a lower alkyl group, Ar 'is a monofluorophenyl group, and (R) is a steric configuration] or a salt thereof, and (4 ) An antifungal agent comprising the compound represented by the above general formula [IV ′] or a pharmaceutically acceptable salt thereof.

The details of each definition of the above general formula are as follows. Regarding the general formulas [I], [IV] and [IV ′], examples of the aliphatic hydrocarbon group represented by R ¹ which may have a substituent include an alkyl, cycloalkyl, Examples thereof include an alkenyl or alkynyl group. As the alkyl group, a linear or branched alkyl group having 1 to 12 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, heptyl,
Examples thereof include octyl, nonyl, decyl, dodecyl, etc., and particularly lower alkyl groups having 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.). Is preferred. Examples of the cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., and particularly 3 to 8 carbon atoms.
A cycloalkyl group of 6 (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) is preferable. Examples of the alkenyl group include alkenyl groups having 2 to 4 carbon atoms, such as vinyl, propenyl, butenyl, etc., and alkenyl groups having 2 to 3 carbon atoms (eg, vinyl, propenyl, etc.) are particularly preferable. Examples of the alkynyl group include alkynyl groups having 2 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, etc., and particularly 2 to 4 carbon atoms.
Preferred are alkynyl groups of 3 (eg, ethynyl, propynyl, etc.).

Regarding the general formulas [I], [IV] and [IV '], examples of the aromatic hydrocarbon group in the aromatic hydrocarbon group which may have a substituent represented by R ¹ include, for example, carbon. The aryl group of several 6-14 is mentioned. Examples of the aryl group include phenyl, naphthyl, biphenylyl,
Anthryl, indenyl, etc. are mentioned, and an aryl group having 6 to 10 carbon atoms (eg, phenyl, naphthyl, etc.) is particularly preferable.

In the general formulas [I], [IV] and [IV '], the aromatic heterocyclic group represented by R ¹ and optionally having a substituent is a nitrogen atom. , An aromatic heterocyclic group containing at least one hetero atom selected from a sulfur atom and an oxygen atom. The aromatic heterocyclic group may be condensed with a benzene ring or a 5- or 6-membered heterocyclic ring. Examples of such an aromatic heterocyclic group include imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, thiazolyl, thiadiazolyl, thienyl, furyl, pyrrolyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, and the like, and benzimidazolyl, Examples thereof include fused aromatic heterocyclic groups such as imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolinyl and indolyl. As the aromatic heterocyclic group, especially 1 to optionally selected from a nitrogen atom, a sulfur atom and an oxygen atom.
A 5- or 6-membered aromatic heterocyclic group containing 3 hetero atoms (eg, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, etc.) is preferable.

Regarding R ¹ , the substituent in the aliphatic or aromatic hydrocarbon group which may have a substituent or the aromatic heterocyclic group which may have a substituent is, for example, a hydroxyl group or an ester. Optionally substituted carboxy group (eg, carboxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, and other alkoxycarbonyl having 1 to 6 carbon atoms), nitro group, amino group, acylamino group (eg, acetylamino, propionylamino) , An alkanoylamino having 1 to 10 carbon atoms such as butyrylamino), an amino group mono- or di-substituted with an alkyl having 1 to 10 carbon atoms (eg, methylamino, dimethylamino, diethylamino, dibutylamino, etc.), substituted Optionally substituted 5- or 6-membered heterocyclic group (eg, pyrrolidinyl, morpholino, piperi Bruno, piperazinyl, 4-benzyl-1-piperazinyl, 4-acetyl-1-piperazinyl, 4- (4-methoxyphenyl) -1-piperazinyl, 4- (4-trifluoromethoxyphenyl) -1-
Piperazinyl, 4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -1-piperazinyl, 4-
[4- (2,2,2-trifluoroethoxy) phenyl] -1-piperazinyl, 4- [4- (2,2,3,
3,3-Pentafluoropropoxy) phenyl] -1-
Piperazinyl, 4- (4-trifluoromethyl) phenyl-1-piperazinyl, 4- [4- (2,2,3,3-
Tetrafluoropropoxy) phenyl] -1-piperazinyl, pyrazolidinyl, perhydroazepinyl, etc.), an alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy,
Butoxy etc.), halogen (eg fluorine, chlorine, bromine etc.), halogeno-alkyl group having 1 to 6 carbon atoms (eg trifluoromethyl, dichloromethyl, trifluoroethyl etc.), halogeno-having 1 to 6 carbon atoms Alkoxy groups (eg trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,
2,3,3-tetrafluoropropoxy, 2,2,3
3,3-pentafluoropropoxy, 2,2,3,3
4,4,5,5-octafluoropentoxy, 2-fluoroethoxy, etc.), oxo group, thioxo group, mercapto group, alkylthio group having 1 to 6 carbon atoms (eg, methylthio,
Ethylthio, butylthio, etc.), an alkylsulfonyl group having 1 to 6 carbon atoms (eg, methanesulfonyl, ethanesulfonyl, butanesulfonyl, etc.), an alkanoyl group having 1 to 10 carbon atoms (eg, acetyl, formyl, propionyl, butyryl, etc.) Can be mentioned. The number of the above-mentioned substituents is preferably 1 to 3, and more preferably 1 to 2.

R ¹ is preferably an aromatic hydrocarbon group which may have a substituent, and particularly preferably an aryl group which may have a substituent (particularly a phenyl group). R ¹ is more preferably halogeno-having 1 to 6 carbon atoms.
6-10 carbon atoms which may be substituted with an alkoxy group of
And an phenyl group substituted with a halogeno-alkoxy group having 1 to 6 carbon atoms is particularly preferable.

In the general formulas [I], [IV] and [IV '], the lower alkyl group in the methine group which may be substituted with a lower alkyl group represented by Y or Z has 1 to 4 carbon atoms. Linear or branched alkyl groups (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.) are preferred, with methyl being particularly preferred. Y or Z
Examples of the methine group which may be substituted with a lower alkyl group represented by include methine, ethylidyne, propyridine, butyridine and the like, and methine and ethylidyne are particularly preferable.

In the general formulas [II], [III] and [IV], the halogenated phenyl group represented by Ar has 1 to 3 halogen atoms selected from fluorine, chlorine, bromine, iodine and the like. Phenyl groups such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluoro Phenyl, 2,
4,6-trifluorophenyl, 4-bromophenyl, etc. are mentioned, and a phenyl group substituted with 1 or 2 fluorine atoms is particularly preferable. The halogenated phenyl group is
Particularly preferred are 2-fluorophenyl, 4-fluorophenyl and 2,4-difluorophenyl. Regarding the general formula [IV ′], 2-fluorophenyl and 4-fluorophenyl are preferable as the monofluorophenyl group represented by Ar ′.

In the general formula [III], the lower alkyl group represented by R ² is a linear or branched alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-
Butyl, tert-butylmethyl, etc.), with methyl being particularly preferred. Examples of the optionally substituted phenyl group represented by R ² include phenyl and p
-Tolyl, p-chlorophenyl, p-nitrophenyl and the like can be mentioned, with p-tolyl being particularly preferred.

A compound represented by the general formula [IV ′] (hereinafter,
Preferred examples of the compound [IV ′]) are 2
-[(1R, 2R) -2- (2-fluorophenyl)-
2-hydroxy-1-methyl-3- (1H-1,2,4
-Triazol-1-yl) propyl] -4- [4-
(2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone,
2-[(1R, 2R) -2- (2-fluorophenyl)
-2-Hydroxy-1-methyl-3- (1H-1,2,
4-triazol-1-yl) propyl] -4- (4-
Trifluoromethylphenyl) -3- (2H, 4H)-
1,2,4-triazolone, 2-[(1R, 2R) -2
-(2-Fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-trifluoromethoxyphenyl) -3 (2H , 4H) -1,2,4-triazolone, 2-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone,
2-[(1R, 2R) -2- (2-fluorophenyl)
-2-Hydroxy-1-methyl-3- (1H-1,2,
4-triazol-1-yl) propyl] -4- [4-
(1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone,
2-[(1R, 2R) -2- (2-fluorophenyl)
-2-Hydroxy-1-methyl-3- (1H-1,2,
4-Triazol-1-yl) propyl] -5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone , 4-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3- (1H
-1,2,4-triazol-1-yl) propyl]-
2- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone, 4-[(1R, 2R) -2- (2- Fluorophenyl) -2-hydroxy-1-methyl-3- (1H
-1,2,4-triazol-1-yl) propyl]-
2- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone, 2-[(1R, 2R) -2- (4- Fluorophenyl) -2-hydroxy-1-methyl-3- (1H
-1,2,4-triazol-1-yl) propyl]-
4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone, 2-[(1R, 2R) -2- (4- Fluorophenyl) -2-hydroxy-1-methyl-3- (1H
-1,2,4-triazol-1-yl) propyl]-
4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone, 2-[(1R, 2R) -2- (4- Fluorophenyl) -2-hydroxy-1-methyl-3- (1H
-1,2,4-triazol-1-yl) propyl]-
5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,
2,4-triazolone, 4-[(1R, 2R) -2-
(4-Fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- [4- (1,1,2,2-tetra Fluoroethoxy) phenyl] -3 (2H, 4H)-
1,2,4-triazolone, 4-[(1R, 2R) -2
-(4-Fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- [4- (2,2,3,3- Tetrafluoropropoxy) phenyl] -3 (2H, 4H)-
1,2,4-triazolone and the like can be mentioned.

Preferred specific examples of the compound represented by the general formula [IV] (hereinafter referred to as compound [IV]) are the same as the preferred specific examples of the compound represented by the general formula [IV ']. To be In addition to the above, as a preferable example of the compound [IV], 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2, Four
-Triazolone, 4-[(1R, 2R) -2- (2,4
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
Propyl] -2- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,
2,4-triazolone, 4-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -2- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H)
-1,2,4-triazolone, 2-[(1R, 2R)-
2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -5-methyl-4- [4-
Examples include (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone.

The compound [IV] or a salt thereof is a compound represented by the general formula [I] (hereinafter referred to as compound [I]).
Alternatively, it can be produced by reacting a salt thereof with a compound represented by the general formula [III] (hereinafter referred to as compound [III]). This reaction is carried out using compound [III] 1
The compound [I] or a salt thereof is used in an amount of about 1 to mol.
It is carried out by reacting about 4 mol, preferably about 1.5 to about 2 mol.

This reaction is usually carried out in a solvent that does not interfere with the reaction. Examples of the solvent that does not inhibit the reaction include ketones such as acetone, sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, aromatic hydrocarbons such as benzene, toluene and xylene. , Halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, esters such as ethyl acetate, dimethylformamide, acetamide, dimethylacetamide, 1-methyl-2-pyrrolidone, 1,3
Examples include amides such as dimethyl-2-imidazolidinone. The solvent is preferably a sulfoxide such as dimethyl sulfoxide or an amide such as dimethylformamide, acetamide, dimethylacetamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone. The solvent is more preferably dimethylformamide, acetamide, dimethylacetamide, 1-
Amides such as methyl-2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone are preferable, and dimethylformamide is particularly preferable. These solvents may be used alone or as a mixture of two or more kinds at an appropriate ratio.

The amount of the solvent used is about 25 times by weight or less, preferably about 5 to about 25 times by weight, and particularly preferably about 10 to about 25 times by weight based on the compound [III].
The reaction temperature is preferably about 50 to about 110 ° C, particularly preferably about 70 to about 100 ° C. The reaction time is preferably about 20 to about 150 hours, particularly preferably about 30 to about 100 hours.

This reaction is preferably carried out in the presence of a base. Examples of the base include alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydroxides, alkali metal hydrides, alkali metal salts of organic carboxylic acids, alkali metal alcoholates, tetrabutylammonium fluoride and the like. The base is preferably an alkali metal carbonate, an alkali metal hydrogen carbonate or an alkali metal hydroxide, and more preferably an alkali metal carbonate or an alkali metal hydrogen carbonate. The base is particularly preferably an alkali metal carbonate.

Examples of the alkali metal carbonate include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, and potassium carbonate is particularly preferable. Examples of the alkali metal hydrogencarbonate include lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like. As the alkali metal hydroxide,
Examples thereof include lithium hydroxide, potassium hydroxide, sodium hydroxide and the like. As the alkali metal hydride,
Examples thereof include potassium hydride and sodium hydride. Examples of the organic carboxylic acid alkali metal salt include sodium acetate. Examples of alkali metal alcoholates include sodium methylate and potassium te.
Examples include rt-butyrate. The amount of the base used is preferably about 1 to about 10 times (molar ratio), and particularly preferably about 1.5 to about 4 times (molar ratio) the amount of the compound [I].

The method of adding the above base is not particularly limited.
For example, compound [I] or a salt thereof and compound [III]
May be added to the solvent and then the base may be added, or the compound [I] or a salt thereof and the compound [III] may be added to the mixture obtained by adding the base to the solvent, or the solvent may be added to the solvent. The compound [I] or a salt thereof, the compound [III] and a base may be sequentially added. Further, the compound [III] and a base may be added to the solvent and the mixture may be heated at about 60 to about 100 ° C. for about 30 minutes to about 2 hours, and then the compound [I] or a salt thereof may be added.

The compound [IV] or its salt is obtained by reacting the compound [I] or its salt with a compound represented by the general formula [II] (hereinafter referred to as compound [II]) in the presence of an alkali metal carbonate. It can also be produced by reacting with. This reaction is carried out by reacting 1 mol of compound [II] with about 1 to about 4 mol, preferably about 1.5 to about 2 mol, of compound [I] or a salt thereof.

Examples of the alkali metal carbonate used in this reaction include lithium carbonate, sodium carbonate,
Examples thereof include potassium carbonate and cesium carbonate, and potassium carbonate is particularly preferable. In this reaction, for example, alkali metal hydrogen carbonate (eg, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxide (eg, lithium hydroxide, potassium hydroxide, sodium hydroxide, etc.) ) Etc. can also be used. The amount of the alkali metal carbonate used is based on the compound [I].
The amount is preferably about 1 to about 10 times (molar ratio), and particularly preferably about 1.5 to about 4 times (molar ratio).

This reaction is usually carried out in a solvent that does not interfere with the reaction. Examples of the solvent used in this reaction include ketones such as acetone, sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, aromatics such as benzene, toluene and xylene. Hydrocarbons, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, esters such as ethyl acetate, dimethylformamide, acetamide,
Dimethylacetamide, 1-methyl-2-pyrrolidone,
Examples thereof include amides such as 1,3-dimethyl-2-imidazolidinone. The solvent is preferably a sulfoxide such as dimethyl sulfoxide or dimethylformamide, acetamide, dimethylacetamide, 1-methyl-2-
Amides such as pyrrolidone and 1,3-dimethyl-2-imidazolidinone. The solvent is more preferably dimethylformamide, acetamide, dimethylacetamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-
Amides such as 2-imidazolidinone are preferred, and dimethylformamide is particularly preferred. These solvents may be used alone or as a mixture of two or more kinds at an appropriate ratio. The amount of the solvent used is about 25 times by weight or less, preferably about 5 to about 25 times by weight, relative to the compound [II].
Particularly preferably, it is about 10 to about 25 times by weight. The method for adding the alkali metal carbonate is not particularly limited. For example, the compound [I] or a salt thereof and the compound [II] may be added to the solvent and then the alkali metal carbonate may be added.
Compound [I] or a salt thereof and compound [II] may be added to a mixed solution obtained by adding an alkali metal carbonate to a solvent, or compound [I] or a salt thereof, compound [II], Alkali metal carbonate may be added sequentially.

The reaction temperature is preferably about 50 to about 110.
C., particularly preferably about 70 to about 100.degree. The reaction time is preferably about 20 to about 150 hours, particularly preferably about 30 to about 100 hours.

The compound [IV] or [IV '] is also used as a salt. Such salts include pharmacologically acceptable salts, for example, salts with inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), organic acids (eg acetic acid, tartaric acid, Citric acid, fumaric acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid, etc.) and the like. Compound [IV] or [I obtained by the above production method
V ′] or a salt thereof can be isolated and purified from the reaction mixture by means known per se, for example, means such as extraction, concentration, neutralization, filtration, recrystallization, chromatography and the like. The salt of the compound [IV] or [IV ′] is
It can be produced by a means known per se, for example, by adding the above-mentioned inorganic acid or organic acid to compound [IV] or [IV ′].

The compound [I] which is the starting material compound of the present invention or a salt thereof can be produced by a method known per se, for example, the method described in EP-A-567982 or a method analogous thereto. Also,
In the compound [I] or a salt thereof, the compound [IX] or a salt thereof in which Y is CH and Z is N can also be produced, for example, by the method shown by the following reaction scheme. As the salt of the compound [I], its alkali metal salt (eg, lithium salt, sodium salt, potassium salt, cesium salt, etc.) is used.

[0040]

[Chemical 15] [In the formula, each symbol has the same meaning as described above.]

Further, the raw material compound [II],
[III] or a salt thereof can be obtained by a method known per se, for example, JP-A-4-74168 and JP-A-5-23003.
It can be produced by the method described in JP-A-8, European Patent Application Publication No. 548553, or the like, or a method similar thereto. Particularly, in the compound [III] or a salt thereof, the compound [XI] or a salt thereof in which R ² is a p-tolyl group can be produced, for example, by the method shown by the following reaction scheme.

[0042]

[Chemical 16]

[Wherein each symbol has the same meaning as described above]
The starting compound [X] or a salt thereof in this reaction can be produced by, for example, the method described in JP-A-5-230038, European Patent Application Publications 548553 and 567982, or a method analogous thereto.

As the salts of the starting compounds such as the compounds [II] and [III], the same salts as the salts of the compounds [IV] or [IV '] can be used. The compound [I], [II], [III] or a salt thereof obtained by the above method can be obtained from the reaction mixture by a means known per se, for example, extraction, concentration, neutralization,
It can be isolated and purified by using means such as filtration, recrystallization and chromatography.

The compound [IV], [IV '] or a salt thereof obtained by the production method of the present invention has low toxicity, strong antibacterial activity against fungi and a broad antifungal spectrum (eg against Candida, Aspergillus, Cryptococcus). (Eg, humans, livestock,
It can be used for the prevention and treatment of fungal infections (eg, poultry, etc.) (eg, candidiasis, aspergillosis, cryptococcosis, etc.). The compounds [IV], [IV '] or salts thereof can also be used as an antifungal agent for agriculture.

When the compound [IV ′] or a salt thereof is administered to a human, it is orally mixed with an appropriate pharmacologically acceptable carrier, excipient or diluent, and then administered orally (eg, powder). , Granules, tablets, capsules, etc.), parenteral administration agents (eg injections, external preparations (nasal administration preparations, transdermal preparations etc.), suppositories (eg rectal suppositories, vaginal suppositories etc.) Etc.] and the like can be safely administered orally or parenterally. These preparations can be produced by a method known per se which is generally used in the preparation process.

For example, the compound [IV ′] or a salt thereof can be stored as a dispersant [eg, TWEEN 80 (manufactured by Atlas Powder Co., USA), HCO60 (manufactured by Nikko Chemicals), carboxymethylcellulose, sodium alginate]. Agents (eg: methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.), isotonic agents (eg: sodium chloride, glycerin, sorbitol, glucose, etc.), aqueous injections, olive oil, sesame oil, peanut oil, cottonseed oil It can be dissolved in, suspended in, or emulsified with a vegetable oil such as corn oil, propylene glycol, etc., and molded into an oily injection to give an injection.

For example, to prepare the compound [IV ′] or a salt thereof for oral administration, the compound [IV ′] or a salt thereof can be prepared by a method known per se, for example, an excipient (eg lactose, sucrose, starch). Etc.), disintegrants (eg starch, calcium carbonate etc.), binders (eg starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose etc.), lubricants (eg:
Oral administration preparation by adding talc, magnesium stearate, polyethylene glycol 6000, etc.) and compression-molding, and then coating with a method known per se for the purpose of taste masking, enteric coating or sustainability, if necessary. Can be As the coating agent, for example, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose,
Hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (produced by Rohm,
West Germany, methacrylic acid / acrylic acid copolymerization), and pigments such as titanium oxide and red iron oxide are used.

For example, in order to use compound [IV '] or a salt thereof as an external preparation, compound [I] can be prepared by a method known per se.
V ′] or a salt thereof can be used as a solid, semi-solid or liquid external preparation. For example, as the above solid, the compound [IV ′] or a salt thereof is used as it is, or as an excipient (eg glucose, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg natural gums). ,
Cellulose derivative, acrylic acid polymer, etc.) are added and mixed to obtain a powdery composition. As the above liquid,
Almost the same as in the case of injection, it is an oily or aqueous suspension. In the case of a semi-solid state, an aqueous or oily gel agent or an ointment type is preferable. Also, these are all
A pH adjuster (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), a preservative (eg: paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.) and the like may be added. Specifically, for example, vaseline,
Based on lanolin, usually about 0.1-10 per 1 g
As an ointment containing 0 mg, it can be used for sterilization and disinfection of skin or mucous membranes.

For example, to prepare the compound [IV ′] or a salt thereof as a suppository, the compound [I] can be prepared by a method known per se.
V ′] or a salt thereof can be made into an oily or aqueous solid, semisolid or liquid suppository. Examples of the oily base used in the above composition include glycerides of higher fatty acids [eg: cacao butter, Witepsols (manufactured by Dynamite Nobel), etc.], intermediate fatty acids [eg: migliols (manufactured by Dynamite Nobel), etc.] , Vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like. Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include
Examples thereof include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers and the like.

The dose of the compound [IV ′] or a salt thereof will vary depending on the state of infection, administration route, etc., but is, for example, an adult (body weight: 50 k) for the purpose of treating candida infection.
g) about 0.01 to 1 by oral administration when administered to a patient
00 mg / kg / day, preferably about 0.1-50 mg /
kg / day. More preferably about 0.1-20 mg
/ Kg / day.

When used as an antifungal agent for agriculture, the compound [IV '] or a salt thereof is dissolved or dispersed in a suitable liquid carrier (eg solvent), and a suitable solid carrier (eg diluent, (A filler, etc.) or adsorbed on it, and if necessary, further emulsifier,
Suspensions, spreading agents, penetrants, wetting agents, thickeners, stabilizers, etc. are added and used as dosage forms such as emulsions, wettable powders, powders and granules. These formulations can be prepared by a method known per se. The amount of the compound [IV ′] or a salt thereof used is, for example, about 25 to 150 g, more preferably about 40 to 8 per 1 are of paddy when controlling rice blast disease.
It is 0 g.

As the liquid carrier to be used, for example, water, alcohols (eg methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethylene glycol etc.), ethers (eg dioxane, tetrahydrofuran etc.), aliphatics Hydrocarbons (eg kerosene, kerosene, fuel oil etc.), aromatic hydrocarbons (eg benzene, toluene etc.), halogenated hydrocarbons (eg methylene chloride, chloroform etc.), acid amides (eg: Dimethylformamide, dimethylacetamide, etc.), esters (eg ethyl acetate, butyl acetate, etc.),
Solvents such as nitric acid (eg acetonitrile, propionitrile etc.) are suitable. These liquid carriers can be used alone or in combination of two or more at an appropriate ratio. As the solid carrier, vegetable powder (eg soybean powder, tobacco powder, wheat flour etc.), mineral powder (eg kaolin, bentonite etc.), alumina, sulfur powder, activated carbon etc. are used. These solid carriers can be used alone or in combination of two or more at an appropriate ratio.

[0054]

EXAMPLES The present invention will be specifically described below with reference to reference examples and examples, but the present invention is not limited thereto. ¹
The 1 H-NMR spectrum was measured using Varian Gemini 200 (200 MH) using tetramethylsilane as an internal standard.
z) type spectrometer, and all δ values are shown in ppm. In the mixed solvent, the value shown in parentheses is the volume mixing ratio of each solvent. % Means percent by weight unless otherwise stated. The symbols in the examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, tt: triple triplet, m: multiplet, quintet: quintet, septet: septet, br: wide, J: Coupling constant

Reference Example 1 A mixture of 4- (1,1,2,2-tetrafluoroethoxy) aniline (29.54 g) and concentrated hydrochloric acid (141 ml) was stirred at -10 ° C with sodium nitrite (1
A solution of 0.24 g) in water (50 ml) was added dropwise. After stirring under ice cooling for 30 minutes, stannous chloride (128.6g)
A concentrated hydrochloric acid (130 ml) solution of was added under ice cooling and stirred for 30 minutes. A solution of sodium hydroxide (200 g) in water (300 ml) was added to the reaction solution to adjust the pH to 12-14.
The insoluble matter was filtered off on Celite and the filtrate was extracted with dichloromethane (300 ml x 3). The extracts were combined, washed with water (300 ml), and dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, 4- (1,1,2,2
-Tetrafluoroethoxy) phenylhydrazine (2
7.2 g) was obtained as an oil. This product was dissolved in ethanol (50 ml), acetone (16 ml) was added, and the mixture was stirred at room temperature for 30 min. After distilling off the solvent under reduced pressure,
The residue was dissolved in 75% acetic acid aqueous solution (200 ml), potassium cyanate (9.86 g) was added, and the mixture was stirred at 60 ° C. for 1 hr. After allowing to cool, water (200 ml) was added to the reaction solution, and the mixture was neutralized with aqueous ammonia under ice cooling (pH 7.0).
The precipitated crystals were collected by filtration, water (100 ml), hexane (1
(00 ml) and dried under reduced pressure to give 3,3-dimethyl-1- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -1,2,4-triazolidine-5.
-One (24.1 g) was obtained as light brown powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.49 (6H, s), 4.55 (1H, s),
5.29 (1H, s), 5.89 (1H, tt, J = 53Hz, J = 2.8Hz), 7.16 (2H,
d, J = 8.8Hz), 7.72 (2H, d, J = 8.8Hz)

This product (24.1 g) was suspended in water (160 ml), concentrated hydrochloric acid (13.3 ml) was added, and then benzaldehyde (12.65 g) was added. The reaction solution was stirred at 80 ° C. for 2 hours and 30 minutes and allowed to cool, and the precipitated crystals were collected by filtration. The obtained crystals were mixed with water (100 ml) and hexane (200
After being washed with (ml), it was dried under reduced pressure to obtain benzaldehyde 2- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] semicarbazone (25.6 g: light brown powder crystal). ¹ H-NMR (CDCl ₃ ) δ: 5.96 (1H, tt, J = 53Hz, J = 2.8
Hz), 7.11-7.72 (10H, m) Dissolve this product (15g) in ethanol (200ml),
2,4-Dinitrophenylhydrazine monohydrate (13.
65 g) was added, followed by concentrated sulfuric acid (0.5 ml). The obtained mixed liquid was stirred at 70 ° C. for 17 hours, allowed to cool, the insoluble matter was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was chromatographed on silica gel (eluent: ethyl acetate /
When purified by subjecting to methanol = 5/1), 2- [4-
(1,1,2,2-Tetrafluoroethoxy) phenyl] semicarbazide (8.68 g) was obtained as colorless prism crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.31 (2H, s), 5.64 (2H, s),
5.89 (1H, tt, J = 53Hz, J = 2.8Hz), 7.20 (2H, d, J = 9Hz), 7.4
9 (2H, d, J = 9Hz)

This product (3.15 g) and formamidine acetate (6.11 g) were dissolved in dimethylformamide (25 ml), and the mixture was stirred at room temperature for 1 hr. Acetic acid (3.5
2 g) was added, and the mixture was stirred at 80 ° C. for 6 hr. After cooling down,
It was poured into ice water (50 ml) and extracted with ethyl acetate (25 ml × 3). The extracts were combined, washed with water (25 ml × 3), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/1 → 3/2), and crystallized from diisopropyl ether to give 2
-[4- (1,1,2,2-tetrafluoroethoxy)
Phenyl] -3 (2H, 4H) -1,2,4-triazolone (2.16 g) was obtained as colorless powder crystals. mp 192-193 ° C. Elemental analysis _{C 10 H 7 F 4 N 3} O 2 Calculated: C, 43.33; H, 2.55 ; N,
15.16 Found: C, 43.26; H, 2.54; N,
15.13 ¹ H-NMR (d ₆ -DMSO) δ: 6.81 (1H, tt, J = 49.8H
z, J = 1.8Hz), 7.37 (2H, d, J = 8.4Hz), 8.00 (2H, d, J = 8.4H)
z), 8.15 (1H, s)

Reference Example 2 When 4- (2,2,3,3-tetrafluoropropoxy) aniline was used as a starting material and the reaction was carried out according to the method described in Reference Example 1, 2- [4- (2,2 2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H)-
1,2,4-triazolone was obtained as colorless powder crystals. mp 186-189 ° C. Elemental analysis value Calculated value as C ₁₁ H ₉ F ₄ N ₃ O ₂ : C, 45.37; H, 3.12; N,
14.43 Found: C, 45.62; H, 3.18; N,
14.39 ¹ H-NMR (d ₆ -DMSO) δ: 4.60 (2H, t, J = 12.8H
z), 6.68 (1H, tt, J = 52.2Hz, J = 5.6Hz), 7.13 (2H, d, J = 9H
z), 7.81 (2H, d, J = 9Hz), 8.08 (1H, s)

Reference Example 3 60% oily sodium hydride (3.52 g) was dispersed in dimethyl sulfoxide (60 ml), and trimethylsulfoxonium iodide (21.14) was added in a nitrogen stream under ice cooling.
g) was added in small portions. The reaction mixture was stirred at room temperature for 1 hr, and dichloromethane (484 ml) was added. Ice-cooling again, (2R) -2 ', 4'-difluoro-2- (3,4,
A solution of 5,6-tetrahydro-2H-pyran-2-yloxy) propiophenone (20 g, 98.7% ee) in dichloromethane (67 ml) was added over 10 minutes, and the mixture was further stirred at room temperature for 2 hours. Cold water (500 ml) was added to the reaction solution, and the dichloromethane layer was separated. The dichloromethane layer was washed with water (100 ml × 2) and then saturated brine (100 ml), and dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, 2- (2,4-difluorophenyl) -2-[(1R) -1- (3,4,5,5) was obtained as a crude product.
6-Tetrahydro-2H-pyran-2-yloxy) ethyl] oxirane (21.4 g, containing an oil of 60% oily sodium hydride) was obtained as a pale yellow oil.

This product (21.4 g), 1H-1,2,4-
Triazole (10.18 g) and potassium carbonate (3
0.6 g) was added to dimethylformamide (180 ml), and the mixture was heated with stirring at 80 ° C. for 12 hours. After cooling the reaction mixture, it was poured into ice water (400 ml) and washed with ethyl acetate (2 ml).
It was extracted with 50 ml × 2). The ethyl acetate layer was added to water (250 ml)
X2), followed by washing with saturated saline (250 ml), drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure.
The residue was chromatographed on silica gel (eluent: ethyl acetate / hexane = 2/1 → ethyl acetate / acetone = 1)
When purified by 0/1), (3R) -2- (2,4-difluorophenyl) -3- (3,4,5,6-tetrahydro-2H-pyran-2-yloxy) -1- (1H-
1,2,4-Triazol-1-yl) -2-butanol (19.8 g) was obtained as a pale yellow oil. This product (19.8 g) is dissolved in methanol (170 ml) and p
-Toluenesulfonic acid monohydrate (10.83 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with an aqueous potassium carbonate solution (potassium carbonate 3.89 g / water 30 ml) and then concentrated under reduced pressure at 35 ° C or lower. Water (20m) on the residue
l) was added, and the mixture was extracted with ethyl acetate (100 ml × 3).
The ethyl acetate layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The diol form (12.34 g) was obtained as a white solid.

This product (12.1 g) was added to ethyl acetate (80 m
l) and heated at 80 ° C. to dissolve. 12 at room temperature
After standing for a time, the precipitated crystals were removed by filtration, and the crystal part was washed with ethyl acetate (5 ml). The filtrate and washings were combined and evaporated under reduced pressure, diisopropyl ether (60 ml) was added to the obtained residue, and the mixture was stirred under ice-cooling for 1 hr. The precipitated crystals were collected by filtration, washed with diisopropyl ether (5 ml) and dried to give (2R, 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole-1. -Yl) -2,3-butanediol (9.0
g) was obtained.

Reference Example 4 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-2,3-butanediol (2 g: JP-A-4-7416
8 and JP-A-5-230038 or the method described in Reference Example 3) was dissolved in pyridine (10 ml), and p-toluenesulfonyl chloride (1.58 g) was added under ice cooling. ) Was added. The reaction solution is cooled under ice for 30
The mixture was stirred for 20 minutes at room temperature for 20 minutes. Water (2 ml) was added under ice cooling, and the mixture was stirred under ice cooling for 15 minutes and at room temperature for 15 minutes, poured into ice water (100 ml), and extracted with ethyl acetate (50 ml × 3). Combine the extracts and add 0.5N hydrochloric acid (50 ml x
4), water (50 ml), 0.5N sodium hydroxide (50
ml) followed by water (50 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (eluent:
Purification by subjecting to dichloromethane / ethyl acetate = 2/1) gave (2R, 3R) -2- (2,4-difluorophenyl) -3- (p-toluenesulfonyloxy) -1-.
(1H-1,2,4-triazol-1-yl) -2-
Butanol (2.3 g, 73% yield) was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, d, J = 6.6Hz), 2.4
7 (3H, s), 4.64 (1H, d, J = 14Hz), 4.82 (1H, s), 4.91 (1H, d,
J = 14Hz), 5.15 (1H, q, J = 6.6Hz), 6.68-6.78 (2H, m), 7.27
-7.45 (1H, m), 7.38 (2H, d, J = 8Hz), 7.76 (1H, s), 7.83 (1
H, s), 7.85 (2H, d, J = 8Hz)

Reference Example 5 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-2,3-Butanediol (2g) was dispersed in dichloromethane (20ml). Triethylamine (1.14 ml) was added under ice cooling, and then methanesulfonyl chloride (0.63 ml) was added. The reaction mixture was stirred at room temperature for 45 minutes and then washed with water (20 ml) and saturated brine (20 ml). The dichloromethane layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / dichloromethane = 4/1) and then crystallized from dichloromethane-diisopropyl ether to give (2R, 3
R) -2- (2,4-Difluorophenyl) -3-methanesulfonyloxy-1- (1H-1,2,4-triazol-1-yl) -2-butanol (2.1 g, yield 81% ) Was obtained as colorless powder crystals. mp 115-116 ° C. [α] ²⁰ _D- 71.9 ° (c = 1, in methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 6.6Hz), 3.1
1 (3H, s), 4.68 (1H, d, J = 14.2Hz), 5.03 (1H, d, J = 14.2Hz),
5.07 (1H, s), 5.28 (1H, q, J = 6.6Hz), 6.71-6.84 (1H, m),
7.40-7.53 (2H, m), 7.79 (1H, s), 7.87 (1H, s) Elemental analysis value Calculated as C ₁₃ H ₁₅ F ₂ N ₃ O ₄ S: C, 44.95; H, 4. 35; N,
12.10 Found: C, 44.87; H, 4.29; N,
12.19

Example 1 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -4
-(4-Methylthiophenyl) -3 (2H, 4H)-
Production of 1,2,4-triazolone

[0065]

[Chemical 17]

(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane (3.
29 g), 4- (4-methylthiophenyl) -3 (2
H, 4H) -1,2,4-Triazolone (4.0 g) and potassium carbonate (powder: 4.5 g) were added to N, N-dimethylformamide (30 ml), and the mixture was stirred at 80
Heat at 24 ° C. for 24 hours, then at 100 ° C. for 4 hours. After cooling the reaction solution, it was diluted with ethyl acetate (100 ml) and added to ice water (100 ml) to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (50 ml x 2). The ethyl acetate layers were combined, 0.5N aqueous sodium hydroxide solution (50 ml x 3),
It was washed with 1N hydrochloric acid (50 ml) and then with saturated saline (50 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 3/2 → ethyl acetate), and crystallized from diisopropyl ether-hexane (2: 1) to give the title compound (2 0.86 g, yield 48%) was obtained as colorless crystals. mp 151-153 ° C

Example 2 4-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -2
-[4- (2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0068]

[Chemical 18]

(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane (3.
6 g), 2- [4- (2,2,3,3-tetrafluoropropoxy) phenyl) -3 (2H, 4H) -1,2,
4-Triazolone (8.33 g) and potassium carbonate (powder form: 9.88 g) were added to N, N-dimethylformamide (60 ml), and the mixture was heated with stirring at 80 ° C. for 64 hours. After cooling the reaction solution, it was diluted with ethyl acetate (200 ml) and added to ice water (200 ml) to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml x 2). The ethyl acetate layers were combined and combined with 0.5N aqueous sodium hydroxide (1
It was washed with 00 ml × 3), 1N hydrochloric acid (100 ml), and then with saturated saline (100 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1) and crystallized from ethyl acetate-hexane (1: 5) to give the title compound (5.2 g, Crude yield 67%) was obtained as colorless crystals.

This product was recrystallized from a mixed solution of ethanol and water to obtain the title compound as colorless crystals. mp 162-163 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 7Hz), 4.14
(1H, d, J = 14.4Hz), 4.49 (2H, t, J = 13Hz), 4.94 (1H, dq, J = 7
Hz, 1.6Hz), 5.08 (1H, d, J = 14.4Hz), 5.54 (1H, d, J = 1.6H
z), 6.10 (1H, tt, J = 52Hz, 5.4Hz), 6.71-6.89 (2H, m), 7.0
3 (2H, d, J = 9.2Hz), 7.34-7.51 (1H, m), 7.77 (1H, s), 7.80
(1H, s), 7.93 (1H, s), 7.95 (2H, d, J = 9.2Hz) Elemental analysis value: Calculated value as C ₂₃ H ₂₀ F ₆ N ₆ O ₃ (%): C, 50.93 H, 3.72;
N, 15.49 Found (%): C, 51.03; H, 3.71;
N, 15.71

Example 3 4-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -2
-[4- (1,1,2,2-tetrafluoroethoxy)
Preparation of phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0072]

[Chemical 19]

(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane (5.
49 g), 2- [4- (1,1,2,2-tetrafluoroethoxy) phenyl) -3 (2H, 4H) -1,2,
4-Triazolone (12.11 g) and potassium carbonate (powder form: 15.14 g) were added to N, N-dimethylformamide (100 ml), and the mixture was stirred at 80 ° C. for 5 days.
Heated for 6 hours. After cooling the reaction solution, ethyl acetate (300
It was diluted with ice water (300 ml) and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (100 ml x 2). The ethyl acetate layers were combined and washed with 0.5N aqueous sodium hydroxide (100 ml × 3), 1N hydrochloric acid (100 ml), and then saturated brine (100 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1) and crystallized from ethyl acetate-hexane (1: 5) to give the title compound (7.1 g, Crude yield 62%) was obtained as colorless crystals.

This product was recrystallized from a mixed solution of ethanol and water to obtain the title compound as colorless crystals. mp 155-156 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7.2Hz), 4.1
3 (1H, d, J = 14.2Hz), 4.95 (1H, dq, J = 7.2Hz, 1.6Hz), 5.08
(1H, d, J = 14.2Hz), 5.55 (1H, d, J = 1.6Hz), 5.93 (1H, tt, J =
53Hz, 2.8Hz), 6.71-6.90 (2H, m), 7.30 (2H, d, J = 9.2Hz),
7.34-7.51 (1H, m), 7.77 (1H, s), 7.80 (1H, s), 7.96 (1H,
s), 8.06 (2H, d, J = 9.2Hz) Elemental analysis value: Calculated as C ₂₂ H ₁₈ F ₆ N ₆ O ₃ (%): C, 50.01; H, 3.43;
N, 15.90 Found (%): C, 50.15; H, 3.35;
N, 15.93

Example 4 4-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -2
-(4-trifluoromethoxyphenyl) -3 (2H,
Production of 4H) -1,2,4-triazolone

[0076]

[Chemical 20]

(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane (5.
04g), 2- (4-trifluoromethoxyphenyl)
-3 (2H, 4H) -1,2,4-triazolone (9.
84 g) and potassium carbonate (powder form: 13.8 g) were added to N, N-dimethylformamide (80 ml), and the mixture was heated with stirring at 70 ° C. for 117 hours. After cooling the reaction mixture, it was diluted with ethyl acetate (250 ml) and ice water (250 m).
l) and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (100 ml x 2). The ethyl acetate layers were combined, 0.5N aqueous sodium hydroxide solution (100 ml x 3), 1
It was washed with N hydrochloric acid (100 ml) and then with saturated saline (100 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 3/2) and crystallized from diisopropyl ether to give the title compound (5.64 g, 57% crude yield). Obtained as a colorless powder.

This product was dissolved in ethanol and diluted with water, and the precipitated colorless powder of the title compound was collected by filtration. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7.2Hz), 4.1
4 (1H, d, J = 14.4Hz), 4.96 (1H, dq, J = 7.2Hz, 1.6Hz), 5.08
(1H, d, J = 14.4Hz), 5.55 (1H, d, J = 1.6Hz), 6.76-6.89 (2H,
m), 7.31 (2H, d, J = 9.2Hz), 7.48-7.52 (1H, m), 7.78 (1H,
s), 7.80 (1H, s), 7.96 (1H, s), 8.08 (2H, d, J = 9.2Hz) Elemental analysis value: C ₂₁ H ₁₇ F ₅ N ₆ O ₃ Calculated value (%): C , 50.81; H, 3.45;
N, 16.93 Found (%): C, 50.66; H, 3.36;
N, 17.02

Example 5 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -4
-[4- (2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0080]

[Chemical 21]

(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane (5.
0g), 4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,
4-triazolone (8.4 g) and potassium carbonate (powder: 13.8 g) were added to N, N-dimethylformamide (1
00 ml), and the mixture was stirred at 80 ° C. for 27 hours and further at 100 ° C. for 4 hours. After cooling the reaction mixture, ethyl acetate (800
The mixture was diluted with water (200 ml), washed with water (200 ml), 1N aqueous sodium hydroxide (200 ml × 3), 1N hydrochloric acid (200 ml × 2), and then saturated saline (100 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, diisopropyl ether (20 ml) was added to the residue, and the mixture was ice-cooled to give a pale brown powder (8.5 g). This product was diluted with ethyl acetate-diisopropyl ether (1: 3, 4
Recrystallisation from 0 ml) gave the title compound (6.88 g) as colorless crystals. The mother liquors were combined and concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/3 → 1/5) and then purified with ethyl acetate-diisopropyl ether (1: 8,
Crystallization from 18 ml of the title compound (1.12
g) was obtained. Total yield 8.0 g (crude yield 74%)

This product was recrystallized from a mixed solution of ethanol and water to obtain the title compound as colorless crystals. mp 154-155 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7Hz), 4.36
(1H, d, J = 15Hz), 4.40 (2H, tt, J = 11.8Hz, J = 1.4Hz), 5.01
(1H, d, J = 15Hz), 5.09 (1H, q, J = 7Hz), 5.47 (1H, s), 6.07 (1
H, tt, J = 53Hz, 4.8Hz), 6.75-6.88 (2H, m), 7.07 (2H, dt, J =
9Hz, J = 2.2Hz), 7.53 (2H, dt, J = 9Hz, J = 2.2Hz), 7.48-7.64
(1H, m), 7.69 (1H, s), 7.75 (1H, s), 7.95 (1H, s) Elemental analysis value: C ₂₃ H ₂₀ F ₆ N ₆ O ₃ Calculated value (%): C, 50 .93; H, 3.72;
N, 15.49 Found (%): C, 50.85; H, 3.59;
N, 15.54

Example 6 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -5
-Methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,
Production of 4-triazolone

[0084]

[Chemical formula 22]

(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane (50
2 mg), 5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H)
-1,2,4-Triazolone (873 mg) and potassium carbonate (powdered form: 1.38 g) were added to N, N-dimethylformamide (10 ml), and the mixture was added at 80 ° C for 26 hours and further 1
The mixture was stirred at 00 ° C for 8 hours. After cooling the reaction solution, it was diluted with ethyl acetate (80 ml) and washed with water (20 ml), 1N aqueous sodium hydroxide (20 ml), 1N hydrochloric acid (20 ml) and then saturated brine (10 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2 → 1/4). , The title compound (0.78 g, yield 72%) was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, d, J = 7Hz), 2.23
(3H, s), 4.41 (1H, d, J = 14.6Hz), 4.97 (1H, d, J = 14.6Hz),
5.06 (1H, q, J = 7Hz), 5.54 (1H, s), 5.95 (1H, tt, J = 53.2Hz,
J = 2.8Hz), 6.75-6.90 (2H, m), 7.40 (4H, s), 7.50-7.65 (1
H, m), 7.70 (1H, s), 7.96 (1H, s) Elemental analysis value: Calculated as C ₂₃ H ₂₀ F ₆ N ₆ O ₃ (%): C, 50.93; H, 3.72 ;
N, 15.49 Found (%): C, 50.53; H, 3.77;
N, 15.26

Example 7 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -4
Production of-[4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0087]

[Chemical formula 23]

(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane (2.
5 g), 4- [4- (2,2,2-trifluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (3.88 g) and potassium carbonate (powder form:
6.9 g) to N, N-dimethylformamide (50 ml)
In addition, the mixture was stirred at 70 ° C. for 54 hours. After cooling the reaction solution,
Dilute with ethyl acetate (200 ml), water (50 ml), 0.
It was washed with 25N aqueous sodium hydroxide (50 ml × 3), 1N hydrochloric acid (50 ml), and then with saturated saline (50 ml).
The ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane / ethyl acetate = 2/3 → 1).
/ 4) and was then crystallized from ethyl acetate-diisopropyl ether (1: 3, 30 ml) to give the title compound (3.89 g, yield 76%) as colorless needle crystals. . mp 168-169 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7Hz), 4.35
(1H, d, J = 14.8Hz), 4.40 (2H, q, J = 8Hz), 5.02 (1H, d, J = 14.
8Hz), 5.08 (1H, q, J = 7Hz), 5.47 (1H, s), 6.74-6.89 (2H,
m), 7.08 (2H, d, J = 9Hz), 7.48-7.65 (1H, m), 7.53 (2H, d, J
= 9Hz), 7.68 (1H, s), 7.75 (1H, s), 7.94 (1H, s) Elemental analysis value: Calculated as C ₂₂ H ₁₉ F ₅ N ₆ O ₃ (%): C, 51.77 H, 3.75;
N, 16.46 Found (%): C, 51.79; H, 3.76;
N, 16.53

Example 8 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -4
-[4- (1,1,2,2-tetrafluoroethoxy)
Preparation of phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0090]

[Chemical formula 24]

(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane (2.
5 g), 4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4
-Triazolone (4.1 g) and potassium carbonate (powder form: 4.2 g) were added to N, N-dimethylformamide (50
ml) and stirred at 70 ° C. for 60 hours and then at 100 ° C. for 9 hours. After cooling the reaction mixture, ethyl acetate (300 ml)
It was diluted with and washed with water (100 ml), 1N aqueous sodium hydroxide (100 ml × 3), 1N hydrochloric acid (100 ml × 2), and then saturated saline (100 ml). After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/3 → 1/3) and crystallized from diisopropyl ether (30 ml) to give the title compound (2.94 g, Crude yield 56
%) Was obtained as colorless crystals.

This product was recrystallized from a mixed solution of ethanol and water to give colorless needle crystals of the title compound. mp 121-123 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7Hz), 4.37
(1H, d, J = 14.4Hz), 5.03 (1H, d, J = 14.4Hz), 5.09 (1H, q, J =
7Hz), 5.41 (1H, s), 5.94 (1H, tt, J = 53Hz, J = 2.8Hz), 6.75
-6.90 (2H, m), 7.38 (2H, d, J = 9Hz), 7.50-7.70 (1H, m), 7.
63 (2H, d, J = 9Hz), 7.69 (1H, s), 7.80 (1H, s), 7.94 (1H, s) Elemental analysis value: Calculated as C ₂₂ H ₁₈ F ₆ N ₆ O ₃ (% ): C, 50.01; H, 3.43;
N, 15.90 Found (%): C, 49.84; H, 3.46;
N, 16.25

Example 9 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -4
-[4- (2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0094]

[Chemical 25]

(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane (0.
5 g), 4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,
4-triazolone (0.83 g) and potassium hydrogen carbonate (powder form: 2 g) were added to N, N-dimethylformamide (5
ml) and heated at 80 ° C. for 39 hours with stirring. After cooling the reaction mixture, dilute it with ethyl acetate (20 ml),
It was added to ice water (20 ml) and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (10 ml x 3). The ethyl acetate layers were combined and combined with 0.5N aqueous sodium hydroxide (15 ml x
3) 1N hydrochloric acid (15 ml x 1), followed by saturated saline solution (1
It was washed with 5 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate /
After purification by subjecting to dichloromethane = 1/1) and crystallizing from diisopropyl ether, the title compound (0.61 g, crude yield 56%) was obtained as colorless crystals. It was confirmed from the mp and NMR values that this product was the same as the compound obtained in Example 5.

Example 10 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -4
-[4- (2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0097]

[Chemical formula 26]

(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane (0.
5 g), 4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,
4-Triazolone (0.83 g) and lithium hydroxide (powder form: 0.84 g) were added to N, N-dimethylformamide (5 ml), and the mixture was heated with stirring at 80 ° C. for 39 hours. The reaction mixture was cooled, diluted with ethyl acetate (20 ml), added to ice water (20 ml) and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (10 ml x 3). The ethyl acetate layers were combined and combined with 0.5N aqueous sodium hydroxide (15
ml × 3), 1N hydrochloric acid (15 ml × 1), and then washed with saturated saline (15 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 1/1) and crystallized from diisopropyl ether to give the title compound (0.49 g, crude yield 45%). Obtained as colorless crystals. It was confirmed from the mp and NMR values that this product was the same as the compound obtained in Example 5.

Example 11 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -4
-[4- (2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0100]

[Chemical 27]

(2R, 3R) -2- (2,4-difluorophenyl) -3- (p-toluenesulfonyloxy)
-1- (1H-1,2,4-triazol-1-yl)
-2-butanol (0.9 g), 4- [4- (2,2,
3,3-Tetrafluoropropoxy) phenyl] -3
(2H, 4H) -1,2,4-triazolone (0.87
g) and potassium carbonate (powder form: 1.46 g) with N, N
-Add to dimethylformamide (18 ml) and heat with stirring at 80 ° C for 44 hours. After cooling the reaction solution, it was diluted with ethyl acetate (100 ml) and added to ice water (200 ml) to separate the ethyl acetate layer. The aqueous layer is ethyl acetate (50 ml
It was extracted in × 2). The ethyl acetate layers were combined, and 0.5N aqueous sodium hydroxide (50 ml x 2), 1N hydrochloric acid (50 m
l), followed by washing with saturated saline (50 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue (eluent: dichloromethane / ethyl acetate = 1/1)
After purification by filtration, crystallization from diisopropyl ether gave the title compound (0.53 g, crude yield 46%).
Was obtained as colorless crystals. It was confirmed from the mp and NMR values that this product was the same as the compound obtained in Example 5.

Example 12 4-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -2
-[4- (1,1,2,2-tetrafluoroethoxy)
Preparation of phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0103]

[Chemical 28]

(2R, 3R) -2- (2,4-difluorophenyl) -3- (p-toluenesulfonyloxy)
-1- (1H-1,2,4-triazol-1-yl)
-2-butanol (1 g), 2- [4- (1,1,2,2
2-Tetrafluoroethoxy) phenyl] -3 (2H,
4H) -1,2,4-Triazolone (0.92 g) and potassium carbonate (powder form: 1.63 g) were added to N, N-dimethylformamide (20 ml), and the mixture was stirred at 80
Heat at 52 ° C. for 52 hours. After cooling the reaction solution, it was diluted with ethyl acetate (100 ml) and added to ice water (200 ml) to separate the ethyl acetate layer. The aqueous layer is ethyl acetate (50 ml x 2)
It was extracted with. The ethyl acetate layers were combined and washed with 0.5N aqueous sodium hydroxide (50 ml × 2), 1N hydrochloric acid (50 ml), and then saturated brine (50 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1) and crystallized from ethyl acetate-hexane (1: 5) to give the title compound (0.48 g, Crude yield 38%) was obtained as colorless crystals. This product was confirmed to be the same as the compound obtained in Example 3 from the mp and NMR values.

Example 13 2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -4
-[4- (2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0106]

[Chemical 29]

(2R, 3R) -2- (2,4-difluorophenyl) -3-methanesulfonyloxy-1- (1
H-1,2,4-triazol-1-yl) -2-butanol (2 g), 4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H)-
1,2,4-Triazolone (2.51 g) and potassium carbonate (powder form: 3.95 g) were added to N, N-dimethylformamide (40 ml) and stirred at 80 ° C. for 24 hours.
Heated at 100 ° C. for 4 hours. After cooling the reaction solution, it was diluted with ethyl acetate (200 ml) and added to ice water (300 ml) to separate the ethyl acetate layer. The aqueous layer was washed with ethyl acetate (10
It was extracted with 0 ml × 2). Combine the ethyl acetate layers to 0.5
N sodium hydroxide water (100 ml x 2), 1N hydrochloric acid (1
(00 ml), followed by washing with saturated saline (100 ml).
The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Silica gel column chromatography of the residue (eluent: ethyl acetate / dichloromethane = 1
/ 1) and then crystallized from diisopropyl ether to give the title compound (1.97 g, crude yield 6
3%) was obtained as colorless crystals. This product is mp and N
From the MR value, it was confirmed to be the same as the compound obtained in Example 5.

Example 14 4-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -2
-[4- (1,1,2,2-tetrafluoroethoxy)
Preparation of phenyl] -3 (2H, 4H) -1,2,4-triazolone

[0109]

[Chemical 30]

(2R, 3R) -2- (2,4-difluorophenyl) -3-methanesulfonyloxy-1- (1
H-1,2,4-triazol-1-yl) -2-butanol (0.82 g), 2- [4- (1,1,2,2-
Tetrafluoroethoxy) phenyl] -3 (2H, 4
H) -1,2,4-Triazolone (1.3 g) and potassium carbonate (powder: 1.63 g) were added to N, N-dimethylformamide (15 ml), and the mixture was heated at 80 ° C. for 64 hours while stirring. After cooling the reaction solution, ethyl acetate (10
It was diluted with 0 ml), added to ice water (200 ml) and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml x 2). The ethyl acetate layers were combined and washed with 0.5N aqueous sodium hydroxide (50 ml × 2), 1N hydrochloric acid (50 ml), and then saturated brine (50 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/1) and crystallized from ethyl acetate-hexane (1: 5) to give the title compound (0.4 g, Crude yield 32%) was obtained as colorless crystals. This product was confirmed to be the same as the compound obtained in Example 3 from the mp and NMR values.

Example 15 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane and 4- [4- [4-
[4- (1,1,2,2-tetrafluoroethoxy) phenyl] -1-piperazinyl] phenyl] -3 (2H,
4H) -1,2,4-triazolone was reacted in the same manner as in Example 5 to give 2-[(1R, 2R) -2- (2,4-
Difluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- [4- [4- (1,1,2,2-
Tetrafluoroethoxy) phenyl] -1-piperazinyl] phenyl] -3 (2H, 4H) -1,2,4-triazolone was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7Hz), 3.23-
3.48 (8H, m), 4.36 (1H, d, J = 14.4Hz), 5.03 (1H, d, J = 14.4H
z), 5.09 (1H, q, J = 7Hz), 5.58 (1H, s), 5.90 (1H, tt, J = 53H
z, 2.8Hz), 6.77-7.00 (6H, m), 7.10 (2H, d, J = 9Hz), 7.43
(2H, d, J = 9Hz), 7.50-7.62 (1H, m), 7.69 (1H, s), 7.74 (1
H, s), 7.97 (1H, s) Elemental analysis value: Calculated value as C ₃₂ H ₃₀ F ₆ N ₈ O ₃ (%): C, 55.81; H, 4.39;
N, 16.27 Found (%): C, 55.81; H, 4.41;
N, 16.16

Example 16 (2R, 3S) -2- (2-fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (2 g), 4- [4-
(2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (3.75 g) and potassium carbonate (powder form: 5.93).
g) was added to N, N-dimethylformamide (40 ml) and stirred at 80 ° C for 21 hours, then at 100 ° C.
And stirred for 9 hours. After cooling the reaction mixture, it was diluted with ethyl acetate (150 ml) and 1N aqueous sodium hydroxide solution (70
ml × 2), 1N hydrochloric acid (70 ml × 2), and then saturated saline (70 ml). The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / acetone = 5/1), then ethyl acetate-diisopropyl ether. Crystallization from (1:10, 20 ml) gave 2-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-triazol-1-yl) propyl] -4
-[4- (2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (1.93 g) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7Hz), 4.35-
4.46 (3H, m), 5.17 (1H, d, J = 7Hz), 5.26 (1H, q, J = 7Hz), 5.
34 (1H, s), 6.07 (1H, tt, J = 4.8Hz, 53Hz), 6.99-7.33 (3H,
m), 7.06 (2H, d, J = 9Hz), 7.49-7.75 (1H, m), 7.54 (2H, d, J
= 9Hz), 7.68 (1H, s), 7.75 (1H, s), 7.89 (1H, s) Elemental analysis value: Calculated as C ₂₃ H ₂₁ F ₅ N ₆ O ₃ (%): C, 52.67 H, 4.04;
N, 16.02 Found (%): C, 52.72; H, 4.05;
N, 16.03

Example 17 (2R, 3S) -2- (2-fluorophenyl) -3-
Methyl-3-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (1 g) and 4- (4-trifluoromethylphenyl) -3 (2H, 4H) -1,
2,4-Triazolone (1.4 g) was reacted in the same manner as in Example 16 to give 2-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3-.
(1H-1,2,4-triazol-1-yl) propyl] -4- (4-trifluoromethylphenyl) -3
(2H, 4H) -1,2,4-triazolone (0.48
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7Hz), 4.40
(1H, d, J = 14Hz), 5.07 (1H, d, J = 14Hz), 5.15 (1H, q, J = 7H
z), 5.24 (1H, s), 7.00-7.34 (3H, m), 7.53-7.79 (5H, m),
7.62 (1H, s), 7.79 (1H, s), 7.88 (1H, s) Elemental analysis value: Calculated as C ₂₁ H ₁₈ F ₄ N ₆ O ₂ (%): C, 54.55; H, 3 .92;
N, 18.17 Found (%): C, 54.44; H, 4.00;
N, 18.11

Example 18 (2R, 3S) -2- (2-Fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (0.89 g) and 4- (4
-Trifluoromethoxyphenyl) -3 (2H, 4H)
-1,2,4-triazolone (1.41 g) in Example 1
The reaction is performed in the same manner as in 6 to give 2-[(1R, 2R) -2- (2
-Fluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -4- (4-trifluoromethoxyphenyl)
-3 (2H, 4H) -1,2,4-triazolone (0.
42 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7Hz), 4.39
(1H, d, J = 14Hz), 5.06 (1H, d, J = 14Hz), 5.15 (1H, q, J = 7H
z), 5.28 (1H, s), 7.00-7.41 (5H, m), 7.54-7.63 (1H, m),
7.65 (2H, d, J = 9Hz), 7.69 (1H, s), 7.80 (1H, s), 7.88 (1H,
s) Elemental analysis value: calculated as C ₂₁ H ₁₈ F ₄ N ₆ O ₃ (%): C, 52.72; H, 3.79;
N, 17.57 Found (%): C, 52.76; H, 3.87;
N, 17.64

Example 19 (2R, 3S) -2- (2-fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (1 g) and 4- [4-
(2,2,2-Trifluoroethoxy) phenyl] -3
(2H, 4H) -1,2,4-triazolone (1.67
g) was reacted as in Example 16 to give 2-[(1R, 2
R) -2- (2-Fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2, 2-Trifluoroethoxy) phenyl] -3 (2H, 4H)-
1,2,4-triazolone (0.77 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7Hz), 4.35-
4.47 (3H, m), 5.07 (1H, d, J = 14Hz), 5.15 (1H, q, J = 7Hz),
5.35 (1H, s), 7.00-7.32 (3H, m), 7.08 (2H, d, J = 9Hz), 7.5
1-7.63 (1H, m), 7.54 (2H, d, J = 9Hz), 7.69 (1H, s), 7.75 (1
H, s), 7.90 (1H, s) Elemental analysis value: calculated as C ₂₂ H ₂₀ F ₄ N ₆ O ₃ (%): C, 53.66; H, 4.09;
N, 17.07 Found (%): C, 53.36; H, 4.14;
N, 17.15

Example 20 (2R, 3S) -2- (2-Fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (2 g) and 4- [4-
(1,1,2,2-Tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (3.57 g) was reacted in the same manner as in Example 16 to give 2-
[(1R, 2R) -2- (2-fluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-
Triazol-1-yl) propyl] -4- [4-
(1,1,2,2-Tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (1.35 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7Hz), 4.39
(1H, d, J = 14Hz), 5.07 (1H, d, J = 14Hz), 5.14 (1H, q, J = 7H
z), 5.29 (1H, s), 5.94 (1H, tt, J = 2.8Hz, 53Hz), 7.00-7.1
2 (2H, m), 7.21-7.62 (4H, m), 7.64 (2H, d, J = 9Hz), 7.68 (1
H, s), 7.80 (1H, s), 7.89 (1H, s) Elemental analysis value: Calculated value as C ₂₂ H ₁₉ F ₅ N ₆ O ₃ (%): C, 51.77; H, 3.75 ;
N, 16.46 Found (%): C, 51.54; H, 3.66;
N, 16.47

Example 21 (2R, 3S) -2- (2-Fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (2.33 g) and 5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4- Triazolone (4.36 g) was reacted in the same manner as in Example 16 to give 2-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4 −
Triazolone (3.06 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, d, J = 7Hz), 2.23
(3H, s), 4.44 (1H, d, J = 14.4Hz), 5.01 (1H, d, J = 14.4Hz),
5.13 (1H, q, J = 7Hz), 5.41 (1H, s), 5.95 (1H, tt, J = 53Hz, 2.
8Hz), 7.00-7.14 (2H, m), 7.20-7.35 (1H, m), 7.40 (4H,
s), 7.53-7.67 (1H, m ), 7.69 (1H, s), 7.91 (1H, s) Elemental analysis: Calculated _{C 23 H 21 F 5 N 6} O 3 (%): C, 52. 67; H, 4.04;
N, 16.02 Found (%): C, 52.56; H, 4.14;
N, 15.99

Example 22 (2R, 3S) -2- (2-fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (2.33 g) and 2- [4
-(1,1,2,2-Tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (5.54 g) was reacted in the same manner as in Example 16 to give 4-
[(1R, 2R) -2- (2-fluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-
Triazol-1-yl) propyl] -2- [4-
(1,1,2,2-Tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (2.6 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 7Hz), 4.14
(1H, d, J = 14Hz), 5.01 (1H, q, J = 7Hz), 5.13 (1H, d, J = 14H
z), 5.43 (1H, s), 5.93 (1H, tt, J = 2.8Hz, 53Hz), 6.99-7.0
9 (2H, m), 7.21-7.43 (4H, m), 7.75 (2H, s), 7.98 (1H, s),
8.07 (2H, d, J = 9Hz) Elemental analysis value: Calculated as C ₂₂ H ₁₉ F ₅ N ₆ O ₃ (%): C, 51.77; H, 3.75;
N, 16.46 Found (%): C, 51.67; H, 3.75;
N, 16.52

Example 23 (2R, 3S) -2- (2-fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (1.99 g) and 2- [4
-(2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (3.74 g) was reacted in the same manner as in Example 16 to give 4-
[(1R, 2R) -2- (2-fluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-
Triazol-1-yl) propyl] -2- [4-
(2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (2.1 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 7Hz), 4.16
(1H, d, J = 14Hz), 4.38 (2H, t, J = 12Hz), 5.02 (1H, q, J = 7H
z), 5.14 (1H, d, J = 14Hz), 5.43 (1H, s), 6.09 (1H, tt, J = 4.
8Hz, 53Hz), 7.02 (2H, d, J = 9Hz), 7.03-7.13 (1H, m), 7.21
-7.48 (3H, m), 7.76 (2H, s), 7.96 (1H, s), 7.97 (2H, d, J = 9
Hz) Elemental analysis: Calculated _{C 23 H 21 F 5 N 6} O 3 (%): C, 52.67; H, 4.04;
N, 16.02 Found (%): C, 52.48; H, 4.11;
N, 16.04

Example 24 (2R, 3S) -2- (4-fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (2.34 g), 4- [4
-(2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (4.37 g) and potassium carbonate (powder form: 6.91)
g) was added to N, N-dimethylformamide (50 ml) and stirred at 80 ° C for 20 hours, then at 100 ° C.
It was stirred for 2 hours. After cooling the reaction solution, ethyl acetate (20
Diluted with 0 ml) and 1N aqueous sodium hydroxide (200 ml x
2) It was washed with 1N hydrochloric acid (200 ml × 1) and then with saturated saline (200 ml). The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 3/1 → ethyl acetate), and then dichloromethane. -Diisopropyl ether (2: 1, 21 ml)
When crystallized from 2-[(1R, 2R) -2- (4
-Fluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,
2,4-Triazolone (3.12 g) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, d, J = 7Hz), 4.38
(1H, d, J = 14Hz), 4.41 (2H, t, J = 12Hz), 4.70 (1H, d, J = 14H
z), 4.84 (1H, d, J = 7Hz), 5.28 (1H, s), 6.07 (1H, tt, J = 53H
z, 4.6Hz), 6.98-7.08 (2H, m), 7.08 (2H, d, J = 9Hz), 7.38-
7.46 (2H, m), 7.52 (2H, d, J = 9Hz), 7.72 (1H, s), 7.73 (1H,
s), 7.84 (1H, s ) Elemental analysis: Calculated _{C 23 H 21 F 5 N 6} O 3 (%): C, 52.67; H, 4.04;
N, 16.02 Found (%): C, 52.60; H, 4.03;
N, 16.29

Example 25 (2R, 3S) -2- (4-fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (2 g) and 4- [4-
(1,1,2,2-Tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (3.57 g) was reacted in the same manner as in Example 24 to give 2-
[(1R, 2R) -2- (4-fluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-
Triazol-1-yl) propyl] -4- [4-
(1,1,2,2-Tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (1.54 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 7Hz), 4.39
(1H, d, J = 14Hz), 4.70 (1H, d, J = 14Hz), 4.84 (1H, d, J = 7H
z), 5.23 (1H, s), 5.95 (1H, tt, J = 2.6Hz, 53Hz), 6.99-7.0
7 (2H, m), 7.33-7.46 (4H, m), 7.62 (2H, d, J = 9Hz), 7.69 (1
H, s), 7.78 (1H, s), 7.84 (1H, s) Elemental analysis value: Calculated as C ₂₂ H ₁₉ F ₅ N ₆ O ₃ (%): C, 51.77; H, 3.75 ;
N, 16.46 Found (%): C, 51.70; H, 3.68;
N, 16.52

Example 26 (2R, 3S) -2- (4-fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (2.33 g) and 5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4- Triazolone (4.36 g) was reacted in the same manner as in Example 24 to give 2-[(1R, 2R) -2- (4-fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -5-methyl-4- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4 −
Triazolone (3.50 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 7Hz), 2.21
(3H, s), 4.42 (1H, d, J = 14.2Hz), 4.65 (1H, d, J = 14.2Hz),
4.81 (1H, q, J = 7Hz), 5.31 (1H, s), 5.96 (1H, tt, J = 53Hz, 2.
8Hz), 6.97-7.12 (2H, m), 7.35-7.54 (6H, m), 7.72 (1H,
s), 7.86 (1H, s ) Elemental analysis: Calculated _{C 23 H 21 F 5 N 6} O 3 (%): C, 52.67; H, 4.04;
N, 16.02 Found (%): C, 52.25; H, 4.42;
N, 15.92

Example 27 (2R, 3S) -2- (4-fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (2.34 g) and 2- [4
-(1,1,2,2-Tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (5.54 g) was reacted in the same manner as in Example 24 to give 4-
[(1R, 2R) -2- (4-fluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-
Triazol-1-yl) propyl] -2- [4-
(1,1,2,2-Tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (2.60 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 7Hz), 4.16
(1H, d, J = 14Hz), 4.68-4.75 (1H, m), 4.70 (1H, d, J = 14Hz),
5.47 (1H, s), 5.93 (1H, tt, J = 53Hz, 2.8Hz), 7.01 (2H, t, J
= 9Hz), 7.27-7.39 (2H, m), 7.31 (2H, d, J = 9Hz), 7.63 (1H,
s), 7.80 (1H, s), 7.97 (1H, s), 8.06 (2H, d, J = 9Hz) Elemental analysis value: C ₂₂ H ₁₉ F ₅ N ₆ O ₃ Calculated value (%): C, 51.77; H, 3.75;
N, 16.46 Found (%): C, 51.73; H, 3.70;
N, 16.63

Example 28 (2R, 3S) -2- (4-Fluorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxirane (2.66 g) and 2- [4
-(2,2,3,3-Tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone (5 g) was reacted in the same manner as in Example 24 to give 4-[(1
R, 2R) -2- (4-Fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -2- [4- (2, Two
3,3-Tetrafluoropropoxy) phenyl] -3
(2H, 4H) -1,2,4-triazolone (4.12
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 7Hz), 4.16
(1H, d, J = 14Hz), 4.38 (2H, t, J = 12Hz), 4.66-4.73 (2H, m),
5.46 (1H, s), 6.08 (1H, tt, J = 4.8Hz, 53Hz), 6.96-7.04 (4
H, m), 7.31-7.38 (2H, m), 7.62 (1H, s), 7.79 (1H, s), 7.9
3 (1H, s), 7.94 (2H, d, J = 9Hz) Elemental analysis: Calculated _{C 23 H 21 F 5 N 6} O 3 (%): C, 52.67; H, 4.04;
N, 16.02 Found (%): C, 52.77; H, 3.98;
N, 16.07

Example 29 (2R, 3S) -2- (2,4-difluorophenyl)
-3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane (0.502 g),
5-methyl-2- [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,
2,4-Triazolone (0.87 g) and potassium carbonate (powder: 1.38 g) were added to N, N-dimethylformamide (10 ml), and the mixture was heated with stirring at 80 ° C for 26 hours and at 100 ° C for 8 hours. After cooling the reaction mixture, it was diluted with ethyl acetate (80 ml) and washed with water (20 ml), 0.5N aqueous sodium hydroxide (20 ml), 1N hydrochloric acid (20 ml) and then saturated brine (20 ml). The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / acetone = 8/1 → 6/1) to give 4-[(1R, 2R) -2- (2,2
4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -5-methyl-2- [4- (1,1,
2,2-Tetrafluoroethoxy) phenyl] -3 (2
H, 4H) -1,2,4-triazolone (0.78 g)
Was obtained as a colorless powder. Elemental analysis: Calculated as _{C 23 H 20 F 6 N 6} O 3 (%): C, 50.93; H, 3.72;
N, 15.49 Found (%): C, 50.53; H, 3.81;
N, 15.22

Table 1 shows the protective effect of the compounds of the present invention against experimental mouse infections. Experimental method: 5 weeks old C
rj: DF ₁ mice were inoculated intravenously with a minimal lethal dose of Candida albicans TA. Test compound 0.5
Oral administration was performed once as a suspension of sodium carboxymethyl cellulose (CMC) immediately after infection. The drug efficacy was indicated by the ED ₅₀ value calculated by the Reed and muench method from the survival rate of mice 7 days after infection.

[Table 1]

[Table 2]

[0127]

EFFECTS OF THE INVENTION According to the production method of the present invention, an optically active azole derivative useful as a therapeutic agent for fungal diseases (antifungal disease) can be produced in a short time, in short steps, in high yield and with high purity. The optically active azole derivative of the present invention is effective for the prevention or treatment of fungal infections in mammals. The optically active azole derivative of the present invention is also useful as a fungal agent for agriculture.

Claims (26)

[Claims] 1. A compound represented by the general formula [I]: [Wherein R ¹ represents an aliphatic or aromatic hydrocarbon group which may have a substituent, or an aromatic heterocyclic group which may have a substituent, and Y and Z are different from each other. A methine group which may be substituted with a nitrogen atom or a lower alkyl group] or a salt thereof and a compound represented by the general formula [III]: [In the formula, Ar represents a halogenated phenyl group, R ² represents a lower alkyl group or an optionally substituted phenyl group,
(R) represents a steric configuration] and is reacted with a compound represented by the general formula [IV] [Wherein each symbol has the same meaning as defined above] to obtain a compound or salt thereof represented by the general formula [I
V] A method for producing a compound represented by the formula V or a salt thereof. 2. The production method according to claim 1, wherein the reaction is carried out in the presence of a base. 3. The base is an alkali metal carbonate, an alkali metal hydrogen carbonate, an alkali metal hydroxide, an alkali metal hydride, an organic carboxylic acid alkali metal salt, an alkali metal alcoholate or a tetrabutylammonium fluoride salt. The manufacturing method according to claim 2. 4. The production method according to claim 2, wherein the base is an alkali metal carbonate or an alkali metal hydrogencarbonate. 5. The production method according to claim 2, wherein the base is an alkali metal carbonate. 6. The production method according to claim 2, wherein the base is potassium carbonate. 7. The production method according to claim 1, wherein the reaction is carried out in a solvent that does not inhibit the reaction. 8. A compound represented by the general formula [I]: [Wherein R ¹ represents an aliphatic or aromatic hydrocarbon group which may have a substituent, or an aromatic heterocyclic group which may have a substituent, and Y and Z are different from each other. A methine group which may be substituted with a nitrogen atom or a lower alkyl group] or a salt thereof and a compound represented by the general formula [II] [Wherein Ar represents a halogenated phenyl group and (R) and (S) represent a configuration] in the presence of an alkali metal carbonate to give a compound of the general formula [IV] 6] [Wherein each symbol has the same meaning as defined above] to obtain a compound or salt thereof represented by the general formula [I
V] A method for producing a compound represented by the formula V or a salt thereof. 9. The alkali metal carbonate is lithium carbonate,
The production method according to claim 8, which is sodium carbonate, potassium carbonate or cesium carbonate. 10. The method according to claim 8, wherein the alkali metal carbonate is potassium carbonate. 11. The production method according to claim 8, wherein the reaction is performed in a solvent that does not inhibit the reaction. 12. The solvent is used in an amount of about 25 times by weight or less based on the compound represented by the general formula [II].
The manufacturing method described. 13. A compound represented by the general formula [IV] is 2
-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -4-
[4- (2,2,3,3-tetrafluoropropoxy)
The production method according to claim 1, which is phenyl] -3 (2H, 4H) -1,2,4-triazolone. 14. The compound represented by the general formula [IV] is 4
-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -2-
[4- (2,2,3,3-tetrafluoropropoxy)
The production method according to claim 1, which is phenyl] -3 (2H, 4H) -1,2,4-triazolone. 15. The compound represented by the general formula [IV] is 4
-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -2-
The production method according to claim 1, which is [4- (1,1,2,2-tetrafluoroethoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone. 16. A compound represented by the general formula [IV] is 2
-[(1R, 2R) -2- (2-fluorophenyl)-
2-hydroxy-1-methyl-3- (1H-1,2,4
-Triazol-1-yl) propyl] -4- [4-
The production method according to claim 1 or 8, which is (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2,4-triazolone. 17. A compound represented by the general formula [IV ′]: [Wherein R ¹ represents an aliphatic or aromatic hydrocarbon group which may have a substituent, or an aromatic heterocyclic group which may have a substituent, and Y and Z are different from each other. A methine group optionally substituted with a nitrogen atom or a lower alkyl group, Ar 'represents a monofluorophenyl group, and (R) represents a steric configuration] or a salt thereof. 18. The compound according to claim 17, wherein Ar ′ is a 2-fluorophenyl group. 19. The compound according to claim 17, wherein Ar ′ is a 4-fluorophenyl group. 20. The compound according to claim 17, wherein R ¹ is an aromatic hydrocarbon group which may have a substituent. 21. The compound according to claim 17, wherein R ¹ is a substituted phenyl group. 22. The compound according to claim 17, wherein R ¹ is a phenyl group substituted with a haloalkoxy group. 23. The compound according to claim 17, wherein R ¹ is 4- (2,2,3,3-tetrafluoropropoxy) phenyl. 24. The compound according to claim 17, wherein R ¹ is 4- (1,1,2,2-tetrafluoroethoxy) phenyl. 25. 2-[(1R, 2R) -2- (2-fluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2, Four
-The compound of claim 17, which is triazolone. 26. An antifungal agent comprising the compound represented by the general formula [IV ′] according to claim 17 or a pharmaceutically acceptable salt thereof.