JP2961538B2 - Synthetic intermediates and production methods of imidazolone and imidazolidinone derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing imidazolone and an imidazolidinone derivative having an antifungal activity, and a synthetic intermediate thereof.

[0002]

2. Description of the Related Art Various azole compounds having an antifungal activity have been known. For example, European Patent Application Publication No. 567982 (JP-A-6-29374)
In the official gazette, the formula:

Embedded image (Wherein, Ar ₁ represents a substituted phenyl group, and R ₁ and R ₂
Whether the same or different and each represents a hydrogen atom or a lower alkyl group, or may form a lower alkylene group linked, R ₃ represents a group attached through a carbon atom, R ₄
Represents a hydrogen atom or an acyl group, X ₁ represents a nitrogen atom or a methine group, and Y and Z represent the same or different and may be a methine group optionally substituted with a nitrogen atom or a lower alkyl group. The azole compound represented by the formula (I) or a salt thereof is described in the above publication and JP-A-8-104676.

Embedded image (Wherein, Ar ₂ represents a halogenated phenyl group, R ₅ represents an aliphatic or aromatic hydrocarbon group which may have a substituent, or an aromatic bicyclic group which may have a substituent. ,
The imidazolone derivative represented by (R) shows a configuration is exemplified as a preferable group of compounds (hereinafter, sometimes referred to as compound (B)). A synthesis method as a starting material is described.

[0003] European Patent Application Publication No. 6876
No. 72 (corresponding to JP-A-8-253452)
As a method for producing the imidazolone derivative represented by the above formula (B), a synthesis method using a (S) -lactic acid derivative as a starting material is described. Further, Japanese Patent Application Laid-Open No. H8-1046 described above
No. 76 publication has the formula:

Embedded image (Wherein each symbol has the same meaning as described above), a preferred group of compounds [hereinafter may be referred to as compound (C). And a synthesis method of subjecting the compound (B) to a reduction reaction as a method for producing the compound. In addition, WO 96
25410A1 (Japanese Unexamined Patent Publication No. 9-183768) has the formula:

Embedded image (Wherein, Ar ₃ represents a phenyl group which may be substituted,
R ₆ and R ₇ are the same or different, a hydrogen atom or a lower alkyl group, or a lower alkylene group together R ₆ and R ₇ are mutually the R ₈ is a hydrogen atom or an acyl group, X ₂
Represents a nitrogen atom or a methine group, and A represents Y = Z (Y and Z
Represents the same or different methine groups which may be substituted with a nitrogen atom or a lower alkyl group. ) Or an ethylene group optionally substituted with a lower alkyl group, n represents an integer of 0-2, and Az represents an azolyl group optionally substituted. An azole compound having antifungal activity or a salt thereof represented by the formula:

Embedded image (Wherein each symbol is as defined above), is exemplified as a preferable group of compounds [hereinafter, sometimes referred to as compound (E)], and further, the production method thereof is represented by (R) -Lactic acid derivative or (S)
-Synthesis methods using lactic acid derivatives as starting materials are described. Further, the above-mentioned WO 9625410 A1 (Japanese Unexamined Patent Publication No.
The formula:

Embedded image (Wherein each symbol has the same meaning as described above.) A preferable group of compounds [hereinafter may be referred to as compound (F)] is an imidazolidinone derivative. And a synthesis method of subjecting the compound (E) to a reduction reaction. The above publication contains, for example, the formula:

Embedded image (Wherein each symbol is as defined above) and a compound represented by the formula:

Embedded image (Wherein each symbol has the same meaning as described above), and a method for producing compounds (B) and (E), which are imidazolone derivatives, by reacting with a compound represented by the following formula:

[0004]

In the above method for producing the compounds (B) and (E), the reaction is carried out under basic conditions, so that a part of the raw material and the product are decomposed, and the desired product (B) is produced.
And the yields of (E) are not sufficiently satisfactory. In particular, when R ₅ contains a group that is unstable under basic conditions, a by-product is generated, so that the purification of the target product is complicated, and the yield is not sufficiently satisfactory. On the other hand, as a method for producing the imidazolidinone derivatives (C) and (F),
For example, a synthesis method for catalytically reducing the above-mentioned compounds (B) and (E) is described in the above-mentioned gazette. However, this synthesis method requires an expensive metal catalyst (such as palladium-carbon), and is therefore economical. It is hard to say that it is satisfactory enough. The present invention provides a compound of formula (B) useful as a therapeutic agent for mycosis,
An object of the present invention is to provide a simple and economical method for synthesizing imidazolone and imidazolidinone derivatives represented by (C), (E) and (F) and an intermediate for synthesizing the same.

[0005]

That is, the present invention provides:
Equation (1):

Embedded image [Wherein, Ar represents a phenyl group which may be substituted;
¹ represents a hydrogen atom or a lower alkyl group, R ² represents an optionally substituted aliphatic be based have or aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group, R ³
It is (wherein, Y represents a hydroxyl group or a halogen atom.) Wherein -CH ₂ Y represents a group or an optionally protected formyl group represented by. Or a salt thereof,
Equation (2):

Embedded image (In the formula, Ar represents an optionally substituted phenyl group,
Represents a hydrogen atom or a benzyl group which may be substituted,
R ¹ represents a hydrogen atom or a lower alkyl group, and R ^{3 ′} represents a hydroxymethyl group or a protected formyl group. Or a salt thereof represented by the formula (3):

Embedded image (In the formula, Ar represents an optionally substituted phenyl group,
¹ represents a hydrogen atom or a lower alkyl group; R ² represents an aliphatic or aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent ^{; '} Represents a formyl group which may be protected. Wherein the compound or a salt thereof is subjected to a ring-closure reaction.

Embedded image (Wherein each symbol is as defined above) or a method for producing a compound thereof, or (4) a formula:

Embedded image (In the formula, Ar represents an optionally substituted phenyl group,
¹ is a hydrogen atom or a lower alkyl group, R ² is an aliphatic or aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, Y is a hydroxyl group Or a halogen atom. ) Or a salt thereof is subjected to a ring closure reaction.

Embedded image (Wherein each symbol is as defined above) or a method for producing a salt thereof,

Embedded image (In the formula, Ar represents an optionally substituted phenyl group,
¹ represents a hydrogen atom or a lower alkyl group. Or a salt thereof, and a compound represented by the formula:

Embedded image Wherein R represents a hydrogen atom or a benzyl group which may be substituted, and R ^{3 ′} represents a hydroxymethyl group or a protected formyl group. formula:

Embedded image (Wherein each symbol has the same meaning as described above), or a method for producing a compound represented by the formula (6):

Embedded image (In the formula, Ar represents an optionally substituted phenyl group,
Represents a hydrogen atom or a benzyl group which may be substituted,
R ¹ represents a hydrogen atom or a lower alkyl group, and R ^{3 ′} represents a hydroxymethyl group or a protected formyl group. )) Or a salt thereof, if necessary, followed by debenzylation,

Embedded image (In the formula, R ² represents an aliphatic or aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, and X represents a leaving group.) Or a compound represented by the formula:

Embedded image (Wherein, R ² has the same meaning as described above).

Embedded image (Wherein each symbol is as defined above) or a method for producing the compound represented by the formula (7):

Embedded image (In the formula, Ar represents an optionally substituted phenyl group,
¹ represents a hydrogen atom or a lower alkyl group, and R ² represents an aliphatic or aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent. Wherein the compound or a salt thereof is reacted with a halogenating agent.

Embedded image (Wherein, Y ′ represents a halogen atom, and other symbols are as defined above) or a method for producing a salt thereof, and formula (8):

Embedded image (In the formula, Ar represents an optionally substituted phenyl group,
¹ represents a hydrogen atom or a lower alkyl group. Wherein a compound represented by the formula (I) or a salt thereof is reacted with a lower alkyl orthoformate and an alkali metal azide:

Embedded image (Wherein each symbol is as defined above) or a method for producing a salt thereof.

The above formulas (I), (Ia), (Ib) and (I
c), (Id), (Ie), (II), (III),
(IIIa), (IIIb), (IIIc) and (I
In V), examples of the substituent in the “optionally substituted phenyl group” represented by Ar include halogen,
(Eg, fluorine, chlorine, bromine, iodine, etc.), halogenated lower (C _1-4 ) alkyl group, halogenated lower (C _1-4 ) alkoxy group, lower (C _1-4 ) alkylsulfonyl group and halogenated And a lower (C _1-4 ) alkylsulfonyl group. The substituent is preferably halogen (eg, fluorine, chlorine, bromine, iodine, etc.), and particularly preferably fluorine. The number of substituents is preferably one to three, more preferably one or two. As Ar, for example, a halogenated phenyl group, a halogenated lower (C
_1-4 ) alkylphenyl group, halogenated lower ( _C1-4 ) alkoxyphenyl group, lower ( _C1-4 ) alkylsulfonylphenyl group, halogenated lower ( _C1-4 ) alkylsulfonylphenyl group and the like. . Examples of the halogenated phenyl group include a phenyl group having 1-3 halogen atoms selected from fluorine, chlorine, bromine, iodine and the like, for example, 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl , 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl,
2-fluoro-4-chlorophenyl, 2-chloro-4-
Fluorophenyl, 2,4,6-trifluorophenyl, 4-bromophenyl and the like.
A phenyl group substituted with two fluorine atoms is preferred.
Examples of the halogenated lower (C _1-4 ) alkylphenyl group include 4-trifluoromethylphenyl.

The halogenated lower (C _1-4 ) alkoxyphenyl groups include, for example, 4-trifluoromethoxyphenyl, 4- (1,1,2,2-tetrafluoroethoxy) phenyl, 4- (2,2,2) -Trifluoroethoxy) phenyl, 4- (2,2,3,3,3-tetrafluoropropoxy) phenyl and the like. Low grade (C
_1-4 ) Examples of the alkylsulfonylphenyl group include 4-methanesulfonylphenyl. Examples of the halogenated lower (C _1-4 ) alkylsulfonylphenyl group include 4- (2,2,2-trifluoroethanesulfonyl) phenyl and 4- (2,2,3,3-tetrafluoropropanesulfonyl) phenyl , 4-
(2,2,3,3,3-pentafluoropropanesulfonyl) phenyl and the like. Ar is, in particular, a phenyl group substituted by one or two halogens, such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, −
Preferred are fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-bromophenyl and the like, and particularly preferred are 2-fluorophenyl and 2,4-difluorophenyl. R ¹ is preferably a lower alkyl group, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl linear or branched alkyl group having 1-4 carbon atoms. And among them, methyl is preferable.

The above formulas (I), (Ia), (Ib), (I
c), (Id), (Ie), (III), (III)
In a), (VI) and (VII), the “aliphatic hydrocarbon group” in the “aliphatic hydrocarbon group which may have a substituent” for R ² includes, for example, an alkyl group, a cycloalkyl Group, alkenyl group and alkynyl group. Examples of the alkyl group include a linear or branched alkyl group having 1 to 12 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl. , Ter
t-butyl, heptyl, octyl, nonyl, decyl, dodecyl and the like, and especially a lower alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl) , Tert
-Butyl and the like). Examples of the cycloalkyl group include those having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. (Eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) are preferred. Examples of the alkenyl group include those having 2 to 4 carbon atoms, specifically, vinyl, propenyl, butenyl and the like, and particularly, an alkenyl group having 2 to 3 carbon atoms (eg,
Vinyl, propenyl, etc.). Examples of the alkynyl group include those having 2 to 4 carbon atoms such as ethynyl, propynyl, and butynyl.
Three alkynyl groups (eg, vinyl, propynyl) are preferred.

The "aromatic hydrocarbon group" in the "aromatic hydrocarbon group optionally having substituent (s)" for R ² includes, for example, phenyl, naphthyl, biphenyl, anthryl, indenyl and the like having 6 to 6 carbon atoms. 14, and an aryl group having 6 to 10 carbon atoms (eg, phenyl, naphthyl, etc.) is particularly preferable. The “aromatic heterocyclic group” in the “aromatic heterocyclic group optionally having substituent (s)” for R ² represents one hydrogen atom bonded to the aromatic heterocyclic ring.
The aromatic heterocyclic ring includes, for example, one to several hetero atoms such as a nitrogen atom (which may be oxidized), an oxygen atom, and a sulfur atom, and preferably 1 to A 5- to 8-membered ring containing four, a condensed ring thereof or a condensed ring with a benzene ring is shown. Specific examples of such an aromatic heterocyclic group include imidazolyl, triazolyl (1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, pyrazolyl, pyridyl, thiazolyl, isothiazolyl, and thiadiazolyl (1, 2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-
Thiadiazolyl), thienyl, furyl, pyrrolyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl and other aromatic heterocyclic groups and benzimidazolyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, benzothiazolyl, quinolyl, Examples include fused aromatic heterocyclic groups such as isoquinolyl, quinazolinyl, and indolyl. As the aromatic heterocyclic group, 5 or 6 containing 1-3 hetero atoms arbitrarily selected from a nitrogen atom, a sulfur atom and an oxygen atom are particularly preferred.
Membered aromatic heterocyclic groups (eg, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, thienyl, furyl,
Pyridyl, pyrimidyl, etc.) are preferred.

With respect to R ² , examples of the substituent in the “optionally substituted aliphatic or aromatic hydrocarbon group or the optionally substituted aromatic heterocyclic group” include a hydroxyl group, A carboxyl group which may be esterified (eg, carboxy; an alkoxycarbonyl group having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.);
Nitro, amino, acylamino groups (eg, alkanoylamino groups having 1-10 carbon atoms such as acetylamino, propionylamino, butyrylamino, etc.), 1-10 carbon atoms
An amino group mono- or di-substituted with an alkyl group (eg, methylamino, dimethylamino, diethylamino, dibutylamino, etc.) and a 5- or 6-membered cyclic amino group which may be substituted (eg, pyrrolidinyl, morpholino, piperidino) , Pyrazolidinyl, perhydroazepinyl, piperazinyl, 4-benzylpiperazinyl, 4-acetylpiperazinyl, 4- (4-trifluoromethoxyphenyl) -1-piperazinyl, 4- [4- (1,1,
2,2-tetrafluoroethoxy) phenyl] -1-piperazinyl, 4- [4- (2,2,3,3-tetrafluoropropoxy) 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-trifluoromethylphenyl) -1-piperazinyl, etc.), an alkoxy group having 1-6 carbon atoms, (eg, methoxy, ethoxy, propoxy, butoxy, etc.), a halogen atom (eg, fluorine, chlorine, Bromine, etc.),
An alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, butyl, etc.), a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl, cyclopentyl, etc.), 6 carbon atoms
-14 aryl group (eg, phenyl, naphthyl, indenyl, etc.), halogeno-alkyl group having 1 to 6 carbon atoms (eg,
Trifluoromethyl, dichloromethyl, trifluoroethyl, etc., halogeno-alkoxy group having 1 to 6 carbon atoms (eg, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoro Ethoxy, 2,2,3,3-tetrafluoropropoxy, 2,
2,3,3,3-pentafluoropropoxy, 2,2
3,3,4,4,5,5-octafluoropentoxy,
2-fluoroethoxy), oxo, thioxo, mercapto, an alkylthio group having 1 to 6 carbon atoms (eg, methylthio, ethylthio, propylthio, 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.) 5- or 6-membered aromatic heterocyclic group (eg, pyrrolyl, pyrazolyl, imidazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanil, 1,3,4
-Thiadiazolyl, 1,2,3-thiadiazolyl, 1,
2,5-thiadiazolyl, 1,2,4-thiadiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyridazinyl and the like, fused aromatic heterocyclic group (eg, benzimidazolyl, imidazopyrimidinyl, imidazopyridinyl,
Imidazopyrazinyl, imidazopyridazinyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolyl, indolyl, and the like), among which halogeno-alkoxy groups having 1 to 6 carbon atoms and 5-membered aromatic heterocyclic groups are preferable. Among them, 1,1,2,2-tetrafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, pyrazolyl (eg, 1H-pyrazol-1-yl), imidazolyl (eg, 1H-imidazol-1-yl) , 1, 2,
3-triazolyl (eg, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazole-2-
Yl), 1,2,4-triazolyl (eg, 1H-1,
Particularly preferred are 2,4-triazol-1-yl) and tetrazolyl (eg, 1H-tetrazol-1-yl, 2H-tetrazol-2-yl). The number of the above substituents is preferably 1-3, more preferably 1-2.
Individual.

The "aliphatic or aromatic hydrocarbon group optionally having substituent (s) or the aromatic hydrocarbon group optionally having substituent (s)" for R ² has a substituent. An aromatic hydrocarbon group which may be substituted is preferable, and a phenyl group having a substituent is particularly preferable. Among them, a phenyl group substituted with a halogeno-alkoxy group having 1 to 6 carbon atoms [eg, 4- (1, 1,2,2-tetrafluoroethoxy) phenyl, 4- (2,2,3,3-tetrafluoropropoxy) phenyl] and a phenyl group substituted with a 5-membered aromatic heterocyclic group [pyrazolyl as a substituent , Imidazolyl, 1,2,3-triazolyl, 1,2,4-
A phenyl group having triazolyl or tetrazolyl,
For example, 4- (1H-pyrazol-1-yl) phenyl, 4- (1H-imidazol-1-yl) phenyl,
4- (1H-1,2,3-triazol-1-yl) phenyl, 4- (2H-1,2,3-triazol-2-
Yl) phenyl, 4- (1H-1,2,4-triazol-1-yl) phenyl, 4- (1H-tetrazole-
1-yl) phenyl, 4- (2H-tetrazol-2-
Yl) phenyl] is preferred.

The above formulas (I), (Ia), (Ic) and (I
During I) and (V), "protected formyl group" in "optionally protected formyl group" represented by R ³ and R ^{3 ",} and" protected formyl group "represented by R ^{3 '} Is a compound wherein the formyl group is protected by a compound known as a protecting group for a formyl group, and the protected formyl group is preferably a compound usually known as an acetal. Such protected formyl groups include dialkoxymethyl (eg, dimethoxymethyl, diethoxymethyl, dipropoxymethyl, dibutoxymethyl, etc.), substituted dialkoxymethyl [eg, bis (2,
2,2-trichloroethoxy) methyl, bis (benzyloxy) methyl, bis (2-nitrobenzyloxy) methyl, etc.], dialkanoyloxymethyl (eg, diacetoxymethyl, etc.), optionally substituted 1,3 -Dioxan-2-yl [eg, 1,3-dioxan-2-yl,
5-methylene-1,3-dioxan-2-yl, 5,5
-Dibromo-1,3-dioxan-2-yl, 5- (2
-Pyridyl) -1,3-dioxan-2-yl and the like, and optionally substituted 1,3-dioxolan-2-yl [eg, 1,3-dioxolan-2-yl, 4- (3-butenyl) ) -1,3-Dioxolan-2-yl, 4-phenyl-1,3-dioxolan-2-yl, 4- (2-nitrophenyl) -1,3-dioxolan-2-yl,
4,5-bis (methoxymethyl) -1,3-dioxolan-2-yl, benzo-1,3-dioxol-2-yl, etc.], 1,5-dihydro-3H-2,4-benzodioxepin -3-yl, bis (alkylthio) methyl [eg, bis (methylthio) methyl, bis (ethylthio)
Methyl, bis (propylthio) methyl, bis (butylthio) methyl, bis (pentylthio) methyl, etc.], bis (arylthio) methyl [eg, bis (phenylthio) methyl etc.], bis (aralkylthio) methyl [eg, bis (benzylthio) methyl ) Methyl etc.], bis (alkanoylthio) methyl [eg, bis (acetylthio) methyl etc.],
1,3-dithian-2-yl, 1,3-dithiolan-2
-Yl, 1,5-dihydro-3H-2,4-benzodithiepin-3-yl, 1,3-oxathiolan-2-yl and the like.

Embedded image (Wherein, R ⁴ and R ⁵ are the same or different and each represents an aliphatic hydrocarbon group, or R ⁴ and R ⁵ are bonded to each other to represent a lower alkylene having 2 or 3 carbon atoms) Is preferred. Examples of the aliphatic hydrocarbon group represented by R ⁴ and R ⁵ include lower alkyl groups having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, butyl, etc.), and among them, methyl and ethyl are preferable. Ethyl is more preferred. When R ⁴ and R ⁵ combine to form a lower alkylene having 2 or 3 carbon atoms, examples of the lower alkylene include ethylene and propylene. R ³ and R ^{3 "}
As the “protected formyl group” in the “optionally protected formyl group” represented by and the “protected formyl group” represented by R ^{3 ′} , dimethoxymethyl, diethoxymethyl, dipropoxymethyl, etc. No
(C _1-4 ) A cyclic group such as an alkoxymethyl group and a 1,3-dioxan-2-yl or 1,3-dioxolan-2-yl group is preferred. In the formulas (II) and (V), the optionally substituted benzyl group represented by R includes, for example, benzyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, p-methylbenzyl and the like. . Among them, benzyl is preferred. Formulas (I), (I
In b) and (Ie), the halogen atom represented by Y and Y ′ includes chlorine, bromine and iodine atoms,
Among them, a chlorine atom is preferred.

In the formula (VI), the leaving group represented by X is removed when reacting the compound represented by the formula (VI) with the compound represented by the formula (II) (debenzylated if necessary). It is preferably a group represented by the formula: R ⁶ —O— (wherein R ⁶ represents a phenyl group which may be substituted). Examples of the optionally substituted phenyl group represented by R ⁶ include halogen, (eg,
Chlorine, bromine, etc.), lower alkyl groups (eg, methyl, ethyl, etc.), and phenyl groups which may be substituted by nitro. Examples of the leaving group represented by X include a phenyloxy group, a chlorophenyloxy group, and a nitrophenyloxy group, and among them, a phenyloxy group is preferable.
The compound represented by the formula (I) or a salt thereof (hereinafter, also referred to as compound (I)) and the compound represented by the formula (II) or a salt thereof (hereinafter also referred to as compound (II)) are represented by a molecule Has one or more asymmetric carbon atoms, and thus has two or more stereoisomers, and both the stereoisomers and mixtures thereof are included in the present invention. In particular, when R ¹ is a methyl group, an optically active substance or the like in which both the carbon to which the optionally substituted phenyl group represented by Ar and the carbon to which R ¹ is bonded have the (R) configuration is preferable.

The compounds (I) and (II) of the present invention include a compound represented by the formula (III) or (IIIa) or a salt thereof [hereinafter sometimes referred to as compound (III) or compound (IIIa). [Examples of the above formula (B),
Compounds Represented by (C), (E) and (F)]. Particularly preferred specific examples of compound (III) include, for example, 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2- Hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1,1,2,2-tetrafluoroethoxy)
Phenyl] -2 (1H, 3H) -imidazolone 1-[(1R, 2R) -2- (2-fluorophenyl)
-2-hydroxy-1-methyl-3- (1H-1,2,2
4-triazol-1-yl) propyl] -3- [4-
(2,2,3,3-tetrafluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone 1-[(1R, 2R) -2- (2-fluorophenyl)
-2-hydroxy-1-methyl-3- (1H-1,2,2
4-triazol-1-yl) propyl] -3- [4-
(1,1,2,2-tetrafluoroethoxy) phenyl] -2 (1H, 3H) -imidazolone 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1- Methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-1,2,3-triazol-1-yl) phenyl] -2 (1H, 3H) -imidazolone 1-[(1R, 2R) -2- (2,4-difluorophenyl)- 2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-tetrazol-1-yl) phenyl]
-2 (1H, 3H) -imidazolone 1-[(1R, 2R) -2- (2-fluorophenyl)
-2-hydroxy-1-methyl-3- (1H-1,2,2
4-triazol-1-yl) propyl] -3- [4-
(1H-1,2,3-triazol-1-yl) phenyl] -2 (1H, 3H) -imidazolone 1-[(1R, 2R) -2- (2-fluorophenyl)
-2-hydroxy-1-methyl-3- (1H-1,2,2
4-triazol-1-yl) propyl] -3- [4-
(1H-tetrazol-1-yl) phenyl] -2 (1
H, 3H) -imidazolone 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-pyrazol-1-yl) phenyl]-
2 (1H, 3H) -imidazolone 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-imidazol-1-yl) phenyl]
-2 (1H, 3H) -imidazolone 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-1,2,4-triazol-1-yl) phenyl] -2 (1H, 3H) -imidazolone and the like. Particularly preferred specific examples of the compound (IIIa) include, for example, 1- [(1R, 2R) -2-
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2-imidazolidinone 1-[(1R, 2R) -2- (2,4-difluorophenyl) ) -2-Hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1,1,2,2-tetrafluoroethoxy)
Phenyl] -2-imidazolidyridinone 1-[(1R, 2R) -2- (2-fluorophenyl)
-2-hydroxy-1-methyl-3- (1H-1,2,2
4-triazol-1-yl) propyl] -3- [4-
(2,2,3,3-tetrafluoropropoxy) phenyl] -2-imidazolidinone 1-[(1R, 2R) -2- (2-fluorophenyl)
-2-hydroxy-1-methyl-3- (1H-1,2,2
4-triazol-1-yl) propyl] -3- [4-
(1,1,2,2-tetrafluoroethoxy) phenyl] -2-imidazolidinone 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3 -(1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy -1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-tetrazol-1-yl) phenyl]
-2-imidazolidinone 1-[(1R, 2R) -2- (2-fluorophenyl)
-2-hydroxy-1-methyl-3- (1H-1,2,2
4-triazol-1-yl) propyl] -3- [4-
(1H-1,2,3-triazol-1-yl) phenyl] -2-imidazolidinone 1-[(1R, 2R) -2- (2-fluorophenyl)
-2-hydroxy-1-methyl-3- (1H-1,2,2
4-triazol-1-yl) propyl] -3- [4-
(1H-tetrazol-1-yl) phenyl] -2-imidazolidinone 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-pyrazol-1-yl) phenyl]-
2-imidazolidinone 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-imidazol-1-yl) phenyl]
-2-imidazolidinone 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (1H-1,2,4-triazol-1-yl) phenyl] -2-imidazolidinone and the like.

The compound represented by the formula (III) and the compound represented by the formula (IIIa) can be produced, for example, by a method represented by the following reaction formula.

Embedded image (Wherein each symbol has the same meaning as described above.) That is, the compound represented by the formula (IV) or a salt thereof (hereinafter, also referred to as compound (IV)) and the compound represented by the formula (V) [ Compound (II) may be produced by reacting compound (II) with compound (II), followed by subjecting compound (II) to a debenzylation reaction, if necessary, to give compound (IIa). Or a compound represented by the formula (Ic) by reacting a compound represented by the following formula (hereinafter sometimes referred to as compound (VI)) or a compound represented by the formula (VII): A salt thereof (hereinafter also referred to as compound (Ic)) is produced, and compound (Ic) is deprotected or halogenated as necessary to obtain compound (I). It can be prepared compound (III) or the compound (IIIa) by subjecting the.

In the reaction of compound (IV) with compound (V), compound (V) is used in an amount of about 1 to 1 mole of compound (IV).
The reaction is carried out by reacting 100 mol, preferably about 3 to 20 mol. This reaction is carried out in a solvent that does not inhibit the reaction in the presence or absence of an organic metal or in the absence of a solvent. Examples of the solvent that does not inhibit the reaction include alcohols such as methanol, ethanol, 1-propanol, 2-propanol and 1-butanol, sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, and acetonitrile and the like. Nitriles, aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; dimethylformamide, acetamide, dimethylacetamide, and 1,3-dimethyl-2 Amides such as -imidazolidinone and 1-methyl-2-pyrrolidone. Among these solvents, methanol,
Ethanol, 1-propanol, 2-propanol, 1
Alcohols such as butanol are preferred. These solvents may be used alone or in a mixture of two or more at an appropriate ratio. The amount of the solvent to be used is generally about 100-fold weight or less, preferably about 1- to 50-fold weight, particularly preferably about 5- to 20-fold weight, relative to compound (IV). The reaction temperature is suitably about 40 to 200 ° C,
About 70-180 ° C is preferred. The reaction time is suitably about 1 to 80 hours, preferably about 5 to 50 hours.

When this reaction is carried out in the presence of an organic metal, examples of the organic metal include titanium alkoxide (eg, titanium tetraisopropoxide, titanium tetraisobutoxide) and ytterbium trifluoromethanesulfonate. Among them, titanium alkoxide is preferable. The amount of these organic metals to be used is about 0.1-5 times (molar ratio), preferably about 1-2 times (molar ratio), relative to compound (IV). The method for adding the organic metal is not particularly limited. For example, the compound (I
The organic metal may be added after adding the compound (V) and the compound (V) to the solvent, or the compound (IV) and the compound (V) may be added to a mixed solution obtained by adding the organic metal to the solvent. May be. Further, the compound (IV), the compound (V) and the organic metal may be sequentially added to the solvent. Compound (II) wherein R is a hydrogen atom [hereinafter sometimes referred to as compound (IIa)] and compound (VI) or compound (VI)
The reaction with I) is carried out in the presence or absence of a base, in a solvent that does not inhibit the reaction, or in the absence of a solvent. In this reaction, compound (V) is added to 1 mole of compound (IIa).
Preferably, about 0.5-5 mol of I) or compound (VII) is reacted, more preferably about 0.7-1.5 mol. When a base is used, examples of the base include inorganic bases (eg, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc.) and organic bases (eg, triethylamine, pyridine, diisopropylethylamine, etc.). Particularly, organic bases such as triethylamine and pyridine are preferable. When a base is present, the amount of the base to be used is preferably about 0.5 to 5 times (molar ratio), particularly preferably about 0.9 to 2 times (molar ratio) with respect to compound (IIa). .

Examples of the solvent which does not inhibit the reaction used in the reaction of compound (IIa) with compound (VI) or compound (VII) include sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, and acetonitrile. Such as nitriles, benzene, toluene, aromatic hydrocarbons such as xylene, dichloromethane, chloroform, 1,
Halogenated hydrocarbons such as 2-dichloroethane, esters such as ethyl acetate, dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-
Amides such as 2-imidazolidinone and 1-methyl-2-pyrrolidone are exemplified. These solvents may be used alone or in combination of two or more at an appropriate ratio. In the reaction of compound (IIa) with compound (VI) or compound (VII), the reaction temperature is about -10 to 1
50 ° C is suitable, with about 0 to 120 ° C being preferred. The reaction time is suitably from about 0.1 to 50 hours, and from about 0.5 to 3 hours.
0 hours is preferred. When R in compound (II) is an optionally substituted benzyl group, the compound can be subjected to a debenzylation reaction to lead to a compound [compound (IIa)] wherein R is a hydrogen atom. . This debenzylation reaction can be easily carried out by a generally known means for removing a benzyl group of a benzylated amino group. These tools are, for example, "Protective Groups in Organic Synthesis,
A Willy Interscience Publication ". When R ^{3 ′} is a protected formyl group in the compound (Ic), the compound can be led to a compound in which R ³ is a formyl group in the formula (I) by deprotecting the formyl group if necessary. . This deprotection reaction can be easily carried out by a generally known means for removing the protecting group of the formyl group. Such means are described, for example, in "Protective Groups in Organic Synthesis, Awillie Interscience Publication". In the compound (Ic), the compound [Compound (Id)] in which R ^{3 ′} is a hydroxymethyl group can be obtained by halogenating the hydroxyl group with a halogenating agent in a solvent that does not inhibit the reaction, if necessary. )), A compound [compound (Ie)] wherein Y is a halogen atom. This halogenation reaction is performed by reacting a halogenating agent in a solvent that does not inhibit the reaction. Examples of the halogenating agent to be used include thionyl halides such as thionyl chloride and thionyl bromide, and phosphorus halide compounds such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, and phosphorus oxychloride. Chlorinating agents such as thionyl and phosphorus oxychloride are preferred. These halogenating agents are used in organic solvents (eg, benzene, toluene, xylene, chloroform,
(Dichloromethane, ethyl acetate, etc.). The amount of the halogenating agent to be used is preferably about 0.5 to 5 times (molar ratio), more preferably about 0.7 to 3.0 times (molar ratio), relative to compound (Id). In the present reaction, solvents that do not inhibit the reaction include sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, nitriles such as acetonitrile, and aliphatic hydrocarbons such as hexane. Aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; esters such as ethyl acetate; dimethylformamide, acetamide, dimethylacetamide; 3-dimethyl-2-imidazolidinone, 1
And amides such as -methyl-2-pyrrolidone. Among these solvents, dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-
Amides such as imidazolidinone and 1-methyl-2-pyrrolidone are preferred, and dimethylformamide, dimethylacetamide and 1-methyl-2-pyrrolidone are particularly preferred. These solvents may be used alone or in a combination of two or more at an appropriate ratio. When two or more are mixed, it is preferable to use the amides (one or more) exemplified as preferred solvents in combination with another solvent and mix them in an appropriate ratio. In the present halogenation reaction, the reaction temperature is suitably about −10 ° C. to 80 ° C., and about 1 ° C.
0 ° C to 60 ° C is preferred. The reaction time is suitably from about 0.1 to 20 hours, preferably from about 0.5 to 8 hours.

In the compound (I), the intramolecular ring closure reaction for producing the compound (III) from the compound [compound (Ia)] wherein R ³ is a formyl group which may be protected is carried out in a solvent which does not inhibit the reaction. It is carried out by the presence of an acid. Examples of the acid used include inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.) and organic acids (eg, methanesulfonic acid, trifluoromethanesulfonic acid, toluenesulfonic acid, etc.)
And particularly preferred are inorganic acids such as hydrochloric acid and sulfuric acid. These acids can be used as an aqueous solution diluted with water. The amount of the acid to be used is preferably about 1 to 20 times (molar ratio) based on 1 mole of compound (Ia), and about 1.0 to 10 times.
A double amount (molar ratio) is particularly preferred. Solvents that do not inhibit the reaction used in this reaction include water or alcohols such as methanol, ethanol, propanol and butanol, sulfoxides such as dimethylsulfoxide, nitriles such as acetonitrile, ethers such as tetrahydrofuran and dioxane, acetone and the like. Ketones and the like, and alcohols such as methanol are particularly preferable. These solvents may be used alone. Two or more kinds may be used by mixing at an appropriate ratio. In the intramolecular ring closure reaction of the compound (Ia), the reaction temperature is suitably about 20 ° C to 100 ° C, and about 40 ° C to 80 ° C.
C is preferred. The reaction time is suitably about 0.5 to 40 hours, preferably about 1 to 20 hours.

In the intramolecular ring closure reaction for producing compound (IIIa) from compound (compound (Ie)) wherein Y is a halogen atom in compound (I), a base is preferably present in a solvent that does not inhibit the reaction. This is done by:
In the present reaction, solvents that do not inhibit the reaction include sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, nitriles such as acetonitrile, and aliphatic hydrocarbons such as hexane. Aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; esters such as ethyl acetate; dimethylformamide, acetamide, dimethylacetamide; 3-dimethyl-2-imidazolidinone, 1
And amides such as -methyl-2-pyrrolidone. These solvents may be used alone or in a combination of two or more at an appropriate ratio. Examples of the base that can be used in this reaction include inorganic bases (eg, sodium hydride, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, etc.) and organic bases (eg, triethylamine, butylamine, dibutylamine, benzyl) Amine, dimethylaminopyridine, pyrrolidine, N-ethyldiisopropylamine, piperidine, morpholine and the like), and particularly, organic bases such as triethylamine, dimethylaminopyridine and piperidine are preferable. When a base is present, the amount of the base to be used is preferably about 0.5 to 50 times (molar ratio), more preferably about 0.5 to 10 times (molar ratio), relative to compound (Ie). The reaction temperature is suitably from about -20C to 100C, preferably from about -10C to 60C. The reaction time is approx.
1 to 24 hours is suitable, preferably about 0.5 to 10 hours.

The intramolecular ring closure reaction for producing compound (IIIa) from compound [compound (Id)] in which Y is a hydroxyl group in compound (I) is carried out in a solvent that does not inhibit the reaction in the presence of a condensing agent. Will be As the condensing agent, a combination of a halogenating agent and a base or a combination of an azodicarboxylic acid and a phosphine is preferable. Solvents that do not inhibit the reaction when used in combination with a halogenating agent and a base as a condensing agent include sulfoxides such as dimethyl sulfoxide, ethers such as diethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, and nitriles such as acetonitrile. , Aliphatic hydrocarbons such as hexane, aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, esters such as ethyl acetate, dimethylformamide And acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone and the like. These solvents may be used alone or in a combination of two or more at an appropriate ratio. When only one kind is used, amides such as dimethylformamide, dimethylacetamide and 1-methyl-2-pyrrolidone are preferable, and dimethylacetamide,
1-methyl-2-pyrrolidone is particularly preferred. When two or more kinds are mixed, it is preferable to mix amides such as dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidone and other solvents at an appropriate ratio. As the halogenating agent used in this reaction,
Examples thereof include thionyl halides such as thionyl chloride and thionyl bromide, and phosphorus halide compounds such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, and phosphorus oxychloride, and particularly chlorine such as thionyl chloride and phosphorus oxychloride. Agents are preferred. These halogenating agents can be used as a solution diluted with an organic solvent (eg, benzene, toluene, xylene, chloroform, dichloromethane, ethyl acetate, etc.). The amount of the halogenating agent to be used is preferably about 0.5 to 5 times (molar ratio) the compound (Id), and is about 0.7 to 5 times.
The amount (molar ratio) is particularly preferable.

As the base used in the present reaction, for example, an inorganic base (eg, sodium hydride, sodium hydroxide,
Sodium carbonate, potassium carbonate, etc.) and organic bases (eg, triethylamine, butylamine, dibutylamine, benzylamine, dimethylaminopyridine, pyrrolidine, N-ethyldiisopropylamine, piperidine,
Morpholine, etc.), and particularly preferred are organic bases such as triethylamine, dimethylaminopyridine and piperidine. The amount of the base to be used is preferably about 0.5 to 50 times (molar ratio) to the compound (Id), and about 0.5 to 20 times.
A double amount (molar ratio) is particularly preferred. The order of addition of the halogenating agent and the base may be, for example, after adding the base to the solution of the compound (Id), the halogenating agent may be added, or after the halogenating agent is added, the base may be added. Both may be added at the same time, and it is not particularly limited, but it is preferable to add a base to the solution of compound (Id), and then add a halogenating agent, or add a halogenating agent and then add a base. The reaction temperature is suitably from about -20C to 100C, preferably from about -10C to 60C. The reaction time is about 0.1 to
Fifty hours is suitable, preferably about 1 to 24 hours. When the intramolecular ring-closure reaction for producing the compound (IIIa) from the compound (Id) is performed using a combination of azodicarboxylic acids and phosphines, examples of the azodicarboxylic acids include diethyl azodicarboxylate, dimethyl azodicarboxylate, Azodicarboxylic acid diisopropyl ester, N, N, N ′, N′-tetramethylazodicarboxamide, 1,1 ′-(azodicarbonyl) dipiperidine,
N, N, N ', N'-tetraisopropylazodicarboxamide, 1,6-dimethyl-1,5,7-hexahydro-1,
Examples include azodicarboxylic acid esters such as 4,6,7-tetrazocine-2,5-dione and azodicarboxylic acid amides. Examples of phosphines include triarylphosphines such as triphenylphosphine, tributylphosphine, and trimethylphosphine; And trialkylphosphines. Further, examples of a combination of azodicarboxylic acids and phosphines and a reactant capable of performing a similar reaction include phospholanes such as cyanomethylenetributylphosphorane and cyanomethylenetriethylphosphorane. These reactants are usually used in an organic synthesis reaction known as the Mitsunobu reaction, and are described, for example, in "Organic Reactions Vol. 42".
And "Journal of the Society of Synthetic Organic Chemistry, 55, 631, 19
1997 ".

Solvents which do not inhibit this reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, nitriles such as acetonitrile, aliphatic hydrocarbons such as hexane, benzene, toluene, xylene and the like. Aromatic hydrocarbons,
These solvents include halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, and esters such as ethyl acetate. These solvents may be used alone, or two or more kinds thereof may be mixed at an appropriate ratio. May be used. The amount of the diazocarboxylic acid and the phosphine used in this reaction is preferably about 0.5 to 5 times (molar ratio), particularly about 1 to 2 times (molar ratio) based on the compound (Id). preferable. The reaction temperature is suitably from about 0 ° C to 50 ° C,
About 10-30 ° C is preferred. The reaction time is about 0.1 to 24
Time is appropriate, with about 1 to 5 hours being preferred. In this reaction, the addition order of the compound (Id), diazocarboxylic acids and phosphines is not particularly limited. General formula (IIIa)
Wherein R ² is 4-aminophenyl [compound (I
IIb)] or a salt thereof, wherein in formula (III), R ² is 4-
Formulas that are nitrophenyl:

Embedded image (Wherein each symbol is as defined above) or a salt thereof (hereinafter, also referred to as compound (IIId)) in a solvent that does not inhibit the reaction, by subjecting the compound to a catalytic reduction reaction. Can be manufactured. Examples of the solvent used in this reaction that do not inhibit the reaction include water or organic solvents such as alcohols (eg, methanol, ethanol, propanol, isopropyl alcohol, butanol, etc.), esters (eg, ethyl acetate, etc.), and hydrocarbons. (Examples: benzene, toluene, hexane, xylene, etc.),
Single or mixed solvents such as organic carboxylic acids (eg, acetic acid, propionic acid, etc.) can be mentioned. This reaction is usually performed in the presence of a catalyst. As the catalyst, a suitable metal catalyst such as palladium-carbon, platinum-carbon, Raney nickel or the like is used. This catalytic reduction reaction is from normal pressure to about 150kg
The reaction is carried out at a temperature from room temperature to about 100 ° C. under a pressure of about / cm ² . Further, the compound (IIIb) or a salt thereof is represented by the formula (IIIa) wherein R ² is 4-nitrophenyl:

Embedded image (Wherein each symbol is as defined above). The compound or a salt thereof can be produced by subjecting the compound or a salt thereof to a reduction reaction in a solvent that does not inhibit the reaction. This reaction is usually performed in the presence of a reducing agent. Examples of the reducing agent include a combination of hydrogen and a metal catalyst (eg, palladium-carbon, platinum-carbon, Raney nickel, etc.), a combination of hydrazine and a metal (eg, palladium-carbon, ferric chloride, etc.), a metal (eg,
Examples thereof include a combination of iron, zinc, tin, aluminum amalgam, Raney alloy, and the like, and an acid (eg, hydrochloric acid, acetic acid, etc.), water or an alkali aqueous solution (eg, sodium hydroxide aqueous solution, etc.). The reaction temperature is suitably from about 0 to 100 ° C,
About 10-40 ° C is preferred. Solvents that do not inhibit the reaction used in this reaction include water or organic solvents such as alcohols (eg, methanol, ethanol, propanol, isopropyl alcohol, butanol, etc.), esters (eg, ethyl acetate, etc.), hydrocarbons (Examples: benzene, toluene, hexane, xylene, etc.), ethers (eg, tetrahydrofuran, etc.), nitriles (eg, acetonitrile, etc.), and organic carboxylic acids (eg, acetic acid, propionic acid, etc.). These solvents can be appropriately selected, singly or mixed depending on the reducing agent used. In the formula (IIIa), a compound wherein R ² is a 4-aminophenyl group or a salt thereof [Compound (IIIb)]
Is reacted with an alkyl orthoformate and a metal azide to form R in the general formula (IIIa)
It can be led to a compound wherein ² is a 4- (1H-tetrazol-1-yl) phenyl group or a salt thereof [compound (IIIc)]. As the alkyl orthoformate,
Lower (C _1-4 ) alkyl orthoformates such as methyl orthoformate, ethyl orthoformate, propyl orthoformate, and butyl orthoformate include, among others, methyl orthoformate and ethyl orthoformate. Orthoformic acid (C
_1-2 ) Alkyl esters are preferred. Examples of the metal azide include alkali metal azides such as sodium azide, and among them, sodium azide is particularly preferred. This reaction is usually performed in the presence of a solvent. As the solvent,
For example, organic acids such as acetic acid and propionic acid are preferred, and acetic acid is particularly preferred. The reaction temperature is usually 0 to 150
° C, preferably 20 to 100 ° C. The reaction time is generally 10 minutes to 24 hours, preferably 1 to 10 hours. Compounds (III), (IIIa), (IIIb),
(IIIc), (IIId), (IIIe) and their synthetic intermediates (I), (Ia), (Ib),
(Ic), (Id), (Ie), (II) and (II)
a) can be obtained from the reaction mixture in a manner known per se, for example by extraction,
Isolation and purification can be performed by using means such as concentration, neutralization, filtration, recrystallization, and chromatography.

Compounds (I), (Ia), (Ib) and (I
c), (Id), (Ie), (II), (IIa),
(III), (IIIa), (IIIb), (III)
c), (IIId) and (IIIe) can also be isolated as salts, such as salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), Salts with organic acids (eg, acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid, and the like) are included. Compound (I),
(Ia), (Ib), (Ic), (Id), (Ie),
(II), (IIa), (III), (IIIa),
(IIIb), (IIIc), (IIId) and (I
The salts of IIe) can be prepared according to known methods, for example, of the formulas (I), (Ia), (Ib), (Ic), (Id),
(Ie), (II), (IIa), (III), (II)
It can be produced by adding an inorganic acid or an organic acid to the compound represented by Ia), (IIIb), (IIIc), (IIId) or (IIIe). Compounds (I), (Ia), (Ib), (Ic), (I
d), (Ie), (II), (IIa), (III),
(IIIa), (IIIb), (IIIc), (III)
d) and (IIIe) may be hydrates or non-hydrates. Compounds (I) and (II) may have at least two stereoisomers as described above, but if desired, these isomers can be produced individually. For example, by carrying out the above reaction using a single isomer of the starting compound (IV), the compounds (I) and (I) of the present invention are obtained.
A single isomer of I) can be obtained. When the product is a mixture of two or more isomers, the product is separated by a usual separation method, for example, a method of forming a salt with an optically active acid (eg, camphorsulfonic acid, tartaric acid, or the like), or a method of producing a chromatographic mixture. Each of them can be separated into isomers by separation means such as chromatography, fractional recrystallization and the like.

Particularly preferred examples of the compounds (III) and (IIIa) useful as antifungal agents produced by the production method of the present invention are, as described above, a compound in which R ¹ is methyl, Ar is bonded to carbon and R ^An optically active substance in which both carbons to which ¹ is bonded have the (R) -configuration. Such an optically active substance is an optically active oxirane derivative in which R ¹ in compound (IV) is methyl, the carbon bonded to Ar is (R) -configuration, and the carbon bonded to R ¹ is (S) -configuration. In the compounds represented by formulas (II) and (I) derived by chemical synthesis from, both the carbon bonded to Ar and the carbon bonded to R ¹ (methyl) are (R)-
It can be synthesized via an optically active synthetic intermediate in the configuration. The raw material compound (IV) in the present invention can be produced by a method known per se, for example, a chemical and pharmaceutical buretan (Chem. Pharm. Bul).
l. ), 41, 1035-1042, 1993 and 43, 432-440, 1995 or a method analogous thereto. The compound (V) which is another starting compound in the present invention
I) can be carried out by a method known per se, for example, Chemical and Pharmaceutical Buretane (Chem. Phar
m. Bull. 44, 314-327, 1996.
It can be produced by the method described in the year and WO9625410A or a method analogous thereto.

The compound (I) obtained by the production method of the present invention
II) and (IIIa) have low toxicity and antifungal activity, and include, for example, Candida (eg, Candida albicans, Candida utilis, Candida glabrata), Histoplasma (eg, Histoplasma capsatum), Aspergillus Genus [eg: Aspergillus niger, Aspergillus fumigatus etc.], Cryptococcus [eg: Cryptococcus neoformans etc.], Trichophyton [eg: Trichophyton
Rupurum, trichophyton mentagrophytes etc.],
It has a strong antibacterial activity against Microsporum bacteria [eg: Microsporum gypseum etc.], Malassezia bacteria [eg: Malassezia furfa etc.], so that fungal infections in mammals (human, livestock, poultry etc.) [ Example: mucosal candidiasis due to Candida (thrush, stomatitis, vulva vaginal candidiasis, penile candidiasis), skin candidiasis (candida albicans, candidal intertrigo, canalida, eczema) Dermatophytosis, candida onychitis, candida peritonitis, candida extraotitis, skin lesions of candida sepsis, generalized superficial candidiasis, Candida granuloma, congenital cutaneous candidiasis, candizide), chronic mucosa Cutaneous and visceral candidiasis (respiratory candidiasis, digestive candidiasis, candida sepsis, candida endocarditis, urinary candidiasis, ocular candidiasis, CNS candidiasis, joint and bone candidiasis, Candida peritonitis, hepatic candidiasis, intrauterine candidiasis), etc .; Acute pulmonary histoplasmosis due to Histoplasma, chronic pulmonary histoplasmosis, disseminated histoplasmosis, etc .; Respiratory aspergillosis due to Aspergillus spp. Central nervous aspergillosis, Aspergillus endocarditis, Aspergillus myocarditis, Aspergillus pericarditis, Aspergillus bacillomatosis, ear canal aspergillosis, Aspergillus nailitis, Aspergillus nail dissection, Aspergillus keratitis, Aspergillus Endophthalmitis, cutaneous aspergillosis, sinus orbital aspergillosis, etc .; pulmonary cryptococcosis due to Cryptococcus, central nervous cryptococcosis, skin and mucosal cryptococcosis, bone and joint cryptococcosis, lymph node cryptococcosis, systemic cryptococcosis, and Hematopoietic cryptococcosis etc .; Trichophyton spp., Microsporum spp., Etc., tinea capitis, tinea, Celsus acne, tinea pedis, vesicular vesicle tinea, eczema tinea pedis, dysentery, sweat blisters Ringworm, tinea unguium, tinea unguium, tinea rash, and tinea granulomas; Malassezia versicolor etc.], and further can be used for the prevention and treatment of atopic dermatitis. Further, compound (II)
I) and (IIIa) can be used as antifungal agents in combination of two or more, and can also be used in combination with antifungal agents other than compounds (III) and (IIIa).
Compounds (III) and (IIIa) can also be used as agricultural antifungal agents. Experimental pharmacological effect, action, administration subject, safety, specific target disease, dosage, administration route, administration method including administration form of compound (III) and (IIIa) as medical antifungal agent, and agricultural use The method of use as an antifungal agent is described in JP-A-6-29374.
0, JP-A-8-104676 and WO9625410
A1 (corresponding to JP-A-9-183768).

[0027]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. ^{The 1} H-NMR spectrum was measured with a Varian Gemini 200 (200 MHz) type spectrometer using tetramethylsilane as an internal standard, and all δ values were shown in ppm. In mixed solvent ()
The numerical values shown in the parentheses are the volume mixing ratios of the respective solvents. % Is
Unless otherwise specified, weight percent is meant. Further, the ratio of the solvent in the silica gel chromatography indicates the volume ratio of the solvent to be mixed. The symbols in the examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, t
t: triple triplet, m: multiplet, b
r: Wide, J: Coupling constant

Reference Example 1 A mixed solution of 4-fluoronitrobenzene (50.4 g), 1H-tetrazole (25 g), potassium carbonate (50 g) and N, N-dimethylformamide (350 ml) was mixed with 7
Stirred at 0-75 ° C for 10 hours. The reaction was cooled and added to water (2500ml). The precipitated crystals were collected by filtration and washed with water (500 ml). The yellow crystal mixture of 1- (4-nitrophenyl) -1H-tetrazole and 2- (4-nitrophenyl) -2H-tetrazole obtained above was treated with methanol (280 ml) and tetrahydrofuran (420).
ml), and ferric chloride (0.33 g) and activated carbon (3.3 g) were added. Hydrazine monohydrate (27 g) was added dropwise to the resulting mixture over 10 minutes under reflux.
After completion of the dropwise addition, the mixture was stirred under reflux for 10 hours. After cooling the reaction solution, the activated carbon was filtered off, and the activated carbon portion was replaced with methanol (200
ml). The filtrate and the washing solution were combined and distilled off under reduced pressure.
The obtained residue was purified by silica gel chromatography (eluent: tetrahydrofuran / hexane = 2/3 → tetrahydrofuran / hexane / ethyl acetate = 1/1/1). After the first eluate was concentrated under reduced pressure, the residue was crystallized from hexane to give 2- (4-aminophenyl)-
2H-tetrazole (14.48 g) was obtained as pale yellow powder crystals. This product was recrystallized from a mixture of ethyl acetate and diisopropyl ether. 124-125 ° C ¹ H-NMR (d ₆ -DMSO) δ: 5.76 (2H,
s), 6.76 (2H, d, J = 8.8 Hz), 7.74
(2H, d, J = 8.8 Hz), 9.08 (1H, s) Elemental analysis: C ₇ H ₇ N ₅ Calculated (%): C, 52.17; H, 4.38; N , 43.45 Found (%): C, 52.01; H, 4.44; N, 43.41 Further, the second elute was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether to give 1- ( 4-Aminophenyl) -1H-tetrazole (25.29 g) was obtained as pale yellow powdery crystals. This product was recrystallized from a mixture of ethyl acetate and diisopropyl ether. 142-143 ° C ¹ H-NMR (d ₆ -DMSO) δ: 5.65 (2H,
s), 6.73 (2H, d, J = 8.8 Hz), 7.48
(2H, d, J = 8.8 Hz), 9.83 (1H, s) Elemental analysis: C ₇ H ₇ N ₅ Calculated (%): C, 52.17; H, 4.38; N , 43.45 Found (%): C, 51.88; H, 4.38; N, 43.62.

Reference Example 2 1- (4-aminophenyl) -1H-tetrazole (1
5.29 g) and pyridine (9 g) were dissolved in a mixture of tetrahydrofuran (200 ml) and ethyl acetate (100 ml). To this solution, phenyl chlorocarbonate (17.6 g) was added dropwise while stirring under ice cooling. After the addition was completed, the reaction solution was stirred at room temperature for 1 hour. Water (100 ml) in the reaction solution
And saturated saline (100 ml) were added to carry out liquid separation. The organic layer was washed with water (100 ml × 2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether (500 ml) was added to the residue, and the crystals were collected by filtration. The obtained crystals were washed with diisopropyl ether (150 ml) and dried to give 4- (1H-tetrazol-1-yl) phenylcarbamic acid phenyl ester (24.1).
5 g) were obtained as colorless scaly crystals. This product was recrystallized from ethyl acetate. Melting point 186-189 ° C ¹ H-NMR (d ₆ -DMSO) δ: 7.25-7.34
(3H, m), 7.42-7.50 (2H, m), 7.7
7 (2H, d, J = 9 Hz), 7.89 (2H, d, J
= 9Hz), 10.0 (1H, s), 10.6 (1H,
s) Elemental analysis: C ₁₄ H ₁₁ N ₅ O ₂ Calculated (%): C, 59.78; H, 3.94; N, 24.90 Found (%): C, 59.56; H, 3.99; N, 24.89

Reference Example 3 p-Nitroaniline (14.75 g) was added to methanol (4
Then, 2,2-dichloroacetaldehyde p-toluenesulfonylhydrazone (10.00 g) was added at −3 to −4 ° C., and the mixture was stirred for 1 hour. After stirring at room temperature overnight, the reaction solution was concentrated to about 170 ml under reduced pressure, and left under ice cooling for 30 minutes. The precipitated crystals were collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give 1- (4-nitrophenyl) -1H-1,2,3-.
Triazole (4.04 g) was obtained as pale yellow crystals. The mother liquor was concentrated, and the residue was dissolved in a mixture of ethyl acetate (200 ml) and tetrahydrofuran (200 ml).
Hydrochloric acid (150 ml), 1N aqueous sodium hydroxide solution (15
0 ml), water (150 ml) and saturated saline (150 ml). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was crystallized from diethyl ether to give an additional 0.47 g of the above compound.
Obtained. Total yield and yield: 4.51 g, 67% The product was recrystallized from a mixture of dichloromethane and diisopropyl ether. 205-206 ° C

Reference Example 4 An ice-cooled 40% glyoxal aqueous solution (23.4 ml),
Add a mixture of acetic acid (1 ml) and methanol (300 ml) to p.
-Nitroaniline (22.25 g) was added and stirred for 1 hour. p-Toluenesulfonylhydrazine (10.00
After adding g), stirring was continued at 0 ° C. for 2 hours and further at room temperature overnight. The solvent was concentrated under reduced pressure, and ethyl acetate (500 ml) was added to the residue. The extract was combined with a 0.5N aqueous sodium hydroxide solution (250 ml) and water (2 mL).
00 ml) and saturated brine (200 ml), and dried over anhydrous magnesium sulfate. The solvent is reduced to about 10 under reduced pressure.
After concentrating to 0 ml and standing at room temperature overnight, the precipitated crystals were collected by filtration to give 1- (4-nitrophenyl) -1H-1,2,3.
-Triazole (5.31 g) was obtained as pale yellow crystals. The mother liquor was concentrated, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / hexane = 1/2).
After purification by (1/1), crystallization from ethyl acetate gave 2.17 g of the above compound. Total yield and yield: 7.48 g, 73%

Reference Example 5 1- (4-Nitrophenyl) -1H-1,2,3-triazole (33.33 g), 10% palladium-carbon (5
A mixture of 0% water (4.00 g), ethanol (200 ml) and tetrahydrofuran (200 ml) was stirred at 50 ° C. for 6 hours under a hydrogen atmosphere. After cooling the reaction solution, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was crystallized from diisopropyl ether to give 1- (4-aminophenyl) -1H-1,2,3-triazole (26.45
g, 94%) as pale yellow crystals. This product was recrystallized from ethyl acetate. Melting point 121-122 ° C ¹ H-NMR (CDCl ₃ ) δ: 3.93 (2H, bs), 6.
77 (2H, dt, J = 9 Hz, 2.2 Hz), 7.48
(2H, dt, J = 9 Hz, 2 Hz), 7.81 (1H,
s), 7.87 (1H, s) Elemental analysis: C ₈ H ₈ N ₄ Calculated (%): C, 59.99; H, 5.03; N, 34.98 Actual (%) : C, 60.02; H, 5.08; N, 34.66.

Reference Example 6 Phenyl chlorocarbonate was added to a mixture of 1- (4-nitrophenyl) -1H-1,2,3-triazole (26.45 g), pyridine (14.40 g) and acetone (550 ml) with stirring. Ester (28.50 g) was added dropwise over 15 minutes under ice cooling. After the addition was completed, the reaction solution was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure.
0 ml), tetrahydrofuran (200 ml) and water (300
ml), and the mixture was separated. The organic layer was washed sequentially with water (200 ml) and saturated saline (200 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from diisopropyl ether to give 4- (1H-
1,2,3-Triazol-1-yl) phenylcarbamic acid phenyl ester (39.68 g) was obtained as colorless powdery crystals. The product was recrystallized from ethyl acetate. _{^{1 H-NMR (d 6 -DMSO}} ) δ: 7.24-7.49
(5H, m), 7.72 (2H, d, J = 9 Hz), 7.
88 (2H, d, J = 9 Hz), 7.96 (1H, s),
8.76 (1H, s), 10.53 (1H, br) Elemental analysis: C ₁₅ H ₁₂ N ₄ O ₂ Calculated (%): C, 64.28; H, 4.31; N, 19.98 Found (%): C, 64.38; H, 4.32; N, 20.02

Reference Example 7 4-Fluoronitrobenzene (70.6 g) was dissolved in N, N-dimethylformamide (490 ml), and 1H-tetrazole (35 g) and potassium carbonate (70 g) were added. Stir for 5 hours. After cooling, the reaction solution was added to ice water (3000 ml), and the precipitated solid was collected by filtration and washed with water (5 ml).
After washing with (00 ml × 3), a mixture of 1- (4-nitrophenyl) -1H-tetrazole and 2- (4-nitrophenyl) -2H-tetrazole was obtained as a white powder. This product was added to a mixture of tetrahydrofuran (500 ml) and methanol (100 ml) without drying. Activated carbon (powder, 12 g) and anhydrous ferric chloride (FeCl ₃ , 1.2 g) were added to the resulting mixture and heated to 75 ° C. Hydrazine monohydrate (70 ml) was added dropwise to the mixture over 2 hours. After completion of the dropwise addition, the mixture was stirred at 75 ° C. for 6 hours, and then the reaction solution was cooled and filtered. The activated carbon portion was washed with ethyl acetate (100 ml × 2). The filtrate and washing solution were combined and washed with a saturated saline solution (100 ml, 50 ml × 2).
(4-aminophenyl) -1H-tetrazole and 2-
A solution containing (4-aminophenyl) -2H-tetrazole was obtained. Water (200 ml) and baking soda (42
g) was added, and phenyl chlorocarbonate (50 ml) was added dropwise over 30 minutes while stirring at room temperature. After completion of the dropwise addition, the reaction solution was stirred for 15 minutes, and the organic layer was separated. The organic layer was washed with saturated saline (100 ml × 2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure until the total amount was about 200 g. Ethyl acetate (100m
l) and diisopropyl ether (100 ml) were added and allowed to stand. The precipitated crystals were collected by filtration and washed with ethyl acetate-diisopropyl ether (1: 1, 100 ml, 50 ml). Tetrahydrofuran (400 ml) was added to the obtained crystals, which were dissolved by heating. This solution was concentrated under reduced pressure to a total amount of 200 g, and ethyl acetate-diisopropyl ether (1: 1) was added.
1,200 ml) was added and allowed to stand. The precipitated crystals were collected by filtration, and ethyl acetate-diisopropyl ether (1: 1, 1
00 ml, 50 ml). Repeat this recrystallization operation for two more
Repeated 4 times, 4- (1H-tetrazol-1-yl)
Phenylcarbamic acid phenyl ester (39 g) was obtained as colorless crystals. This product had the same physicochemical properties as the compound obtained in Reference Example 2.

Reference Example 8 p-Nitroaniline (138 g) was added to Chemistry of Hete
According to the method described in Rocyclic Compounds, Vol. 21, p. 1257, 1985, 1- (4-nitrophenyl) -1H-tetrazole was derived. This product was dissolved in tetrahydrofuran (2800 ml) by heating to 60 ° C. without purification, and 1.8 g of anhydrous ferric chloride and activated carbon (powder, 19 g) were added. The resulting mixture is secretly refluxed and stirred while hydrazine monohydrate (180
g) was added dropwise over 30 minutes. After completion of the dropwise addition, the mixture was stirred under reflux for 2.5 hours. After cooling, the insolubles were removed by filtration and washed with ethyl acetate (1400 ml). The filtrate and washing solution were combined and washed with a saturated saline solution (1500 ml × 2).
A solution containing (4-aminophenyl) -1H-tetrazole was obtained. Pyridine (95 g) was added to this solution, and phenyl chlorocarbonate (1
88 g) was added dropwise over 15 minutes. After dropping, leave at room temperature for 1 hour.
After stirring for an hour, saturated brine (1500 ml) was added. The organic layer was separated, washed with water (1500 ml × 2), and the solvent was distilled off under reduced pressure. Diisopropyl ether (2000 ml) was added to the residue, and the mixture was stirred. The precipitated crystals were collected by filtration to obtain 4- (1H-tetrazol-1-yl) phenylcarbamic acid phenyl ester (230.9 g). This product had the same physicochemical properties as the compound obtained in Reference Example 2.

Reference Example 9 Benzyl bromide (49.5 g) was added to a solution of p-nitroaniline (10 g) in N, N-dimethylformamide (50 ml).
And potassium carbonate (22 g) were added, and the mixture was heated and stirred at 160 ° C. for 32 hours. After cooling the reaction solution to room temperature, ice water (200 m
l) and extracted with ethyl acetate (300 ml).
The organic layer was washed with water (300 ml x 3) and saturated saline (300 ml).
ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and hexane (100 m
l) and diisopropyl ether (100 ml) were added, and the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether (50 ml) and dried under reduced pressure to obtain N, N-dibenzyl-p-nitroaniline (19 g) as yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.76 (4H, s),
6.70 (2H, d, J = 9.2 Hz), 7.81-7.4
1 (10H, m), 8.07 (2H, d, J = 9.2H
z).

REFERENCE EXAMPLE 10 Activated carbon (2.2 g) and ferric chloride (0.55 g) were added to a methanol (120 ml) solution of N, N-dibenzyl-p-nitroaniline (18 g) for 30 minutes. Heated to reflux. Hydrazine monohydrate (27.4 ml) was added dropwise to the reaction solution over 1 hour under reflux, and the mixture was heated under reflux for 24 hours. The reaction was cooled to room temperature and activated carbon (2.2 g) and ferric chloride (0.2 g).
55 g) was added and refluxed again for 10 minutes. Hydrazine monohydrate (27.4 ml) was added dropwise over 1 hour under reflux, and the mixture was further heated under reflux for 24 hours. After cooling, the activated carbon was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was treated with ethyl acetate (13
0 ml), washed successively with water (100 ml × 3) and saturated saline (100 ml), and dried over anhydrous sodium sulfate. Hexane-diisopropyl ether (3: 1, 24 ml) was added to the residue obtained by concentration under reduced pressure to cause crystallization. The resulting crystals were collected by filtration and dried under reduced pressure to give N, N-dibenzyl-p-phenylenediamine (15 g) as purple crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.29 (2H, br)
s), 4.51 (4H, s), 6.57 (2H, d, J = 8.
4Hz), 6.64 (2H, d, J = 8.4Hz), 7.1
8-7.34 (10H, m).

Reference Example 11 N, N-dibenzyl-p-phenylenediamine (15
g), ethyl orthoformate (25.5 ml) and sodium azide (4 g) in a mixture of acetic acid (40 ml) at room temperature.
It was added dropwise over a period of minutes. After stirring at room temperature for 5 minutes in a nitrogen stream, the mixture was heated and stirred at 90 ° C. for 4 hours. After cooling to room temperature,
Water (50 ml) and a 6N aqueous hydrochloric acid solution (18 ml) were added to the reaction mixture, and sodium nitrite (2 g) in water (8.4 m) was added.
l) The solution was added. After stirring for 10 minutes under ice cooling, the resulting powder was collected by filtration, washed with water (120 ml), diisopropyl ether (30 ml), and dried under reduced pressure. The obtained brown powder was treated with ethanol (350 ml) -methanol (10
re-crystallized from a mixed solution of 1- [4-ml) and THF (1 ml).
(N, N-dibenzylamino) phenyl] -1H-tetrazole (12.4 g) was obtained as brown scaly crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.74 (4H, s),
6.82 (2H, d, J = 9.2 Hz), 7.23-7.4
3 (12H, m), 8.80 (1H, s).

Reference Example 12 1- [4- (N, N-dibenzylamino) phenyl] -1H-
A solution of tetrazole (30 mg) in methanol (1 ml) was mixed with 10% palladium on carbon (50 mg) and a 6N aqueous hydrochloric acid solution (0.1%).
015 ml), and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction solution was filtered, water (1 ml) was added to the obtained filtrate, and a 1N aqueous sodium hydroxide solution (0.11 m
l) was added dropwise. After extraction with ethyl acetate (10 ml), the obtained organic layer was washed with saturated saline (20 ml × 3) and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain 1- (4-aminophenyl) -1H-tetrazole (11 mg) as a brown powder. This product had the same physicochemical properties as 1- (4-aminophenyl) -1H-tetrazole obtained in Reference Example 1.

Reference Example 13 1- [4- (N, N-dibenzylamino) phenyl] -1H-
Tetrazole (2 g) in methanol-THF (2: 1,3
0 ml) solution, 10% palladium on carbon (0.5 g) and 6N hydrochloric acid aqueous solution (1 ml) were added, and the mixture was added at room temperature under a hydrogen atmosphere at room temperature.
Stirred for minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
Ethyl acetate-THF (2: 1.45 ml) and water (5 ml) were added to the residue, and a solution of sodium hydrogen carbonate (1.3 g) in water (20 ml) was added dropwise over 5 minutes under ice cooling. At room temperature, phenyl chlorocarbonate (0.89 ml) was added dropwise over 5 minutes. After stirring at room temperature for 20 minutes, water (1
0 ml) and stirred for another 30 minutes. The organic layer was washed with a saturated saline solution (10 ml × 3), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure until the total amount was 6.6 g. Diisopropyl ether (15 m
l) was added, and the resulting crystals were collected by filtration and dried under reduced pressure.
(1H-tetrazol-1-yl) phenylcarbamic acid phenyl ester (1.5 g) was obtained as light brown crystals. This product had the same physicochemical properties as the compound obtained in Reference Example 2.

Example 1 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazole-
1-yl) methyloxirane (40 g) was dissolved in 1-propanol (400 ml), and titanium tetraisopropoxide (68 g) and then 2,2-diethoxyethylamine (464 ml) were added thereto. Heated to reflux for an hour. After cooling the reaction solution, the solvent and 2,2-diethoxyethylamine were distilled off under reduced pressure. The residue was dissolved in ethyl acetate (800 ml) and stirred with 1N
-Sodium hydroxide solution (260 ml) and saturated saline (2
60 ml) and stirred at room temperature for 1 hour.
The resulting hardly soluble material was separated by filtration and washed with ethyl acetate (250 ml). After combining the filtrate and the washings, the layers were separated and the ethyl acetate layer was extracted with 1N hydrochloric acid (150 ml × 4). The hydrochloric acid layers are combined, and 2N-sodium hydroxide solution (300 m
After neutralization with l), the mixture was extracted with ethyl acetate (400 ml × 2). The ethyl acetate layers were combined, washed sequentially with a 1N sodium hydroxide solution (200 ml) and a saturated saline solution (200 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give (2R, 3R) -3- (2,2-diethoxyethyl) amino-2- (2,4-difluorophenyl) -1- (1H-1,2,4- Triazol-1-yl) -2-butanol (49.4 g) was obtained as a pale yellow oil. Yield 73% ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, d, J
= 6.6 Hz), 1.0-1.2 (1H, br), 1.23
(6H, t, J = 7 Hz), 2.66 (1H, dd, J =
12 Hz, 4.6 Hz), 2.95 (1 H, dd, J = 1)
2 Hz, 6.4 Hz), 3.14 (1H, q, J = 6.6)
Hz), 3.48-3.81 (4H, m), 4.56 (1
H, dd, J = 6.4 Hz, 4.6 Hz), 4.75 (1
H, d, J = 14 Hz), 4.88 (1H, s), 4.8
9 (1H, d, J = 14 Hz), 6.69-6.80 (2
H, m), 7.33-7.45 (1H, m), 7.76
(1H, s), 7.93 (1H, s)

Example 2 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazole-
1-yl) methyloxirane (10.0 g) was dissolved in ethanol (100 ml), and titanium tetraisopropoxide (17.0 g) and then 2,2-diethoxyethylamine (106 g) were added thereto. , 40
Heated to reflux for an hour. After cooling the reaction solution, the solvent and 2,2-
Diethoxyethylamine was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (200 ml), and a mixed solution consisting of a 1N sodium hydroxide solution (65 ml) and a saturated saline solution (65 ml) was added thereto while stirring, followed by stirring at room temperature for 1 hour. The resulting hardly soluble material was separated by filtration and washed with ethyl acetate (50 ml). After combining the filtrate and the washings, the layers were separated and the ethyl acetate layer was extracted with 1N hydrochloric acid (150 ml). The hydrochloric acid layer was neutralized with 1N-sodium hydroxide solution (150 ml) under ice cooling, and extracted with ethyl acetate (300 ml). The ethyl acetate layer was washed with brine (100 ml) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography [silica gel 500
g, eluate (acetone: hexane = 1: 2)] to give (2R, 3R) -3- (2,2-diethoxyethyl) amino-2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol (12.4 g) was obtained as a pale yellow oil. 81% yield

Example 3 (2R, 3S) -2- (2-fluorophenyl) -3-
Methyl-2- (1H-1,2,4-triazol-1-yl) methyloxirane (10.0 g) was dissolved in 1-propanol (100 ml), and titanium tetraisopropoxide (183 g) was added. , 2-Diethoxyethylamine (114 g) was added, and the mixture was heated and refluxed for 24 hours under a nitrogen stream. After cooling the reaction solution, the solvent and 2,2-diethoxyethylamine were distilled off under reduced pressure. The residue was dissolved in ethyl acetate (200 ml) and stirred with 1N
Sodium hydroxide solution (65 ml) and saturated saline (65
ml) and stirred at room temperature for 1 hour. The resulting hardly soluble material was separated by filtration and washed with ethyl acetate (100 ml). The combined filtrate and washings were separated, and the ethyl acetate layer was extracted with 1N hydrochloric acid (200 ml, 100 ml). The hydrochloric acid layers were combined, and 2N-sodium hydroxide solution (15
0 ml) and then ethyl acetate (200 ml, 100 ml).
Extracted in l). The combined ethyl acetate layers were combined with a 1N sodium hydroxide solution (100 ml) and a saturated saline solution (100 ml).
And then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain (2R, 3R) -3-
(2,2-Diethoxyethyl) amino-2- (2-fluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol (13.6 g) was a yellow oil. Was obtained as Yield 87% ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, d, J
= 6.6 Hz), 1.0-1,2 (1H, br), 1.23
(6H, t, J = 7 Hz), 2.67 (1H, dd, J =
12 Hz, 4.6 Hz), 2.95 (1 H, dd, J = 1)
2 Hz, 6.4 Hz), 3.14 (1H, q, J = 6.6)
Hz), 3.49-3.80 (4H, m), 4.56 (1
H, dd, J = 6.4 Hz, 4.6 Hz), 4.79 (1
H, d, J = 14 Hz), 4.84 (1H, s), 4.9
4 (1H, d, J = 14 Hz), 6.93-7.45 (4
H, m), 7.76 (1H, s), 7.89 (1H, s)

Example 4 (2R, 3R) -3- (2,2-diethoxyethyl) amino-2- (2,4-difluorophenyl) -1- (1
H-1,2,4-Triazol-1-yl) -2-butanol (0.64 g) was dissolved in ethanol (6.4 ml),
4- (2,2,3,3-Tetrafluoropropoxy) phenylcarbamic acid phenyl ester (1.13 g) and pyridine (0.14 ml) were added, and the mixture was heated under reflux for 18 hours.
After cooling, the reaction solution was concentrated under reduced pressure. Ethyl acetate (30 ml) and water (30 ml) were added to the residue, and the mixture was partitioned.
0 ml) and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography (eluent: ethyl acetate / hexane =
After purification by 2/1), recrystallization from diisopropyl ether gave 1- (2,2-diethoxyethyl).
-1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3
-[4- (2,2,3,3-tetrafluoropropoxy)
[Phenyl] urea (0.72 g) was obtained as colorless powdery crystals. 69% mp 148-150 ° C. Elemental analysis yields _{C 28 H 33 F 6 N 5} O 5 Calculated (%): C, 53.08; H, 5.25; N, 11.05 Found (% ): C, 53,14; H, 5.09; N, 11.14 1 H-NMR (CDCl 3) δ: 1.05 (1.2H, d,
J = 7.2 Hz), 1.21 (1.8 H, d, J = 6.8 H)
z), 1.28-1.37 (6H, m), 3.48-4.0
2 (6.6H, m), 4.26-4.54 (3H, m),
4.71 (0.6H, m), 4.93-5.00 (1H,
m), 5.21-5.42 (1.2H, m), 6.06 (1
H, tt, J = 53 Hz, 5.0 Hz), 6.69-6.
93 (4H, m), 7.25-7.42 (2.6H, m),
7.49-7.79 (2.4H, m), 8.24 (0.6
H, s), 8.43 (0.6H, br), 8.69 (0.4
H, s)

Example 5 1- (2,2-diethoxyethyl) -1-[(1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2, Two,
3,3-Tetrafluoropropoxy) phenyl] urea (0.63 g) was dissolved in a mixture of methanol (25 ml) and water (5 ml), 1N hydrochloric acid (1 ml) was added thereto, and the mixture was stirred at 50 ° C. for 24 hours. did. After cooling the reaction solution, 1N
-Sodium hydroxide solution (1 ml) was added and concentrated under reduced pressure. Ethyl acetate (40 ml) and water (40 ml) were added to the residue, and the mixture was separated. The ethyl acetate layer was washed with water (40 ml) and saturated saline (40 ml) in that order, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 2/1), and recrystallized from a mixture of ethyl acetate and diisopropyl ether to obtain 1 −
[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-Triazol-1-yl) propyl] -3-
[4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2 (1H, 3H) -imidazolone (0.40
g) was obtained as colorless powder crystals. Yield 74% ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J
= 7Hz), 4.20 (1H, d, J = 14Hz), 4.
38 (2H, t, J = 12 Hz), 4.95 (1H,
q, J = 7 Hz), 5.10 (1H, d, J = 14H)
z), 5.50-5.75 (1H, br), 6.07 (1
H, tt, J = 53 Hz, 5 Hz), 6.60 (1H,
d, J = 3 Hz), 6.73 (1H, d, J = 3 Hz),
6.74-6.84 (2H, m), 7.02 (2H, d,
J = 9 Hz), 7.43-7.56 (1H, m), 7.59
(2H, d, J = 9 Hz), 7.73 (1H, s), 7.8
6 (1H, s)

Example 6 (2R, 3R) -3- (2,2-diethoxyethyl) amino-2- (2-fluorophenyl) -1- (1H-
1,2,4-Triazol-1-yl) -2-butanol (13.0 g) was dissolved in dimethylsulfoxide (40 ml) and 4- (2,2,3,3-tetrafluoropropoxy) was added to the resulting solution. ) Phenylcarbamic acid phenyl ester (12.2 g) was added, and the mixture was heated and stirred at 110 ° C for 3 hours. After cooling, the reaction solution was diluted with ethyl acetate (200 ml) and washed with dilute saline (220 ml × 2). The ethyl acetate layer was washed with 0.5N hydrochloric acid (150 ml) and diluted saline (150 ml).
l), 0.5N-sodium hydroxide solution (150 × 2m
l), dilute saline (150ml), saturated saline (150ml)
And then dried over anhydrous magnesium sulfate.
After evaporating the solvent under reduced pressure, the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1-
(2,2-diethoxyethyl) -1-[(1R, 2R)
-2- (2-fluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1-
Yl) propyl] -3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] urea (13.0 g)
Was obtained as colorless powder crystals. The recrystallized mother liquor was concentrated, the residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/1), and recrystallized from diisopropyl ether to give the above compound (1.
8g) were obtained as colorless powder crystals. Total yield 68% mp 133-134 ° C. Elemental analysis _{C 28 H 34 F 5 N 5} O 5 Calculated (%): C, 54.63; H, 5.57; N, 11.38 Found ( %): C, 54, 53; H, 5.49; N, 11.41 ¹ H-NMR (CDCl ₃ ) δ: 1.05 (1.2 H, d,
J = 7.4 Hz), 1.21 (1.8 H, d, J = 6.6 H)
z), 1.28-1.37 (6H, m), 3.50-4.0
5 (6.6H, m), 4.32 (2H, t, J = 12H)
z), 4.37 (0.4 H, d, J = 14 Hz), 4.5
5 (0.6 H, d, J = 14 Hz), 4.71 (0.6
H, m), 4.96-5.10 (1.4H, m), 5.31
−5.50 (0.8H, m), 6.07 (1H, tt, J
= 53 Hz, 5.0 Hz), 6.86-7.06 (4H,
m), 7.15-7.42 (3.4H, m), 7.54-
7.66 (1.8H, m), 7.76 (0.8H, s),
8.23 (0.6H, s), 8.43 (0.6H, br), 8.7
0 (0.4H, s)

Example 7 1- (2,2-diethoxyethyl) -1-[(1R, 2
R) -2- (2-Fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole-
1-yl) propyl] -3- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] urea (12.8
g) was dissolved in methanol (130 ml), 2N hydrochloric acid (104 ml) was added to the resulting solution, and the mixture was heated under reflux for 2 hours. After cooling the reaction solution, sodium bicarbonate (17.5
g) was added and concentrated under reduced pressure. Ethyl acetate (200 ml) and water (200 ml) were added to the residue, and the mixture was partitioned. The ethyl acetate layer was washed successively with water (100 ml) and saturated saline (100 ml), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to obtain 1-[(1R,
2R) -2- (2-Fluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (2,2, 3,3-
Tetrafluoropropoxy) phenyl] -2 (1H, 3
H) -Imidazolone (9.85 g) was obtained as colorless powder crystals. Calculated 91% Elemental analysis yields _{C 24 H 22 F 5 N 5} O 3 (%): C, 55.07; H, 4.24; N, 13.38 Found (%): C, 54 H, 4.03; N, 13.55 ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, d, J
= 7Hz), 4.21 (1H, d, J = 14Hz), 4.
37 (2H, t, J = 12 Hz), 5.03 (1H,
q, J = 7 Hz), 5.15 (1H, d, J = 14H)
z), 5.42 (1H, br), 6.07 (1H, tt,
J = 53Hz, 4.8Hz), 6.59 (1H, d, J =
3.2Hz), 6.76 (1H, d, J = 3.2Hz),
6.97-7.07 (2H, m), 7.01 (2H, d,
J = 9 Hz), 7.17-7.29 (1H, m), 7.4
3-7.51 (1H, m), 7.59 (2H, d, J = 9
Hz), 7.72 (1H, s), 7.81 (1H, s)

Example 8 (2R, 3R) -3- (2,2-diethoxyethyl) amino-2- (2,4-difluorophenyl) -1- (1
H-1,2,4-triazol-1-yl) -2-butanol (188 mg) and 4- (1H-1,2,3-triazol-1-yl) phenylcarbamic acid phenyl ester (137 mg) were dissolved in dimethylformamide (2 ml) and heated at 110 ° C. for 2 hours with stirring under an argon atmosphere. After cooling, the reaction solution was poured into water (20 ml) and extracted with ethyl acetate (20 ml, 15 ml × 2). The extracts were combined, washed with water (30 ml) and then with saturated saline (30 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 3/1 → ethyl acetate) to give 1- (2,2-diethoxyethyl) -1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3-
(1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-1,2,3-triazol-1
-Yl) phenyl] urea (262 mg) was obtained as a white powder. 94% Elemental analysis yields _{C 27 H 32 F 2 N 8} O 4 Calculated (%): C, 56.83; H, 5.65; N, 19.64 Found (%): C, 56 H, 5.76; N, 19.44 ¹ H-NMR (CDCl ₃ ) δ: 1.07 (1.2 H, d,
J = 7.0 Hz), 1.23 (1.8 H, d, J = 7.0 H)
z), 1.34 (6H, t, J = 7.0 Hz), 3.51-
4.07 (7H, m), 4.39 (0.4H, d, J = 14
Hz), 4.54 (0.6 H, d, J = 14 Hz), 4.5.
74 (0.6H, m), 4.94-5.01 (1H, m),
5.24-5.41 (1.4H, m), 6.72-6.82
(2H, m), 7.37-7.84 (8.2H, m), 7.
95 (0.6H, s), 8.24 (0.4H, s), 8.7
5 (0.4H, br), 9.05 (0.4H, s)

Example 9 1- (2,2-diethoxyethyl) -1-[(1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H- One,
2,3-Triazol-1-yl) phenyl] urea (228 mg) was dissolved in methanol (2.4 ml).
Hydrochloric acid (2.4 ml) was added and the mixture was heated at 60 ° C. for 4 hours. After cooling the reaction solution, 1N aqueous sodium hydroxide solution (4.8 ml)
Neutralized. The methanol was distilled off under reduced pressure, and the residue was extracted with ethyl acetate (20 ml, 10 ml × 2). The extracts were combined, washed with water (20 ml) and saturated saline (20 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to give 1-[(1R, 2R) -2-.
(2,4-difluorophenyl) -2-hydroxy-1
-Methyl-3- (1H-1,2,4-triazole-1-
Yl) propyl] -3- [4- (1H-1,2,3-triazol-1-yl) phenyl] -2 (1H, 3H)-
Imidazolone (161 mg) was obtained as colorless powdery crystals. 84% Elemental analysis yields _{C 23 H 20 F 2 N 8} O 2 Calculated (%): C, 57.74; H, 4.21; N, 23.42 Found (%): C, 57 H, 4.25; N, 23.48 ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J
= 7Hz), 4.22 (1H, d, J = 14.4Hz),
5.01 (1H, q, J = 7 Hz), 5.12 (1H,
d, J = 14.4 Hz), 5.49 (1H, br), 6.
72-6.86 (4H, m), 7.42-7.50 (1
H, m), 7.75 (1H, s), 7.81-7.91
(6H, m), 8.02 (1H, s)

Example 10 (2R, 3R) -3- (2,2-diethoxyethyl) amino-2- (2,4-difluorophenyl) -1- (1
H-1,2,4-triazol-1-yl) -2-butanol (30 g) was converted to N, N-dimethylformamide (30 g).
0 (ml), 4- (1H-tetrazol-1-yl) phenylcarbamic acid phenyl ester (21.93g) was added to the resulting solution, and the mixture was stirred at 80 ° C for 5 hours. After cooling, the reaction solution was poured into water (300 ml) and extracted with ethyl acetate (300 ml × 2). The ethyl acetate layer was washed with water (200 ml × 3) and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1- (2,2-diethoxyethyl) -1-[(1
(R, 2R) -2- (2,4-difluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H
-Tetrazol-1-yl) phenyl] urea (35.
7g) were obtained as colorless powder crystals. The recrystallized mother liquor was concentrated, the residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 3/1 → ethyl acetate), and recrystallized from diisopropyl ether to give 4 g of the above compound as a colorless powder Obtained as crystals. Total yield 39.7 g (89% yield) mp 180-182 ° C. Elemental analysis _{C 26 H 31 F 2 N 9} O 4 Calculated (%): C, 54.63; H, 5.47; N, 22.05 Found (%): C, 54, 58; H, 5.37; N, 21.61 ¹ H-NMR (CDCl ₃ ) δ: 1.08 (1.5 H, d,
J = 7Hz), 1.24 (1.5H, d, J = 7Hz),
1.31-1.38 (6H, m), 3.50-4.06 (7
H, m), 4.39 (0.5H, d, J = 14 Hz),
4.59 (0.5H, d, J = 14 Hz), 4.76 (0.5.
5H, m), 4.93-5.08 (1.5H, m), 5.2
5-5.48 (1H, m), 6.73-6.83 (2H,
m), 7.31-7.69 (5.5H, m), 7.79
(0.5H, s), 7.82 (0.5H, s), 8.24
(0.5H, s), 8.85 (0.5H, br), 8.94
(0.5H, s), 8.96 (0.5H, s), 9.16
(0.5H, s)

Example 11 1- (2,2-diethoxyethyl) -1-[(1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H- [Tetrazol-1-yl) phenyl] urea (39 g) was dissolved in methanol (342 ml), and 2N-
Hydrochloric acid (342 ml) was added and the mixture was stirred at 50-55 ° C for 17 hours. After cooling the reaction solution, 2N-NaOH (342 ml)
And the solvent was concentrated under reduced pressure. Ethyl acetate (400 ml) and water (400 ml) were added to the residue, and the mixture was separated. The ethyl acetate layer was washed with water (200 ml) and saturated saline (200 ml) in that order, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1-[(1
(R, 2R) -2- (2,4-difluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H
-Tetrazol-1-yl) phenyl] -2- (1H,
3H) -Imidazolone (28.6 g) was obtained as colorless powdery crystals. 87% Elemental analysis yields _{C 22 H 19 F 2 N 9} O 2 Calculated (%): C, 55.11; H, 3.99; N, 26.29 Found (%): C, 54 H, 4,04; N, 26.05 ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, d, J
= 7Hz), 4.22 (1H, d, J = 14Hz), 5.
03 (1H, q, J = 7 Hz), 5.13 (1H, d,
J = 14Hz), 5.45 (1H, br), 6.74-
6.88 (4H, m), 7.42-7.54 (1H, m),
7.76 (1H, s), 7.82 (2H, d, J = 9H)
z), 7.86 (1H, s), 7.96 (2H, d, J =
9Hz), 9.06 (1H, s)

Example 12 (2R, 3S) -2- (2,4-difluorophenyl)-
3-methyl-2- (1H-1,2,4-triazole-1
-Yl) methyloxirane (30 g), 1-propanol (300 ml), titanium tetraisopropoxide (51
g) and 2-aminoethanol (109.4 g) were refluxed with stirring for 7.5 hours under a nitrogen stream.
After cooling, add ethyl acetate (500 ml) and, with stirring, 2N-sodium hydroxide saturated saline solution (98 ml)
Was added in about 3 minutes, and stirring was continued for 30 minutes. Saturated saline (195 ml) was further added to the mixture, and the mixture was stirred for 10 minutes. After standing, the ethyl acetate layer was separated by decantation. After adding ethyl acetate (400 ml) to the aqueous layer and stirring at room temperature for 3 minutes, the ethyl acetate layer was separated again by decantation. This decantation operation was performed twice more using ethyl acetate (300 ml).
The ethyl acetate layers were combined and washed with a saturated saline solution (250 ml). The ethyl acetate layer was extracted with 1N-hydrochloric acid (225 ml × 2). The hydrochloric acid layers were combined, made alkaline with 2N-sodium hydroxide saturated saline (230 ml) under ice cooling, and extracted with ethyl acetate (300 ml × 2). The ethyl acetate layers were combined and washed with a saturated saline solution (200 ml).
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
The residue was dried under reduced pressure to give (2R, 3R) -2-
(2,4-Difluorophenyl) -3- (2-hydroxyethyl) amino-1- (1H-1,2,4-triazol-1-yl) -2-butanol (34.2 g) as a colorless oil Obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, d, J
= 6.6Hz), 1.60-1.80 (2H, br), 2.
61-2.73 (1H, m), 2.98-3.16 (2
H, m), 3.65-3.71 (2H, m), 4.81
(1H, d, J = 14 Hz), 4.96 (1H, d, J)
= 14Hz), 4.77-4.99 (1H, br), 6.
70-6.80 (2H, m), 7.36-7.48 (1
H, m), 7.78 (1H, s), 7.87 (1H,
s)

Example 13 (2R, 3R) -2- (2,4-difluorophenyl)
-3- (2-hydroxyethyl) amino-1- (1H-
To a solution of 1,2,4-triazol-1-yl) -2-butanol (34.2 g) in ethyl acetate (600 ml) was added 4-
(1H-tetrazol-1-yl) phenylcarbamic acid phenyl ester (23.7 g) and triethylamine (17.6 ml) were added, and the mixture was heated under reflux with stirring for 90 minutes. After cooling, the mixture was stirred under ice cooling for 2 hours. The precipitated crystals are collected by filtration, washed with ethyl acetate (50 ml),
When dried under reduced pressure at 40 ° C., 1-[(1R, 2R) -2-
(2,4-difluorophenyl) -2-human peroxy-1-methyl-3- (1H-1,2,4
-Triazol-1-yl) propyl] -1- (2-hydroxyethyl) -3- [4- (1H-tetrazole-1
-Yl) phenyl] urea (37.9 g) was obtained as colorless powdery crystals. The product was a crystal containing ethyl acetate. ¹ H-NMR (d ₆ -DMSO) δ: 0.93, 1.16 (3H,
d, J = 7 Hz); 3.47-4.09 (4.5 H, m);
4.56 (1H, d, J = 14 Hz); 4.91-5.0
3 (1H, m); 5.30 (0.5H, q, J = 7H
z); 5.79, 6.12, 6.21 (2H, br);
6.87-6.96 (1H, m); 7.13-7.45 (2
H, m); 7.59-7.88 (5H, m); 8.21,
8.32 (1H, s); 9.41, 9.49 (1H, s);
10.02, 10.05 (1H, s) SIMS (m / z): 500 (MH ⁺ )

Example 14 (2R, 3R) -2- (2,4-difluorophenyl)
-3- (2-hydroxyethyl) amino-1- (1H-
1,2,4-Triazol-1-yl) -2-butanol (6.6 g) was added to N, N-dimethylformamide (132
ml), and 4- (1H-tetrazole-1) was added thereto.
-Yl) phenylcarbamic acid phenyl ester (4.7 g) was added, and the mixture was stirred at 50 ° C for 2.5 hours under a nitrogen stream. After cooling the reaction mixture, it was poured into water (160 ml),
The mixture was extracted twice with ethyl acetate (120 ml). The ethyl acetate layer was washed five times with water (160 ml), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and concentrated under reduced pressure.
6-ml) and 1-[(1R, 2R) -2- (2,
4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
Propyl] -1- (2-hydroxyethyl) -3- [4-
(1H-tetrazol-1-yl) phenyl] urea
(6.5 g) was obtained as white crystals. This product was identical in physicochemical data with the compound obtained in Example 13.

Example 15 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -1- (2
-Hydroxyethyl) -3- [4- (1H-tetrazol-1-yl) phenyl] urea (5.0 g) was added to N, N-dimethylacetamide (60 ml) and ethyl acetate (15 g).
of thionyl chloride (0.1 ml) in a nitrogen stream.
A solution of 67 ml) in ethyl acetate (15 ml) was added dropwise over 75 minutes. After the reaction solution was stirred at 24 ° C for 4 hours, the internal temperature was kept at 10-12 ° C, and triethylamine (8.98 ml) was added dropwise over 10 minutes. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1.5 hours.
(120 ml) and extracted with ethyl acetate (120 ml). Further, the aqueous layer was extracted with ethyl acetate (70 ml). Combine the ethyl acetate layers with water (90 ml) 3
The extract was washed twice, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in acetone (15 ml), concentrated under reduced pressure, and ethyl acetate (25 ml) was added.
-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3- [4
-(1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (3.7 g) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) d: 1.08 (3H, d, J =
7 Hz), 3.74-4.11 (4H, m), 4.52
(1H, d, J = 14 Hz), 4.71 (1H, q, J =
7 Hz), 5.11 (1H, d, J = 14 Hz), 5.
34 (1H, br), 6.73-6.84 (2H, br)
m), 7.36-7.49 (1H, m), 7.69 (2H,
d, J = 9 Hz), 7.77 (1H, s), 7.81
(2H, d, J = 9Hz), 7.86 (1H, s), 8.9
7 (1H, s).

Example 16 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -1- (2
-Hydroxyethyl) -3- [4- (1H-tetrazol-1-yl) phenyl] urea (23.4 g) in N, N-dimethylacetamide-ethyl acetate (1: 1, 240 m).
l) To the solution was added phosphorus oxychloride (6 ml) in ethyl acetate (70 ml).
ml) The solution was added dropwise at an internal temperature of 22 to 25 ° C over 2.5 hours, and then stirred at room temperature for 16 hours. Triethylamine (60 ml) was added dropwise at an internal temperature of -5 to -3 ° C over 2 hours, and the mixture was stirred at room temperature for 3.5 hours. Ice water (300
ml), extracted with ethyl acetate (300 ml × 2), and extracted with water (300 ml), 5% phosphoric acid aqueous solution (30 ml).
0 ml x 2), saturated aqueous sodium hydrogen carbonate solution (300
ml) and saturated saline (300 ml). Anhydrous magnesium sulfate and activated carbon (5 g) were added to the organic layer, and the mixture was allowed to stand for 10 minutes and filtered. The residue obtained by concentration under reduced pressure was crystallized from ethyl acetate (50 ml) and collected by filtration. The obtained crystals were recrystallized from ethanol (600 ml) and dried over phosphorous pentoxide at 40 ° C. for 1 hour to give 1-[(1R, 2R).
-2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazole- 1-yl) phenyl] -2-imidazolidinone (1
1.1 g) were obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J =
7Hz), 3.68-4.14 (4H, m), 4.52
(1H, d, J = 14 Hz), 4.71 (1H, q, J
= 7Hz), 5.12 (1H, d, J = 14Hz), 5.
34 (1H, br), 6.74-6.83 (2H, m),
7.36-7.48 (1H, m), 7.68 (2H, d,
J = 9 Hz), 7.77 (1H, s), 7.81 (2H,
d, J = 9 Hz), 7.86 (1H, s), 8.96
. (IH, s) Elemental _{analysis: C 22 H 21 F 2 N} 9 O 2 Calculated (%):. C, 54.88 ; H, 4.40; N, 26.18 Found (%) : C, 54.80; H, 4.41; N, 26.17. [Α] _D ²⁰ = −60.1 (c = 1.01%, MeOH).

Example 17 (2R, 3R) -3- (2,2-diethoxyethyl) amino-2- (2,4-difluorophenyl) -1- (1H
1,2,4-Triazol-1-yl) -2-butanol (0.25 g) was dissolved in dimethylformamide (2 ml), and 4-nitrophenyl isocyanate (0.11 g) was added to the resulting solution. And stirred at room temperature for 2 hours. The reaction solution was poured into water (30 ml) and extracted with ethyl acetate (30 ml). The ethyl acetate layer was washed sequentially with water (30 ml × 2) and saturated saline (20 ml), and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 1/3 → 1/2).
(2,2-diethoxyethyl) -1-[(1R, 2R)-
2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole-
1-yl) propyl] -3- (4-nitrophenyl) urea (0.29 g) was obtained as a pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.07 (1.5 H, d,
J = 7Hz), 1.23 (1.5H, d, J = 7Hz),
1.30-1.38 (6H, m), 3.50-4.10
(6.5H, m), 4.36 (0.5H, d, J = 14H
z), 4.53 (0.5 H, d, J = 14 Hz), 4.7
2-4.77 (0.5H, m), 4.91-5.01 (1
H, m), 5.26-5.42 (2H, m), 6.70-
6.84 (2H, m), 7.31-7.64 (3.5H,
m), 7.78 (0.5H, s), 7.81 (0.5H,
s), 8.16-8.23 (2.5H, m), 9.02
(0.5H, br), 9.37 (0.5H, s).

Example 18 1- (2,2-diethoxyethyl) -1-[(1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (4-nitrophenyl) Urea (0.15 g) was dissolved in methanol (3 ml), 1N hydrochloric acid (2.8 ml) was added to the resulting solution, and the mixture was stirred under reflux for 2 hours. After adding sodium hydrogencarbonate (0.24 g) to the reaction mixture under ice-cooling, ethyl acetate (40 ml) and water (40 ml) were added to carry out liquid separation. The ethyl acetate layer was washed with water (3
0 ml) and then with a saturated saline solution (30 ml).
After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H
-1,2,4-triazol-1-yl) propyl] -3
-(4-Nitrophenyl) -2 (1H, 3H) -imidazolone (0.11 g) was obtained as a yellow powder. ¹ H-N
MR (CDCl ₃ ) δ: 1.20 (3H, d, J = 7H
z), 4.19 (1H, d, J = 14 Hz), 5.02
(1H, q, J = 7 Hz), 5.11 (1H, d, J =
14Hz), 5.41 (1H, br), 6.76-6.9
0 (4H, m), 7.41-7.53 (1H, m), 7.7
6 (1H, s), 7.82 (1H, s), 7.94 (2
H, d, J = 9.2 Hz), 8.34 (2H, d, J =
9.2 Hz).

Example 19 (2R, 3R) -3- (2,2-diethoxyethyl) amino-2- (2,4-difluorophenyl) -1- (1H
-1,2,4-Triazol-1-yl) -2-butanol (8.9 g) was dissolved in dimethyl sulfoxide (30 ml), and to the resulting solution was added 4-nitrophenyl isocyanate (4.2 g). And stirred at room temperature for 2 hours. The reaction solution was poured into ice water (200 ml), and ethyl acetate (200 ml) was added.
Extracted. The ethyl acetate layer was sequentially washed with water (200 ml × 2) and saturated saline (100 ml), and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, methanol (180 ml) was added to the residue (13.7 g),
To this was added 2N hydrochloric acid (115 ml), and the mixture was stirred under reflux for 3 hours. After cooling, the precipitated crystals were separated by filtration, and the filtrate was added with sodium hydrogencarbonate (19.3 g) under ice-cooling and concentrated under reduced pressure. Ethyl acetate (200 ml) and water (200 ml) were added to the residue, and the mixture was partitioned. The ethyl acetate layer was washed sequentially with water (200 ml) and saturated saline (100 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 2/1) to give 1-[(1R, 2
R) -2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- (4-nitrophenyl) -2 (1H, 3H) -imidazolone (8.6 g) was obtained as a yellow powder. This product had the same physicochemical properties as the compound obtained in Example 18.

Example 20 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3- (4
-Nitrophenyl) -2 (1H, 3H) -imidazolone (1.0 g) was dissolved in acetic acid (15 ml), and 10% palladium-carbon (1.0 g) was added.
Stirred at 5 ° C. for 7 hours. The catalyst was separated by filtration, the catalyst part was washed with acetic acid (30 ml), and the filtrate and the washing were combined and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 9/1 → ethyl acetate), and recrystallized from ethyl acetate to give 1- (4
-Aminophenyl) -3-[(1R, 2R) -2- (2,
4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)
Propyl] -2-imidazolidinone (0.48 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J
= 7Hz), 3.58-3.87 (6H, m), 4.46
(1H, br), 4.54 (1H, d, J = 14H
z), 5.07 (1H, d, J = 14 Hz), 5.80
(1H, br), 6.69-6.81 (4H, m), 7.
31 (2H, d, J = 9 Hz), 7.35-7.52
(1H, m), 7.72 (1H, s), 7.92 (1H,
s).

Example 21 1- (4-aminophenyl) -3-[(1R, 2R)-
2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole-
1-yl) propyl] -2-imidazolidinone (1.0
g) and ethyl orthoformate (1.16 ml) were added with sodium azide (0.18 g) and acetic acid (2 ml), and the mixture was stirred at room temperature for 20 minutes.
Stirred at ° C for 1.5 hours. After cooling the reaction solution, water (2 m
l) and 6N hydrochloric acid (0.85 ml) were added successively.
After adding a sodium nitrite aqueous solution (0.3 ml), the mixture was cooled with ice. The precipitated crystals were collected by filtration, washed with water (20 ml),
Recrystallization from ethanol gives 1-[(1R, 2R)-
2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole-
1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (0.6
2 g) were obtained as colorless powder crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, d, J =
7Hz), 3.70-4.15 (4H, m), 4.52 (1H,
d, J = 14 Hz), 4.71 (1H, q, J = 7H)
z), 5.12 (1H, d, J = 14 Hz), 5.35
(1H, br), 6.74-6.85 (2H, m), 7.3
6-7.49 (1H, m), 7.68 (2H, d, J =
9Hz), 7.77 (1H, s), 7.82 (2H, d,
J = 9 Hz), 7.85 (1H, s), 8.96 (1H,
s).

Example 22 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -1- (2
-Hydroxyethyl) -3- [4- (1H-tetrazol-1-yl) phenyl] urea (0.5 g) in N, N-dimethylformamide (5 ml) was treated with thionyl chloride (0.0).
9 ml) and stirred at 50 ° C. for 30 minutes. The reaction solution was cooled, poured into water (20 ml) and ethyl acetate (2 mL).
0 ml × 2). Wash the ethyl acetate layer with water (15
After drying (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate → ethyl acetate / acetone = 1/1), and crystallized from diisopropyl ether.
1- (2-chloroethyl) -1-[(1R, 2R) -2
-(2,4-difluorophenyl) -2-hydroxy-
1-methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1H-tetrazole-
1-yl) phenyl] urea (0.22 g) was obtained as white powdery crystals. SIMS (m / z): 518 (MH ⁺ )

Example 23 (2R, 3R) -2- (2,4-difluorophenyl)
-3- (2-hydroxyethyl) amino-1- (1H-
1,2,4-Triazol-1-yl) -2-butanol (10.0 g) was dissolved in dimethyl sulfoxide (50 ml), and 4-nitrophenyl isocyanate (5.25 g) was added to the resulting solution. Stirred at room temperature for 1 hour. The reaction solution was poured into ice water (200 ml), and ethyl acetate (200 m
Extracted in l). The ethyl acetate layer was washed with water (200 ml ×
2) After successively washing with saturated saline (100 ml), the extract was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethyl acetate to give 1-
[(1R, 2R) -2- (2,4-difluorophenyl)
-2-Hydroxy-1-methyl-3- (1H-1,2,4
-Triazol-1-yl) propyl] -1- (2-hydroxyethyl) -3- (4-nitrophenyl) urea (5.9 g) was obtained as yellow powdery crystals. ¹ H-NMR (d ₆ -DMSO) δ: 0.94 (1.8 H, d,
1.13 (1.2H, d, J = 7Hz);
3.40-4.55 (4.4H, m); 4.54,4.58
(1H, d, J = 14 Hz); 4.94, 4.97 (1
H, d, J = 14 Hz); 5.28 (0.6 H, q, J =
7 Hz); 6.08, 6.25 (2H, br);
6.96 (1H, m); 7.12-7.46 (2H, m);
7.59-7.72 (3.4H, m); 8.17-8.3
0 (3H, m); 9.90 (0.6H, br).

Example 24 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -1- (2
-Hydroxyethyl) -3- (4-nitrophenyl) urea (2.6 g) was dissolved in dimethylacetamide (40 ml) and thionyl chloride (0.38 ml) was added to the resulting solution.
Was added dropwise over 30 minutes.
After stirring at room temperature for 20 minutes, thionyl chloride (0.19m
A solution of l) in ethyl acetate (5 ml) was added dropwise over 15 minutes. After stirring at room temperature for 30 minutes, ethyl acetate (100 m
1) and washed with water (100 ml × 2). The ethyl acetate layer was washed with a saturated saline solution (50 ml) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 4/1) to give 1- (2-
Chloroethyl) -1-[(1R, 2R) -2- (2,4-
Difluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -3- (4-nitrophenyl) urea (0.68
g) was obtained as a yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (0.6 H, d,
1.34 (2.4H, d, J = 7Hz);
3.48-3.60 (1H, m); 3.88-4.28
(4H, m); 4.40 (0.2H, d, J = 14H
z); 4.67 (0.8 H, d, J = 14 Hz); 5.1
3 (0.8 H, d, J = 14 Hz); 5.25 (0.2
H, d, J = 14 Hz); 5.28-5.42 (1H, b
r); 6.74-6.91 (3H, m); 7.35-7.7
2 (1.2H, m); 7.62, 7.65 (2H, d, J
= 9 Hz); 7.79, 7.82 (1H, s); 7.98
(0.8H, s); 8.23 (2H, d, J = 9Hz).

Example 25 1- (2-chloroethyl) -1-[(1R, 2R) -2
-(2,4-difluorophenyl) -2-hydroxy-
1-methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- (4-nitrophenyl) urea (0.50 g) was dissolved in ethyl acetate (10 ml) and triethylamine (0.28 ml) in ethyl acetate (2 m
l) The solution was added dropwise over 15 minutes and then stirred at room temperature. 1
After 2 hours and 2 hours, respectively, triethylamine (0.1%) was used.
28 ml) and stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate (40 ml) and washed with water (40 ml ×
2) I did. A 10% phosphoric acid aqueous solution (40 m
l), washed sequentially with water (40 ml) and saturated saline (40 ml), and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent: ethyl acetate / hexane = 6/1) to obtain 1-[(1R, 2R) -2- (2, 4-difluorophenyl) -2-hydroxy-1-methyl-3
-(1H-1,2,4-Triazol-1-yl) propyl] -3- (4-nitrophenyl) -2-imidazolidinone (0.21 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, d, J
= 7Hz), 3.70-4.18 (4H, m), 4.48
(1H, d, J = 14 Hz), 4.68-4.80 (1
H, m), 5.11 (1H, d, J = 14 Hz), 5.3
0 (1H, br), 6.73-6.85 (2H, m),
7.35-7.48 (1H, m), 7.75 (2H, d,
J = 9 Hz), 7.77 (1H, s), 7.84 (1H,
s), 8.24 (2H, d, J = 9 Hz).

Example 26 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3- (4
-Nitrophenyl) -2-imidazolidinone (1.0 g)
Was dissolved in a mixture of methanol (36 ml) and water (4 ml), 10% palladium-carbon (0.5 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was filtered off, the catalyst portion was washed with a 90% aqueous methanol solution (60 ml), and the filtrate and the washing were combined and concentrated under reduced pressure. Silica gel chromatography of the residue (eluent: ethyl acetate → ethyl acetate)
/ Acetone = 4/1) and recrystallized from ethyl acetate to give 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3. −
(1H-1,2,4-triazol-1-yl) propyl]
-3- (4-Aminophenyl) -2-imidazolidinone (0.45 g) was obtained as colorless powdery crystals. This product had the same physicochemical properties as the compound obtained in Example 20.

Example 27 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -1- (2
-Hydroxyethyl) -3- (4-nitrophenyl) urea (2.4 g) was dissolved in dimethylacetamide (40 ml) and thionyl chloride (0.35 ml) was added to the resulting solution.
Was added dropwise over 20 minutes.
After stirring at room temperature for 15 minutes, thionyl chloride (0.17m
A solution of l) in ethyl acetate (5 ml) was added dropwise over 15 minutes. After stirring at room temperature for 40 minutes, a solution of thionyl chloride (0.09 ml) in ethyl acetate (2 ml) was further added dropwise over 10 minutes. After stirring at room temperature for 40 minutes, triethylamine (2.8 ml) was added dropwise at 15-18 ° C for 5 minutes, and the mixture was stirred at room temperature for 3 hours. The reaction solution was treated with ethyl acetate (10
0 ml) and washed with water (100 ml × 4). The ethyl acetate layer was washed with a saturated saline solution (50 ml) and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography (eluent:
Purification by ethyl acetate / hexane = 6/1) gave 1
-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3- (4
-Nitrophenyl) -2-imidazolidinone (1.2 g)
Was obtained as a yellow powder. This product had the same physicochemical properties as the compound obtained in Example 25.

Example 28 To a solution of triphenylphosphine (0.07 g) in tetrahydrofuran (3 ml) at -20 ° C. was added a 40% solution of azodicarboxylic acid diethyl ester in toluene (0.12 g), and the mixture was stirred for 10 minutes. , 1-[(1R, 2R) -2
-(2,4-difluorophenyl) -2-hydroxy-
1-methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -1- (2-hydroxyethyl)-
3- [4- (1H-tetrazol-1-yl) phenyl]
A solution of urea (0.1 g) in tetrahydrofuran (3 ml) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was flash column chromatography on silica gel (silica gel; 15 g, elution solvent; hexane: ethyl acetate: acetone = 4: 3:
3 → ethyl acetate) and the obtained solid was recrystallized from ethanol to give 1-[(1R, 2R) -2- (2,4
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl)
[Phenyl] -2-imidazolidinone (0.052 g) was obtained as white crystals. This product had the same physicochemical properties as the compound obtained in Example 16.

Example 29 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -1- (2
-Hydroxyethyl) -3- [4- (1H-tetrazol-1-yl) phenyl] urea (2.0 g) in N, N-dimethylacetamide-ethyl acetate (1: 1, 20 ml) was treated with phosphorus oxychloride ( 0.51 ml) of ethyl acetate (6 m
l) The solution was added dropwise at an internal temperature of 21 to 23 ° C over 1 hour, and then stirred at room temperature for 16 hours. The reaction solution was treated with ethyl acetate (3
0 ml) and washed with water (20 ml × 3). After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl ether (30 ml) and collected by filtration to give 1- (2-chloroethyl)-
1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -3- [4
-(1H-tetrazol-1-yl) phenyl] urea (1.44 g) was obtained as white powdery crystals. ¹ H-NMR (d ₆ -DMSO) δ: 1.02, 1.16 (3H,
d, J = 7 Hz); 3.61-4.09 (4.5H, m);
4.43, 4.57 (1H, d, J = 14 Hz);
87, 4.97 (1H, d, J = 14 Hz); 5.20
(0.5H, q, J = 7 Hz); 5.98 (1H, b
r); 6.89-6.98 (1H, m); 7.13-7.4
8. (2H, m); 7.64-7.85 (5H, m);
31 (1H, s); 9.02, 9.22 (1H, s);
10.02 (1H, s) SIMS (m / z): 500 (MH ⁺ )

Example 30 1- (2-chloroethyl) -1-[(1R, 2R) -2
-(2,4-difluorophenyl) -2-hydroxy-
1-methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- [4- (1H-tetrazole-
1-yl) phenyl] urea (1.2 g) in N, N-dimethylacetamide-ethyl acetate (3: 5,16 ml) was added to a solution of triethylamine (0.96 ml) in ethyl acetate (2 m).
l) The solution was added dropwise at an internal temperature of 0 to 2 ° C over 15 minutes. After stirring at room temperature for 3 hours, ice water (20 ml) was poured into the reaction solution, and extracted with ethyl acetate (20 ml × 2).
5% phosphoric acid aqueous solution (20 ml × 2), saturated aqueous sodium hydrogen carbonate solution (20 ml), saturated saline solution (20 ml)
ml × 2). After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate (10 ml) and collected by filtration. The obtained crystals were recrystallized from ethanol (40 ml) and dried over phosphorous pentoxide at 40 ° C. for 1 hour to give 1-[(1R,
2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazole-1
-Yl) fluoro] -3- [4- (1H-tetrazol-1-yl) phenyl] -2-imidazolidinone (0.765 g)
Was obtained as white crystals. This product had the same physicochemical properties as the compound obtained in Example 16.

Example 31 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,
2,4-triazol-1-yl) propyl] -1- (2
-Hydroxyethyl) -3- (4-nitrophenyl) urea (3.0 g) was added to a solution of N, N-dimethylacetamide-ethyl acetate (1: 1, 30 ml) in phosphorus oxychloride (0.1 g).
88 ml) of ethyl acetate (10 ml) in 21-22.
The solution was added dropwise at 20 ° C for 20 minutes. After stirring at room temperature for 16 hours,
Triethylamine (8.8 ml) was added dropwise at -5 ° C over 20 minutes, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (100 ml) and washed with water (100 ml × 2). The ethyl acetate layer was added to a 5% phosphoric acid aqueous solution (100 ml ×
2), saturated aqueous sodium bicarbonate (100 ml), saturated saline (100
ml) and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography (eluent: ethyl acetate / hexane =
6 /) and purified to give 1-[(1R, 2R) -2.
-(2,4-difluorophenyl) -2-hydroxy-
1-methyl-3- (1H-1,2,4-triazole-1
-Yl) propyl] -3- (4-nitrophenyl) -2
-Imidazolidinone (2.3 g) was obtained as a yellow powder. This product had the same physicochemical properties as the compound obtained in Example 25.

Example 32 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -3-
(4-nitrophenyl) -2-imidazolidinone (1.
0 g) was dissolved in a mixture of ethyl acetate (18 ml) and water (2 ml), 10% palladium-carbon (0.5 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The catalyst was separated by filtration, and the catalyst part was washed with ethyl acetate (50 ml). The filtrate and the washing were combined and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 1- (4-aminophenyl) -3-[(1
(R, 2R) -2- (2,4-difluorophenyl) -2
-Hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl-2-imidazolidinone (0.35 g) was obtained as colorless powdery crystals. This product had the same physicochemical properties as the compound obtained in Example 20.
After concentration of the mother liquor under reduced pressure, the residue was purified by silica gel chromatography (eluent: ethyl acetate / acetone = 3/1) and crystallized from ethyl acetate-diisopropyl ether to give additional 1- (4- Aminophenyl)-
3-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -2-
Imidazolidinone (0.35 g) was obtained as colorless powdery crystals.

Example 33 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazole-
A mixture of 1-yl) methyloxirane (20 g) and 2- (N-benzyl) aminoethanol (80 g) was heated at 160 ° C. for 8 hours under a nitrogen atmosphere. After cooling, ethyl acetate (200 ml) was added to the reaction solution, and the resulting solution was extracted with 4N hydrochloric acid (205 ml). The hydrochloric acid layer was separated and neutralized with 2N aqueous sodium hydroxide (410 ml) under ice-cooling (p.
H 7.0 ± 0.2). The mixture was mixed with ethyl acetate (150 ml
× 2), and the extract was washed successively with saturated saline (100 ml) and water (100 ml × 2). The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Diisopropyl ether (50 ml) was added to the residue, and the mixture was stirred at room temperature for 20 hours and then under ice cooling for 3 hours. The precipitated crystals were collected by filtration, washed with cold diisopropyl ether (5 ml), and dried at 40 ° C. under reduced pressure to give (2R, 3R) -3-
[N-benzyl-N- (2-hydroxyethyl) amino] -2- (2,4-difluorophenyl) -1- (1
H-1,2,4-Triazol-1-yl) -2-butanol (17.6 g) was obtained as white powder crystals. 55% mp 105-107 ° C. Elemental analysis yields _{C 21 H 24 F 2 N 4} O 2 Calculated (%): C, 62.67; H, 6.01; N, 13.92 Found (% ): C, 62.45; H, 6.07; N, 13.90.

Example 34 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2- (1H-1,2,4-triazole-
A mixture of 1-yl) methyloxirane (20 g) and 2- (N-benzyl) aminoethanol (80 g) was heated at 160 ° C. for 8 hours under a nitrogen atmosphere. After cooling, the reaction solution was dissolved by adding ethyl acetate (200 ml). The resulting solution was extracted with 4N hydrochloric acid (205ml). Separate the hydrochloric acid layer,
Under ice-cooling, the mixture was neutralized (pH 7.0 ± 2) with 2N aqueous sodium hydroxide (410 ml), and then ethyl acetate (150 ml × 2).
Extracted. The extract was washed with saturated saline (100 ml) and water (1
(2R, 3R) -3-
[N-benzyl-N- (2-hydroxyethyl) amino] -2- (2,4-difluorophenyl) -1- (1
An ethyl acetate solution of (H-1,2,4-triazol-1-yl) -2-butanol was obtained. To this solution was added 5% palladium on carbon (6.3 g), and while stirring, formic acid (1 g) was added.
4.3 g) was added dropwise over 30 minutes. After dripping, 4
Stirred at 0 ° C. for 2 hours. After cooling, the catalyst was removed by filtration, and the catalyst was washed with ethyl acetate (120 ml). The filtrate and the washing solution were combined, anhydrous magnesium sulfate was added, and the mixture was stirred for 30 minutes. The insoluble matter was removed by filtration, and the insoluble matter was washed with ethyl acetate (50 ml). Combining filtration and washing, (2
(R, 3R) -2- (2,4-difluorophenyl) -3
-(2-hydroxyethyl) amino-1- (1H-1,
A solution of 2,4-triazol-1-yl) -2-butanol in ethyl acetate was obtained. To this solution was added triethylamine (7.63 g) and 4- (1H-tetrazol-1-yl) phenylcarbamic acid phenyl ester (21.
6 g) and stirred at 50 ° C. for 8 hours. The reaction solution was further stirred at room temperature for 1 hour and under ice cooling for 1 hour. The precipitated crystals were collected by filtration, washed with cold ethyl acetate (20 ml), and dried at 45 ° C under reduced pressure to give 1-[(1R, 2R).
-2- (2,4-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -1- (2-hydroxyethyl) -3 -[4- (1H-Tetrazol-1-yl) phenyl] urea (34.5 g) was obtained as white powdery crystals. This product was identical to the compound obtained in Example 13.

Example 35 1-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-
1,2,4-Triazol-1-yl) propyl] -1-
(2-Hydroxyethyl) -3- [4- (1H-tetrazol-1-yl) phenyl] urea (20 g) was treated with 1-
Methyl-2-pyrrolidone (120 ml) and ethyl acetate (2
00 ml). The internal temperature of the obtained solution was adjusted to 5
While maintaining the temperature at 0 ° C., a solution of phosphorus oxychloride (5 g) in ethyl acetate (80 ml) was added dropwise over 30 minutes. After completion of the dropwise addition, the mixture was stirred at 50 ° C. for 30 minutes. The reaction was cooled to 5 ° C. and piperidine (23.9 g) was added over 2 minutes.
After stirring the reaction solution at 5 ° C. for 30 minutes, water (150 m
l) and stirred for 30 minutes. The pH of the reaction solution was adjusted to 6.5 by adding 1N hydrochloric acid. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (100ml). The ethyl acetate layers were combined, washed with water (100 ml × 2), and concentrated under reduced pressure.
To the residue was added 50% aqueous ethanol (240 ml), and the mixture was stirred at room temperature for 8 hours, and the precipitated crystals were collected by filtration. After washing the obtained crystals with cold ethyl alcohol (28 ml),
After drying under reduced pressure, 1-[(1R, 2R) -2- (2,4
-Difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -3- [4- (1H-tetrazol-1-yl) phenyl]- 2-Imidazolidinone (16 g) was obtained as white crystals. This product had the same physicochemical properties as the compound obtained in Example 16.

[0075]

According to the method of the present invention, imidazolone and imidazolidinone derivatives having excellent antifungal activity can be obtained with high purity and high yield.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 31/415 A61K 31/415 (72) Inventor Dr. Hosono 1-3-5-902 Shimae-cho, Toyonaka-shi, Osaka (72 ) Inventor Hiroyuki Kodera 31-8 Machikaneyamacho, Toyonaka-shi, Osaka (56) References JP-A-7-2788 (JP, A) JP-A-9-183769 (JP, A) JP-A 8-253452 (JP, A) European Patent Application Publication No. 884311 (EP, A2) Journal of Medicinal Chemistry; vol. 38 (No. 20), pp. 3918-3392 (1995) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 249/08 C07D 403/06 CAPLUS (STN) REGISTRY (STN)

Claims (30)

(57) [Claims] [Claim 1] The formula: [Wherein, Ar represents a phenyl group which may be substituted;
¹ represents a hydrogen atom or a lower alkyl group, R ² represents an optionally substituted aliphatic be based have or aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic group, R ³
It is (wherein, Y represents a hydroxyl group or a halogen atom.) Wherein -CH ₂ Y represents a group or an optionally protected formyl group represented by. Or a salt thereof. 2. A compound represented by the formula: (In the formula, Ar represents an optionally substituted phenyl group,
Represents a hydrogen atom or a benzyl group which may be substituted,
R ¹ represents a hydrogen atom or a lower alkyl group, and R ^{3 ′} represents a hydroxymethyl group or a protected formyl group. Or a salt thereof. 3. The compound according to claim 1, wherein R ¹ is a methyl group. 4. The compound according to claim 1, wherein Ar is a phenyl group substituted with one or two halogen atoms. 5. The compound according to claim 1, wherein Ar is a 2,4-difluorophenyl group or a 2-fluorophenyl group. 6. The compound according to claim 1, wherein R ² is a phenyl group having a substituent. 7. The compound according to claim 1, wherein R ² is a phenyl group substituted with a halogeno (C _1-6 ) alkoxy group. 8. The method according to claim 8, wherein R ² is a 4- (2,2,3,3-tetrafluoropropoxy) phenyl group or 4- (1,1,2,2
The compound according to claim 1, which is a 2-tetrafluoroethoxy) phenyl group. 9. The compound according to claim 1, wherein R ² is a phenyl group substituted with a 5-membered aromatic heterocyclic group. 10. The compound according to claim 1, wherein R ² is a phenyl group having pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or tetrazolyl as a substituent. 11. The compound according to claim 1, wherein R ² is a phenyl group substituted with a nitro group. 12. R ³ and R ^{3 ′} are of the formula: (Wherein, R ⁴ and R ⁵ are the same or different and each represents an aliphatic hydrocarbon group, or R ⁴ and R ⁵ are bonded to each other to represent an alkylene having 2 or 3 carbon atoms). 3. A compound according to claim 1 or claim 2. 13. The compound according to claim 12, wherein R ⁴ and R ⁵ are each a methyl group or an ethyl group. 14. The compound according to claim 2, wherein R is a benzyl group. 15. The compound according to claim 2, wherein R is a hydrogen atom. 16. (2R, 3R) -2- (2,4-difluorophenyl) -3- (2-hydroxyethyl) amino-1- (1H-1,2,4-triazol-1-yl)-
The compound according to claim 2, which is 2-butanol. 17. (2R, 3R) -3- [N-benzyl-
N- (2-hydroxyethyl) amino] -2- (2,4
-Difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol.
A compound as described. 18. A method according to claim 18, wherein 1-[(1R, 2R) -2- (2,4-
Difluorophenyl) -2-hydroxy-1-methyl-
3- (1H-1,2,4-triazol-1-yl) propyl] -1- (2-hydroxyethyl) -3- [4-
The compound according to claim 1, which is (1H-tetrazol-1-yl) phenyl] urea. 19. A compound of the formula: (In the formula, Ar represents an optionally substituted phenyl group,
¹ represents a hydrogen atom or a lower alkyl group; R ² represents an aliphatic or aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent ^{; '} Represents a formyl group which may be protected. Wherein the compound represented by the formula or a salt thereof is subjected to a ring closure reaction: (Wherein each symbol is as defined above) or a method for producing a salt thereof. 20. The cyclization reaction in the presence of an acid.
Production method as described. 21. The method according to claim 20, wherein the acid is an inorganic acid. 22. The formula: (In the formula, Ar represents an optionally substituted phenyl group,
¹ is a hydrogen atom or a lower alkyl group, R ² is an aliphatic or aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, Y is a hydroxyl group Or a halogen atom. ) Or a salt thereof is subjected to a ring closure reaction. (Wherein each symbol is as defined above) or a method for producing a salt thereof. 23. The process according to claim 22, wherein the compound wherein Y is a hydroxyl group is subjected to a ring closure reaction in the presence of a halogenating agent and a base. 24. The method according to claim 23, wherein the halogenating agent is a thionyl halide or a phosphorus halide compound. 25. The process according to claim 22, wherein the compound wherein Y is a halogen atom is subjected to a ring-closure reaction in the presence of a base. 26. The method according to claim 23, wherein the base is an organic base. 27. A compound of the formula: (In the formula, Ar represents an optionally substituted phenyl group,
¹ represents a hydrogen atom or a lower alkyl group. Or a salt thereof and a compound represented by the formula: Wherein R represents a hydrogen atom or a benzyl group which may be substituted, and R ^{3 ′} represents a hydroxymethyl group or a protected formyl group. Formula: (Wherein each symbol is as defined above) or a method for producing a salt thereof. 28. A compound of the formula: (In the formula, Ar represents an optionally substituted phenyl group,
Represents a hydrogen atom or a benzyl group which may be substituted,
R ¹ represents a hydrogen atom or a lower alkyl group, and R ^{3 ′} represents a hydroxymethyl group or a protected formyl group. ) Or a salt thereof, if necessary, after debenzylation, (In the formula, R ² represents an aliphatic or aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent, and X represents a leaving group.) Or a compound represented by the formula: (Wherein R ² has the same meaning as described above). (Wherein each symbol is as defined above) or a method for producing a salt thereof. 29. A compound represented by the formula: (In the formula, Ar represents an optionally substituted phenyl group,
¹ represents a hydrogen atom or a lower alkyl group, and R ² represents an aliphatic or aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent. Wherein the compound or a salt thereof is reacted with a halogenating agent. (Wherein, Y ′ represents a halogen atom, and other symbols are as defined above) or a salt thereof. (30) The formula: (In the formula, Ar represents an optionally substituted phenyl group,
¹ represents a hydrogen atom or a lower alkyl group. ) Or a salt thereof, and a lower alkyl orthoformate and an alkali metal azide. (Wherein each symbol is as defined above) or a method for producing a salt thereof.