JPH054975A - Triazole antimycotic agent - Google Patents

Abstract

PURPOSE:To provide a new compound useful as an antimycotic agent. CONSTITUTION:The compound of formula I [Ar is (substituted) phenyl; R<1> is lower alkyl; R<2> is substituted 1-5C alkyl, substituted 3-6C cycloalkyl, substituted 4-8C cycloalkylalkyl, etc.; n is 0-2], e.g. (2R,3R)-2-(2,4- difluorophenyl)-3-[(2-hydroxyethyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-b utanol. The compound of formula I can be produced by reacting an epoxide compound of formula II with a mercaptan derivative of formula HSR<2> under basic condition.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 1,2,4-triazole compound represented by the formula (1) which is particularly effective against fungal diseases of humans and animals.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 61-85369 describes that a compound of the present invention in which R ² is an alkyl, cycloalkylalkyl or cycloalkyl group in formula (1) has antifungal activity. ing.

[0003]

There is no disclosure of the compound of the present invention. It was found that the compound of the present invention has excellent antifungal activity, and has completed the present invention.

[0004]

The present invention is a compound having formula (1) or an acid addition salt or alkali metal salt thereof.

[0005]

[Chemical 2]

In the formula, Ar represents a phenyl group which is unsubstituted or substituted by 1 to 3 substituents selected from halogen atom and trifluoromethyl, R ¹ represents a lower alkyl group, and R ² represents 1 to 1. Alkyl group consisting of 1 to 5 carbon atoms having 3 substituents, 3 carbon atoms having 1 to 3 substituents
To 6 cycloalkyl groups, 1 to 3 substituents having 4 to 8 carbon atoms, cycloalkylalkyl groups optionally having 1 to 3 nitrogen, oxygen, and sulfur atoms Represents a 3- to 6-membered heterocyclic group having at least one or a 3- to 6-membered heterocyclic-substituted alkyl group having at least one nitrogen, oxygen or sulfur atom which may have 1 to 3 substituents. , N is 0, 1 or 2.

The halogen atom of the Ar substituent is, for example, a fluorine atom or a chlorine atom.

The lower alkyl group for R ¹ is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
Examples of the alkyl group having 1 to 5 carbon atoms of R ² include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Examples are isopentyl or tert-pentyl. R
Examples of the cycloalkyl group having ² to 3 carbon atoms of ² include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The cycloalkyl moiety of the cycloalkylalkyl group having 4 to 8 carbon atoms is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the alkyl moiety of the cycloalkylalkyl group is, for example, methyl, ethyl, propyl and the like. Having an alkyl group having 1 to 5 carbon atoms having 1 to 3 substituents, a cycloalkyl group having 3 to 6 carbon atoms having 1 to 3 substituents, and 1 to 3 substituents The substituent of the cycloalkylalkyl group having 4 to 8 carbon atoms is, for example, -OR.
³ groups (in the formula, R ³ represents a hydrogen atom or a lower alkyl group), = NOR ⁴ group (in the formula, R ⁴ represents a hydrogen atom or a lower alkyl group), -NHOR ⁵ group (in the formula, R ⁵ represents a hydrogen atom or a lower alkyl group), —NR ⁶ R ⁷ group (in the formula, R ⁶ and R ⁷ are the same or different and represent a hydrogen atom or a lower alkyl group), —NHCOR ⁸ group ( In the formula, R ⁸
Represents a hydrogen atom or a lower alkyl group. ), -COOR ⁹ group (in the formula, R ⁹ represents a hydrogen atom or a lower alkyl group), -CONR ¹⁰ R ¹¹ group (in the formula, R ¹⁰ and R ¹¹ are the same or different and are a hydrogen atom or a lower alkyl group). , -S (O) _m R ¹² (R ¹² represents a hydrogen atom or a lower alkyl group, m represents 0, 1, 2), formyl, oxo, hydroxymethyl, nitro or cyano. ..

Heterocyclic group of 3 to 6 membered heterocyclic group having at least one nitrogen, oxygen and sulfur atom which may have 1 to 3 substituents and 1 to 3 substituents The heterocyclic group of a 3- to 6-membered heterocyclic-substituted alkyl group having at least one nitrogen, oxygen or sulfur atom which may be, for example, is aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, oxiranyl, oxetanyl, tetrahydrofuryl, tetrahydropyraniyl. 1,3-dioxolanyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, thiazolidinyl, thiazolyl,
Thiilanyl, thietanyl, tetrahydrothienyl, S-
Examples include oxothiylanyl, S-oxothietanyl, S-oxothiolanyl, S, S-dioxothiyanyl, S, S-dioxothietanyl or S, S-dioxothiolanyl.

The alkyl moiety of the 3- to 6-membered heterocyclic-substituted alkyl group having at least one nitrogen, oxygen or sulfur atom which may have 1 to 3 substituents is, for example, methyl, ethyl, propyl or isopropyl. Can be given.

Nitrogen optionally having 1 to 3 substituents, oxygen having 3 to 6 membered ring heterocyclic group having at least one sulfur atom, and nitrogen optionally having 1 to 3 substituents. ,oxygen,
The substituent of the heterocyclic group of the 3- to 6-membered heterocyclic-substituted alkyl group having at least one sulfur atom is, for example, an alkyl group such as methyl, ethyl, propyl, or isopropyl, a —S (O) _m R ¹² group. (In the formula, R ¹² represents a hydrogen atom or a lower alkyl group, and m represents 0, 1, 2.), -CONR ¹⁰ R ¹¹
A group (in the formula, R ¹⁰ and R ¹¹ are the same or different and represent a hydrogen atom or a lower alkyl group), a —NR ⁶ R ⁷ group (in the formula,
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a lower alkyl group. ), A —COOR ⁹ group (in the formula, R ⁹ represents a hydrogen atom or a lower alkyl group), a —OR ³ group (in the formula, R ³ represents a hydrogen atom or a lower alkyl group),
Examples include formyl, oxo or hydroxymethyl.

The lower alkyl group of R ^{3 to} R ¹¹ is R
It has the same meaning as the lower alkyl group of ¹ .

Preferred compounds of formula (1) have Ar of 2,4
-Dichlorophenyl, 2,4-difluorophenyl, 4-
Chlorophenyl, 2-chloro-4-fluorophenyl,
2-fluoro-4-chlorophenyl, 2-fluoro-4
-(Trifluoromethyl) phenyl or 4- (trifluoromethyl) phenyl, particularly preferably 2,4-
A compound which is dichlorophenyl, 2,4-difluorophenyl, 4-chlorophenyl or 2-fluoro-4-chlorophenyl. Compounds in which R ¹ is methyl, ethyl, propyl, especially methyl.

A compound in which n is 0, 1 or 2.

R ² is

[0016]

[Chemical 3]

[0017]

[Chemical 4]

[0018]

[Chemical 5]

It is a compound selected from:

Specific examples of the preferred compound (1) of the present invention include the compounds shown in Tables 1 to 13.

[0021]

[Table 1]

[0022]

[Table 2]

[0023]

[Table 3]

[0024]

[Table 4]

[0025]

[Table 5]

[0026]

[Table 6]

[0027]

[Table 7]

[0028]

[Table 8]

[0029]

[Table 9]

[0030]

[Table 10]

[0031]

[Table 11]

[0032]

[Table 12]

[0033]

[Table 13]

The triazole compound (1) of the present invention has at least two asymmetric carbons and exists as an optical isomer and a diastereomer. Both enantiomers can be obtained from the optical isomers by a general optical resolution method or an asymmetric synthesis method. Further, the separation of diastereomers can be carried out by using an ordinary separation method such as fractional recrystallization or chromatography. Formula (1) includes one or a mixture of these isomers.

The triazole compound (1) of the present invention can be used as it is, or in the form of an acid addition salt, or in the form of an alkali metal salt when R ² has a carboxyl group, as an antifungal agent. You can Compound (1)
Examples of the acid addition salt of (1) include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid and methanesulfonic acid salt, and the alkali metal salt of compound (1) is, for example, lithium, sodium or potassium salt.

Among the compounds having the formula (1) of the present invention,
The compound having n = 0 can be produced by the method shown below.

[0037]

[Chemical 6]

(In the above formula, Ar and R ¹ have the same meanings as described above, R ² has the same meanings as described above, and when R ² has an amino or alkylamino group, those groups are not included. The protecting group is, for example, an acyl group such as formyl, acetyl, propionyl, benzoyl or tert-butoxycarbonyl.) That is, JP-A-2-191262.
(Head 2.7.27) is a method for producing the target compound (1) by reacting the epoxide compound (2) with the mercaptan derivative (3) under basic conditions. As the solvent used in the reaction, methanol, ethanol,
Preference is given to propanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane or mixtures of these with water. The base used in the reaction is sodium hydride, sodium methoxide, sodium ethoxide, lithium methoxide, potassium tert-butoxide,
It is lithium hydroxide, sodium hydroxide or potassium hydroxide, and the amount used is 0.1 to 2 molar equivalents relative to compound (2). The mercaptan (3) is used at 1 to 3 molar equivalents. The reaction temperature is room temperature to 100 ° C, and the reaction time is 2 to
10 hours. The compound (1) (n = 0) is obtained by treating the reaction solution according to a conventional method. The R of the product (1)
^{When 2} has a protected amino group or alkylamino group, further deprotection reaction (when the protecting group is an acyl group,
Treat with an acid or alkali according to a conventional method. The protecting group is te
When it is rt-butoxycarbonyl, it is treated with an acid according to a conventional method. The target compound (1)
It is possible to lead to (n = 0).

Among the compounds of formula (1) of the present invention,
The compound with n = 0 can also be produced by the following method.

[0040]

[Chemical 7]

(In the above formula, Ar and R ¹ have the same meanings as described above. R ² has the same meanings as described above, and when R ² has an amino or alkylamino group, those substituents are not included. Examples of the protecting group include an acyl group such as formyl, acetyl, propionyl and benzoyl, or tert-butoxycarbonyl, X is chlorine, bromine or iodine atom, methanesulfonyloxy or benzene. That is, sulfonyloxy, toluenesulfonyloxy or acetoxy.) That is, a triazolyl mercaptoalcohol derivative (4) described in Japanese Patent Application No. 2-35928 is reacted with an alkylating reagent (5) under basic conditions. This is a method for producing the target compound (1). Examples of the solvent used in the reaction include methanol, ethanol, propanol, butanol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, acetone, benzene, toluene, xylene and the like. The base used in the reaction is triethylamine, diisopropylethylamine, sodium hydride, sodium methoxide, sodium ethoxide, lithium methoxide,
It is potassium tert-butoxide, sodium hydroxide, potassium hydroxide and the like, and the amount used is 1 to 3 molar equivalents relative to compound (4). Alkylation reagent (5) is 1 to
3 molar equivalents are used. Reaction temperature is -50 ° to 100 ° C
The reaction time is 2 to 10 hours. The compound (1) is obtained by treating the reaction solution according to a conventional method. When R ^{2 of the} product (1) has a protected amino group or alkylamino group, it is further deprotected (when the protecting group is an acyl group, it is treated with an acid or an alkali according to a conventional method. Is tert-butoxycarbonyl, it can be led to the target compound (1) (n = 0) by performing treatment with an acid according to a conventional method.

Among the compounds (1) of the present invention, compounds having n = 1 or n = 2 can be produced by the method described below. That is, the compound (1) of n = 1 is produced by oxidizing the compound (1) of the present invention having n = 0 obtained by the above-mentioned method with 1 equivalent of an oxidizing agent in a solvent. Further, the compound (1) having n = 2 can be produced by oxidizing the compound with 2 equivalents or more of an oxidizing agent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably methylene chloride,
Mention may be made of halogenated hydrocarbons such as chloroform. Examples of the oxidizing agent used include peracetic acid and 3-chloroperbenzoic acid. The reaction temperature is 0 ° C to 50 ° C, preferably room temperature.

The reaction time is usually 30 minutes to 3 hours. When the reaction solution is treated according to a conventional method, compound (1) (n
= 1 or 2) is obtained.

[0044]

The effects of the compound (1) of the present invention on experimental candidiasis are as follows.

Candida albicans
Albicans) 7-9 × 10 ⁶ mice (10 per group) were inoculated with the drug 20 mg /
After oral administration of kg, the survival rate on the 9th day after infection was examined. The survival rate on the second day of the non-administration group was 0%.

[0046]

[Table 14] As mentioned above, the compound (1) of the present invention exhibits antifungal activity superior to that of the control compound ketoconazole.

The compound (1) of the present invention is used alone or in the form of a formulation for oral or parenteral administration with other excipients, diluents, dispersants and the like. To be done.

The dose and the frequency of administration vary depending on the symptoms, age, body weight, dosage form, etc., but in the case of oral administration, it is usually 50 to 2000 mg, preferably 100 to 600 mg per day for an adult.
It is possible to administer mg once or divided into several times.

Examples will be described below in more detail.

[0050]

【Example】

Example 1 (2R, 3R) -2- (2,4-difluorophenyl)-
3-[(2-hydroxyethyl) thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol

[0051]

[Chemical 8]

70% of 55% sodium hydride (1.60
(mmol) was washed with hexane, and then suspended in 3 ml of dimethylformamide under a nitrogen atmosphere, 187 mg (2.4 mmol) of 2-mercaptoethanol was added under ice cooling, and the mixture was stirred for 10 minutes. Then (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4-
Triazol-1-yl) methyl] oxirane 200 mg
(0.80 mmol) was added and the mixture was stirred at 50-60 ° C for 30 minutes. After cooling, ethyl acetate was added and the mixture was washed with saturated brine and the solvent was evaporated under reduced pressure. The resulting crude product is silica gel 1
It was subjected to column chromatography using 0 g and eluted with a mixed solvent of ethyl acetate / hexane (4/1) to obtain 195 mg of the target compound. Recrystallization was carried out from a mixed solvent of ethyl acetate-hexane to obtain a pure product having a melting point of 89 to 90 ° C.

Specific optical rotation [α] ²⁵ _D −85.9 ° (C = 0.
58, CHCl _3).

Infrared absorption spectrum ν _max (KBr) cm ⁻¹ :
3447, 3234, 1615. NMR spectrum (CDCl ₃ ) δppm: 1.14 (3H, d, J = 7H
z), 2.6-3.1 (3H, m), 3.45 (1H, q, J =
7Hz), 3.83 (2H, t, J = 6.5Hz), 4.83 (1H,
d, J = 14.5Hz), 4.85 (1H, br), 5.14 (1H,
d, J = 14.5Hz), 5.51 (1H, s), 6.5-7.0
(2H, m), 7.2-7.6 (1H, m), 7.74 (1H,
s), 8.03 (1H, s). Example 2 (2R, 3R) -2- (2,4-difluorophenyl)-
3-[(2-hydroxyethyl) sulfonyl] -1-
(1H-1,2,4-triazol-1-yl) -2-butanol

[0055]

[Chemical 9]

(2R, 3R) -2- (2,4-difluorophenyl) -3-[(2-hydroxyethyl) thio]-
1- (1H-1,2,4-triazol-1-yl) -2-
84 mg (0.26 mmol) of butanol was added to 1 m of methylene chloride.
Dissolve in 1, l-chloroperbenzoic acid 96mg (0.56mmo
l) is added and stirred at room temperature for 15 minutes. The reaction solution is diluted with ethyl acetate and washed successively with an aqueous solution of sodium sulfite, dilute aqueous sodium hydrogen carbonate and saturated brine. After drying, the solvent was distilled off and the obtained crude product was subjected to column chromatography using 5 g of silica gel and eluted with a mixed solvent of ethyl acetate / chloroform / ethanol (10/10/1) to obtain the target compound 63.
mg was obtained as a solid. Recrystallization was performed from a mixed solvent of ethyl acetate-benzene to obtain a pure product having a melting point of 122 ° C.

Specific rotation [α] ²⁵ _D −55.8 ° (C = 0.
48, CHCl _3).

Infrared absorption spectrum ν _max (KBr) cm ⁻¹ :
3389, 1616. NMR spectrum (CDCl ₃ ) δppm: 1.27 (3H, d, J = 7H
z), 3.3 (1H, br), 3.4-3.6 (2H, m)
, 3.76 (1H, q, J = 7Hz), 4.22 (2H, t, J = 6
Hz), 5.01 (1H, d, J = 14Hz), 5.43 (1H, d,
J = 14Hz), 5.6 (1H, br), 6.6-7.0 (2H,
m), 7.1-7.6 (1H, m), 7.79 (1H, s),
7.90 (1H, s). Example 3 (2R ^* , 3R ^* )-2- (2,4-difluorophenyl) -3-[(3-hydroxypropyl) thio] -1-
(1H-1,2,4-triazol-1-yl) -2-butanol

[0059]

[Chemical 10]

In the same manner as in Example 1, (2R ^* , 3
S ^* )-2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl)
42 mg of the target compound was obtained by the reaction of 50 mg of methyl] oxirane and 54 mg of 3-mercaptopropanol.

Melting point 119-120 ° C. (recrystallized from ethyl acetate-benzene mixed solvent) Infrared absorption spectrum ν _max (CHCl ₃ ) cm ⁻¹ : 3420, 161
8, 1598, 1500. NMR spectrum (CDCl ₃ ) δppm: 1.15 (3H, d, J = 7Hz
), 1.7-2.1 (2H, m), 2.6-3.1 (3H,
m), 3.34 (1H, q, J = 7Hz), 3.78 (2H, t, J =
6Hz), 4.82 (1H, d, J = 14Hz), 4.9 (1H, br
), 5.10 (1H, d, J = 14Hz), 6.6-7.0 (2
H, m), 7.1-7.6 (1H, m), 7.75 (1H,
s), 7.89 (1H, s). Example 4 (2R, 3R) -2- (2,4-difluorophenyl)-
3-[(methoxycarbonylmethyl) thio] -1- (1
H-1,2,4-triazol-1-yl) -2-butanol

[0062]

[Chemical 11]

100 mg of (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) -2-butanol (0.
35 mmol) was dissolved in 3 ml of dry dimethylformamide, methyl bromacetate 64.2 mg (0.42 mmol) and potassium carbonate 48 mg (0.35 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with benzene, washed with saturated brine, and the solvent was evaporated under reduced pressure. The obtained crude product was subjected to column chromatography using 5 g of silica gel and eluted with a mixed solvent of hexane / ethyl acetate (3/1) to obtain 120 mg of the target compound. Recrystallization was carried out from an acetone-hexane mixed solvent to obtain a pure product having a melting point of 86 to 87 ° C.

Specific rotation [α] ²⁵ _D −116.5 ° (C = 0.8
4, CHCl ₃ ).

Infrared absorption spectrum ν _max (KBr) cm ⁻¹ :
3200 (br), 1742. NMR spectrum (CDCl ₃ ) δppm: 1.17 (3H, d, J = 7Hz
), 3.46 (2H, S), 3.49 (1H, q, J = 7Hz),
3.80 (3H, s), 4.84 (1H, d, J = 15Hz),
5.15 (1H, s), 5.18 (1H, d, J = 15Hz),
6.5-7.0 (2H, m), 7.1-7.6 (1H, m),
7.73 (1H, s), 7.87 (1H, s). Example 5 (2R, 3R) -3- (cyanomethylthio) -2- (
2,4-Difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol

[0066]

[Chemical formula 12]

301 mg of (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) -2-butanol (1.
(05 mmol) was dissolved in 12 ml of dry methylene chloride, 90 mg (1.2 mmol) of chloroacetonitrile and 112 mg (1.11 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and dilute sodium hydrogen carbonate solution under ice cooling. The organic layer is washed twice with saturated brine, dried and the solvent is distilled off, and the resulting oily substance is subjected to column chromatography using silica gel. Elution with a mixed solvent of ethyl acetate / hexane (1 / 1-2 / 1) gave the desired compound (280 mg) as an oil.

Specific rotation [α] ²⁵ _D −158.5 ° (C = 1.1
1, CHCl ₃ ).

Infrared absorption spectrum ν _max (CHCl ₃ ) c
m ⁻¹ : 3410, 1620, 1600, 1500. NMR spectrum (CDCl ₃ ) δppm: 1.23 (3H, d, J = 7Hz
), 3.48 (1H, q, J = 7Hz), 3.58 (2H, s),
5.02 (2H, br.s), 5.36 (1H, br.s), 6.5
-7.1 (2H, m), 7.1-7.7 (1H, m), 7.8
(1H, s), 7.87 (1H, s). 110 mg (0.339 mmol) of this compound was dissolved in 5 ml of ethyl acetate, and 35.9 mg (0.339 mmol) of oxalic acid was added. The solvent was distilled off and recrystallization from ether-hexane was performed to give a melting point of 11
133 mg of oxalate having a temperature of 3-116 ° C was obtained.

Specific rotation [α] ²⁵ _D −72.4 ° (C = 0.55, MeOH)
..

Example 6 (2R, 3R) -3-[(cyanomethyl) sulfonyl]
-2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -2-butanol

[0072]

[Chemical 13]

(2R, 3R) -3- (Cyanomethylthio) -2- (2,4-difluorophenyl) -1- (1H
86 mg (0.27 mmol) of -1,2,4-triazol-1-yl) -2-butanol was dissolved in 2 ml of methylene chloride, and 117 mg (0.678 mmol) of 3-chloroperbenzoic acid was added under ice cooling. The reaction solution was returned to room temperature and stirred for 2 hours, then an aqueous sodium thiosulfate solution and diluted aqueous sodium hydrogen carbonate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and the solvent was distilled off to give an oily substance, which was purified by column chromatography using silica gel. Ethyl acetate / hexane (1 / 1-2 /
1) Elution with a mixed solvent gave 82 mg of the desired compound as an oil.

Specific rotation [α] ²⁵ _D −64.8 ° (C = 0.
52, CHCl _3).

Infrared absorption spectrum ν _max (CHCl ₃ ) c
m ⁻¹ : 3360, 1620, 1600, 1510. NMR spectrum (CDCl ₃ ) δppm: 1.37 (3H, d, J = 7.5
Hz), 3.90 (1H, q, J = 7.5Hz), 4.44 (2H, s
), 4.97 (1H, d, J = 15 Hz), 5.43 (1H, d, J =
15Hz), 6.09 (1H, s), 6.5-7.1 (2H, m
), 7.1-7.6 (1H, m), 7.81 (1H, s)
, 7.83 (1H, s). 77 mg (0.22 mmol) of this compound was added to 3 ml of ethyl acetate.
2% nitric acid-ether solution 0.7 ml under ice cooling
Was added. The solid obtained by distilling off the solvent was washed with ethyl acetate-
Recrystallized from hexane, melting point 143-147 ° C
72 mg of nitrate with (decomposition) were obtained.

Specific rotation [α] ²⁵ _D −29.8 ° (C = 0.
52, MeOH).

Example 7 (2R, 3R) -2- (4-chlorophenyl) -3-
(Cyanomethylthio) -1- (1H-1,2,4-triazol-1-yl) -2-butanol

[0078]

[Chemical 14]

In the same manner as in Example 5, (2R, 3R)-
2- (4-chlorophenyl) -3-mercapto-1-
Using 80 mg of (1H-1,2,4-triazol-1-yl) -2-butanol as a starting material, the target compound 77
mg was obtained as an oil.

Specific rotation [α] ²⁵ _D −141 ° (C = 0.5
1, CHCl ₃ ).

Infrared absorption spectrum ν _max (CHCl ₃ ) c
m ⁻¹ : 3430, 1610, 1508, 1498. NMR spectrum (CDCl ₃ ) δppm: 1.24 (3H, d, J = 7Hz
), 3.26 (1H, q, J = 7Hz), 3.53 (2H, s),
4.58 (1H, d, J = 14 Hz), 5.02 (1H, d, J = 14 Hz
), 5.13 (1H, br.s), 6.23 (4H, s),
7.70 (1H, s), 7.75 (1H, s) 71 mg of this compound in a mixed solvent of ethyl acetate-hexane 1
77 mg of oxalate having a melting point of 76-80 ° C (decomposition) was obtained by mixing with an equivalent amount of oxalic acid.

Specific rotation [α] ²⁵ _D −33.1 ° (C = 0.
51, MeOH).

Example 8 (2R, 3R) -3- (carbamoylmethylthio) -2
-(2,4-Difluorophenyl) -1- (1H-1, 2,4
-Triazol-1-yl) -2-butanol

[0084]

[Chemical 15]

100 mg of (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) -2-butanol (0.
35 mmol) was dissolved in 3 ml of dry dimethylformamide, 58 mg (0.42 mmol) of 2-bromoacetamide and 48 mg (0.35 mmol) of potassium carbonate were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with benzene, washed with saturated saline, and the solvent was evaporated under reduced pressure. The crystalline product obtained is recrystallized from acetone-hexane to give a melting point of 144-1.
90 mg of the target compound at 45 ° C was obtained.

Specific optical rotation [α] ²⁵ _D −39.9 ° (C = 1.
03, MeOH).

Infrared absorption spectrum ν _max (KBr) cm ⁻¹ :
3366, 3219, 1658. NMR spectrum (DMSO-d ₆ ) δppm: 1.03 (3H, d, J
= 7Hz), 3.21 (1H, d, J = 14.5Hz), 3.29 (1H,
d, J = 14.5Hz), 3.60 (1H, q, J = 7Hz), 4.74 (
1H, d, J = 14.5Hz), 4.98 (1H, d, J = 14.5Hz), 6.
24 (1H, s), 6.6-7.0 (1H, m), 7.0-7.
5 (3H, m), 7.62 (2H, s), 8.27 (1H, s). Example 9 (2R, 3R) -3-[(carbamoylmethyl) sulfonyl] -2- (2,4 -Difluorophenyl) -1- (1
H-1,2,4-triazol-1-yl) -2-butanol

[0088]

[Chemical 16]

(2R, 3R) -3- (carbamoylmethylthio) -2- (2,4-difluorophenyl) -1-
140 mg (0.41 mmol) of (1H-1,2,4-triazol-1-yl) -2-butanol was added to 30 ml of methylene chloride.
The mixture was dissolved in water, 149 mg (0.86 mmol) of 3-chloroperbenzoic acid was added, and the mixture was stirred overnight at room temperature. The reaction solution is washed with an aqueous solution of sodium thiosulfate, a dilute sodium bicarbonate solution and a saturated saline solution in this order, and the solid obtained by distilling off the solvent under reduced pressure is recrystallized from methanol-hexane to give the target compound 120 having a melting point of 184 to 185 ° C.
to obtain mg.

Specific optical rotation [α] ²⁵ _D −35.4 ° (C = 1.
00, DMF).

Infrared absorption spectrum ν _max (KBr) cm ⁻¹ :
3367, 3286, 1670. NMR spectrum (DMSO-d ₆ + D ₂ O) δppm: 1.14 (3
H, d, J = 7Hz), 3.39 (2H, s), 4.42 (1H,
q, J = 7Hz), 4.81 (1H, d, J = 14.5Hz), 5.31
(1H, d, J = 14.5Hz), 6.4-7.0 (1H, m), 7.
0-7.5 (2H, m), 7.64 (1H, s), 8.31
(1H, s). Example 10 (2R, 3R) -3-[[(R and S) -2-azetidinone-4-yl] thio] -2- (2,4-difluorophenyl) -1- ( 1H-1,2,4-triazol-1-yl) -2-butanol

[0092]

[Chemical 17]

22.5 mg (55% mineral oil suspension, 0.5%) of sodium hydride in 5 ml of methanol under ice cooling.
2mmol), followed by (2R, 3R) -2- (2,4
-Difluorophenyl) -3-mercapto-1- (1H
-1,2,4-Triazol-1-yl) -2-butanol 138 mg (0.48 mmol) and 4-acetoxy-2-azetidinone 150 mg (1.16 mmol) were added, and the mixture was cooled to 3 with ice.
Stir for 0 minutes. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The oily substance obtained by washing with saturated brine and distilling off the solvent was subjected to silica gel column chromatography and eluted with a mixed solvent of ethyl acetate-hexane to obtain the target compound 15
0 mg was obtained as a foamy 1: 1 mixture of diastereomers.

Specific rotation [α] ²⁵ _D −26.5 ° (C = 1.
10, CHCl _3).

IR spectrum ν _max (CHCl ₃ ) cm ⁻¹ : 34
00 (br.), 1760. NMR spectrum (CDCl ₃ + D ₂ O) δppm: 1.23 (1.
5H, dd, J = 7, 1 Hz), 1.33 (1.5H, d, J = 7Hz),
2.89 (0.5H, dd, J = 15,2.4 Hz), 2.94 (0.5H, d
d, J = 15, 2.4 Hz), 3.37 (0.5H, q, J = 7Hz), 3.
43 (0.5H, q, J = 7 Hz), 3.43 (0.5H, dd, J = 15, 5
Hz), 3.49 (0.5H, dd, J = 15, 5Hz), 4.85 (
0.5H, dd, J = 14, 1 Hz), 4.87 (0.5H, d, J = 14 H
z), 4.96 (0.5H, dd, J = 14, 1 Hz), 5.07 (
0.5H, d, J = 14 Hz), 5.09 (0.5H, dd, J = 5, 2.4
Hz), 5.21 (0.5H, dd, J = 5, 2.4 Hz), 6.65
-6.85 (2H, m), 7.3-7.5 (1H, m),
7.78 (0.5H, s), 7.80 (0.5H, s), 7.8
2 (0.5H, s), 7.84 (0.5H, s). 87 mg of the title compound was dissolved in ethyl acetate, 47 mg of p-toluenesulfonic acid (monohydrate) was added, the solvent was distilled off,
Solidification in ether gave 121 mg of salt as an amorphous powder.

Example 11 (2R, 3R) -2- (2,4-difluorophenyl)-
3-[(1,3-dioxolan-2-yl) methylthio]
-1- (1H-1,2,4-triazol-1-yl) -2
-Butanol

[0097]

[Chemical 18]

In the same manner as in Example 1, (2R, 3S)-
2- (2,4-difluorophenyl) -3-methyl-2-
[(1H-1,2,4-triazol-1-yl) methyl]
193 mg of oxirane was reacted with 160 mg of (1,3-dioxolan-2-yl) methanethiol to obtain 178 mg of the target compound as an oily substance.

Specific rotation [α] ²⁵ _D −56 ° (C = 0.5
3, MeOH) NMR spectrum (CDCl ₃ ) δppm: 1.16 (
3H, d, J = 7 Hz), 2.91 (2H, d-like, J = 5 Hz),
3.57 (1H, q, J = 7 Hz), 3.8-4.2 (4H, m)
, 4.87 (1H, d, J = 14 Hz), 4.95 (1H, s)
, 5.15 (1H, t, J = 5 Hz), 5.19 (1H, d, J = 1
4 Hz), 6.6-7.0 (2H, m), 7.2-7.6
(1H, m), 7.78 (1H, s), 7.88 (1H, s). Oxalic acid 1 was added to this compound in a mixed solvent of ethyl acetate-hexane.
Mixing with equivalents gave an oxalate salt with a melting point of 115-117 ° C.

Example 12 (2R, 3R) -3-[(1-cyanoethyl) thio]-
2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -2-butanol

[0101]

[Chemical 19]

(2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,2
4-triazol-1-yl) -2-butanol 143
Dissolve mg (0.50 mmol) in 3 ml of dimethylformamide,
134 mg (1.00 mmol) of 2-bromopropionitrile and 69 mg (0.50 mmol) of potassium carbonate were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Benzene was added to the reaction mixture, and the mixture was washed with water and saturated brine in that order. The oily product obtained by evaporating the solvent under reduced pressure was separated and purified by preparative thin layer chromatography on silica gel [developing solvent: ethyl acetate-hexane (3: 2)]. 57 mg of the less polar oily stereoisomer A and 72 mg of the more polar stereoisomer B were obtained. The latter was recrystallized from a benzene-hexane mixed solvent to obtain a pure product having a melting point of 66-68 ° C.

Stereoisomer A; specific rotation [α] _D ²⁵ -192 ° (C = 0.97, CHCl ₃ ).

Infrared absorption spectrum ν _max (CHCl ₃ ) cm ⁻¹ :
3400,1617,1498.

NMR spectrum (CDCl ₃ ) δppm: 1.24 (3H,
d, J = 7Hz), 1.64 (3H, d, J = 7Hz), 3.54 (1H, brq, J = 7Hz), 3.90
(1H, q, J = 7Hz), 4.90 (1H, d, J = 14Hz), 5.10 (1H, d, J = 14Hz),
5.26 (1H, s), 6.5-7.0 (2H, m), 7.1-7.6 (1H, m), 7.79 (1H, s),
7.80 (1H, s).

57 mg of this compound and 17 mg of oxalic acid were dissolved in 2 ml of ethyl acetate, hexane was added, and the precipitated crystals were collected by filtration to give 60 mg of oxalate (melting point 137-138 ° C.).

Stereoisomer B; specific rotation [α] _D ²⁵ -46.0 ° (C = 0.83, CHCl ₃ ).

Infrared absorption spectrum ν _max (CHCl ₃ ) cm ⁻¹ :
3400,1615,1498.

NMR spectrum (CDCl ₃ ) δppm: 1.24 (3H,
d, J = 7Hz), 1.64 (3H, d, J = 7Hz), 3.51 (1H, brq, J = 7Hz), 3.93
(1H, q, J = 7Hz), 4.99 (2H, s), 5.28 (1H, s), 6.5-7.0 (2H, m),
7.1-7.6 (1H, m), 7.76 (1H, s), 7.83 (1H, s).

Example 13 (2R, 3R) -3-[(1-cyanoethyl) sulfinyl] -2- (2,4-difluorophenyl) -1-
(1H-1,2,4-triazol-1-yl) -2-
Butanol

[0111]

[Chemical 20]

(2R, 3R) -3-described in Example 12
[(1-Cyanoethyl) thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol isomer A 402 mg
(1.19 mmol) was dissolved in 15 ml of methylene chloride, 205 mg (1.19 mmol) of m-chloroperbenzoic acid was added with stirring under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was washed with 5% aqueous sodium thiosulfate solution and then with 3% aqueous sodium hydrogen carbonate. The solvent was evaporated under reduced pressure and the oily residue obtained was subjected to column chromatography using 15 g of silica gel, and the fractions eluted with a mixed solvent of ethyl acetate-hexane (4: 1) were collected to give 381 mg of the oily target compound. Got Although this substance was a mixture of two diastereomers, it was subjected to Rover column chromatography (ethyl acetate solvent) to obtain 220 mg of a more polar isomer as an oily pure product.

Infrared absorption spectrum ν _max (CHCl ₃ ) cm ⁻¹ :
3390,2250,1615,1500.

NMR spectrum (CDCl ₃ ) δppm: 1.13 (3H,
d, J = 7Hz), 1.74 (3H, d, J = 7Hz), 3.69 (1H, q, J = 7Hz), 3.76 (1
H, q, J = 7Hz), 4.91 (2H, s), 5.78 (1H, s), 6.5-7.1 (2H, m), 7.1
-7.7 (1H, m), 7.80 (1H, s), 7.92 (1H, s).

The above compound was dissolved in ether and added with 5% HN.
O ₃ -ether solution (1 eq) was added to obtain nitrate crystals.

Melting point 140-142 ° C. (2) (2R, 3R) -3-[(1
-Cyanoethyl) thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole-1
The crude product obtained by oxidizing 570 mg of isomer B of -yl) -2-butanol with 1 equivalent of m-chloroperbenzoic acid in the same manner as above was purified by silica gel chromatography. 521 mg of the oily target compound are obtained as a mixture of two diastereomers. Isolate 228, which is a more polar compound by low-bar column chromatography.
mg was obtained as an oily pure product.

Infrared absorption spectrum ν _max (CHCl ₃ ) cm ⁻¹ :
3400,2255,1620,1505.

NMR spectrum (CDCl ₃ ) δppm: 1.11 (3H,
d, J = 7Hz), 1.65 (3H, d, J = 7Hz), 3.72 (1H, q, J = 7Hz), 3.78 (1
H, q, J = 7Hz), 4.89 (2H, s), 5.87 (1H, s), 6.5-7.1 (2H, m), 7.1
-7.7 (1H, m), 7.80 (1H, s), 7.97 (1H, s).

The above compound was dissolved in ether and added with 5% HN.
O ₃ -ether solution (1 eq) was added to obtain nitrate crystals.

Melting point 128-131 ° C.

Example 14 (2R, 3R) -2- (2,4-difluorophenyl)
-3- (methoxymethylthio) -1- (1H-1,2,
4-triazol-1-yl) -2-butanol

[0122]

[Chemical 21]

(2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,2
4-triazol-1-yl) -2-butanol 400
Dissolve mg (1.40 mmol) in 10 ml of methylene chloride and stir at 0 ° C with 215 mg (2.67 mm) of methoxymethyl chloride.
ol) then 217 mg of diisopropylethylamine (1.68
mmol) was added. After stirring at the same temperature for 15 minutes, the mixture was allowed to stand at room temperature for 30 minutes. Dilute aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying, the solvent was distilled off under reduced pressure and the crystalline residue obtained was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain 235 mg of the target compound having a melting point of 110-112 ° C.

Specific rotation [α] _D ²⁵ -55 ° (C = 0.59, CHCl ₃ ).

Infrared absorption spectrum ν _max (KBr) cm ⁻¹ : 31
86 (br), 1615,1499.

NMR spectrum (CDCl ₃ ) δppm: 1.18 (3H,
d, J = 7Hz), 3.50 (3H, s), 3.59 (1H, q, J = 7Hz), 4.63 (1H, d, J = 1
2Hz), 4.83 (1H, d, J = 14Hz), 4.84 (1H, d, J = 14Hz), 4.88 (1H,
s), 6.5-7.0 (2H, m), 7.2-7.6 (1H, m), 7.75 (1H, s), 7.89 (1H,
s).

Example 15 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[(methoxymethyl) sulfonyl] -1- (1H
-1,2,4-triazol-1-yl) -2-butanol

[0128]

[Chemical formula 22]

(2R, 3R) -2- (2,4-difluorophenyl) -3- (methoxymethylthio) -1- (1
190 mg (0.58 mmol) of H-1,2,4-triazol-1-yl) -2-butanol was dissolved in 7 ml of methylene chloride, and 280 mg of m-chloroperbenzoic acid was stirred with ice cooling.
(1.62 mmol) was added. After 5 minutes, the mixture was returned to room temperature and stirred for 1 hour. Aqueous sodium sulfite solution and then dilute aqueous sodium hydrogen carbonate were added to the reaction solution and the mixture was extracted with ethyl acetate. The crude product obtained by distilling off the solvent after drying was subjected to column chromatography using silica gel, and the fractions eluted with a mixed solvent of ethyl acetate-hexane (1: 1) were collected to obtain 171 mg of the desired compound as a solid. It was Recrystallization from a benzene-hexane mixed solvent gave a pure product having a melting point of 102-103 ° C.

Specific rotation [α] _D ²⁵ −108 ° (C = 0.51, CHCl ₃ ).

Infrared absorption spectrum ν _max (KBr) cm ⁻¹ : 34
39,1617,1505.

NMR spectrum (CDCl ₃ ) δppm: 1.26 (3H,
d, J = 7Hz), 3.77 (3H, s), 3.81 (1H, q, J = 7Hz), 4.50 (1H, d, J = 1
2Hz), 4.97 (1H, d, J = 12Hz), 4.99 (1H, d, J = 15Hz), 5.43 (1H,
s), 5.49 (1H, s), 6.5-7.0 (2H, m), 7.1-7.6 (1H, m), 7.77 (1H,
s), 7.86 (1H, s).

Example 16 (2R, 3R) -2- (4-chlorophenyl) -3-
(Methoxymethylthio) -1- (1H-1,2,4-triazol-1-yl) -2-butanol

[0134]

[Chemical formula 23]

In the same manner as in Example 14, (2R, 3R)
-2- (4-chlorophenyl) -3-mercapto-1-
(1H-1,2,4-triazol-1-yl) -2-
Using 360 mg of butanol as a starting material, 220 mg of the target compound (purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1)) was obtained as a solid. Recrystallization was carried out from a mixed solvent of ethyl acetate-hexane to obtain a pure product having a melting point of 122 ° C.

Specific rotation [α] _D ²⁵ -12.0 ° (C = 0.50, CHC
l ₃ ).

NMR spectrum (CDCl ₃ ) δppm: 1.20 (3H,
d, J = 7Hz), 3.31 (1H, q, J = 7Hz), 3.47 (3H, s), 4.55 (1H, d, J = 1
2Hz), 4.58 (1H, d, J = 14Hz), 4.76 (1H, s), 4.81 (1H, d, J = 12H
z), 4.90 (1H, d, J = 14Hz), 7.25 (4H, s), 7.82 (2H, s).

Example 17 (2R, 3R) -2- (4-chlorophenyl) -3-
[(1-Methoxyethyl) thio] -1- (1H-1,
2,4-triazol-1-yl) -2-butanol

[0139]

[Chemical formula 24]

401 mg (1.41) of (2R, 3R) -2- (4-chlorophenyl) -3-mercapto-1- (1H-1,2,4-triazol-1-yl) -2-butanol
mmol) in methylene chloride (8 ml) and stirred at 0 ° C. with 1-methoxyethyl chloride (267 mg, 2.82 mmol),
Then 219 mg of diisopropylethylamine (1.69 mmo
l) was added. It returned to room temperature and stirred for 1 hour. Dilute aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying, the solvent was distilled off under reduced pressure, and the obtained oily product was subjected to column chromatography using silica gel, ethyl acetate-
Fractions eluted with a mixed solvent of hexane (2: 1) were collected to obtain 245 mg of the target compound as an oil. This substance is a mixture of two diastereomers (1: 1).

Infrared absorption spectrum ν _max (CHCl ₃ ) cm ⁻¹ :
3350,1515,1495.

NMR spectrum (CDCl ₃ ) δppm: 1.20,1.2
6 (3H, d, J = 7Hz), 1,47,1.50 (3H, d, J = 6Hz), 3.30,3.38 (3H,
s), 3.13,3.32 (1H, q, J = 7Hz), 4.47,4.54 (1H, d, J = 14Hz), 4.
80 (1H, q, J = 6Hz), 4.88,5.02 (1H, d, J = 14Hz), 5.00,5.05 (1
H, s), 7.00-7.55 (4H, m), 7.75,7.79 (1H, s), 7.83,7.96 (1H,
s) 155 mg of the above compound was dissolved in ethyl acetate, 1 equivalent of oxalic acid was added, and then hexane was added to collect the precipitated crystals to obtain 180 mg of oxalate having a melting point of 147.5-149 ° C.

Example 18 (2R, 3R) -2- (2,4-difluorophenyl)
-3- (methylthiomethylthio) -1- (1H-1,
2,4-triazol-1-yl) -2-butanol

[0144]

[Chemical 25]

55% sodium hydride 31 mg (0.70 mmo
l) was washed with dry hexane, suspended in 2 ml of dimethylformamide, and stirred at 0 ° C. with (2R, 3R) -2.
-(2,4-Difluorophenyl) -3-mercapto-
1- (1H-1,2,4-triazol-1-yl)-
2-Butanol 100 mg (0.35 mmol) was added. When the generation of hydrogen gas subsides, methylthiomethyl chloride 67
mg (0.70 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was partitioned between ethyl acetate and brine. After drying the organic layer, the crude product obtained by distilling off the solvent was subjected to column chromatography using silica gel and eluted with a mixed solvent of ethyl acetate-hexane (3: 1) to obtain 105 mg of the target compound as a solid. Obtained. Recrystallization from ethyl acetate-hexane gave 78 mg of pure product having a melting point of 108-109 ° C.

Specific rotation [α] _D ²⁵ -240 ° (C = 0.84, CHC
l ₃ ).

NMR spectrum (CDCl ₃ ) δppm: 1.17 (3H,
d, J = 7Hz), 2.25 (3H, s), 3.63 (1H, brq, J = 7Hz), 3.77 (2H, s),
4.85 (1H, d, J = 14Hz), 5.08 (1H, d, J = 14Hz), 8.6-7.0 (2H, m),
7.2-7.6 (1H, m), 7.76 (1H, s), 7.82 (1H, s).

Example 19 (2R, 3R) -2- (4-chlorophenyl) -3-
(Methylthiomethylthio) -1- (1H-1,2,4-
Triazol-1-yl) -2-butanol

[0149]

[Chemical formula 26]

In the same manner as in Example 17, (2R, 3R)
-2- (4-chlorophenyl) -3-mercapto-1-
(1H-1,2,4-triazol-1-yl) -2-
Using butanol 150 mg as starting material, melting point 16
138 mg (recrystallized from ethyl acetate-hexane) of the target compound having a temperature of 3-163.5 ° C was obtained.

Specific rotation -217 ° (C = 1.05, CHCl ₃ ).

Infrared absorption spectrum ν _max (KBr) cm ⁻¹ : 31
84,1511,1492.

NMR spectrum (CDCl ₃ ) δppm: 1.20 (3H,
d, J = 7Hz), 2.20 (3H, s), 3.32 (1H, q, J = 7Hz), 3.71 (2H, s), 4.
55 (1H, d, J = 14Hz), 4.56 (1H, s), 5.05 (1H, d, J = 14Hz), 7.10-
7.45 (4H, m), 7.76 (1H, s), 7.83 (1H, s).

Example 20 (2R, 3R) -3-[(cyanomethyl) sulfinyl] -2- (2,4-difluorophenyl) -1- (1
H-1,2,4-triazol-1-yl) -2-butanol

[0155]

[Chemical 27]

Obtained by the method of Example 5 (2R, 3
R) -3- (Cyanomethylthio) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol 350 mg (1.08 mmo
To 7 ml of a methylene chloride solution of l), 205 mg (1.19 mmol) of 3-chloroperbenzoic acid was added with stirring under ice cooling, and the mixture was heated to 2 at the same temperature.
Stir for hours. The reaction solution was added to an aqueous solution of ethyl acetate and sodium sulfite, the ethyl acetate layer was separated, washed successively with sodium hydrogen carbonate and brine, and then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel (10 g) column chromatography, and ethyl acetate: benzene = 4: 1.
The less polar isomer 113 mg was obtained as crystals from the fractions eluting with. When this crystal was recrystallized with a mixed solvent of ethyl acetate and hexane, a crystal having a melting point of 138 to 140 ° C was obtained.

Specific rotation [α] _D ²⁵ −156 ° (C = 0.53, CHCl ₃ ) Infrared absorption spectrum ν _max (CHCl ₃ ) cm ⁻¹ : 3505, 225
0, 1618, 1598, 1504 NMR spectrum (CDCl ₃ ) δppm: 1.06 (3H, d, J = 7Hz), 3.
64 (1H, d, J = 16.5Hz), 3.77 (1H, q, J = 7Hz), 4.08 (1H, d, J = 1
6.5Hz), 4.98 (1H, d, J = 14Hz), 5.22 (1H, d, J = 14Hz), 5.82
(1H, s), 6.7-6.9 (2H, m), 7.2-7.4 (1H, m), 7.78 (1H, s),
7.81 (1H, s).

Then, ethyl acetate: methanol = 95: 5
169 mg of the more polar isomer was obtained as crystals from the fraction eluting with. Recrystallization of this crystal from a mixed solvent of acetone and diisopropyl ether gave a melting point of 80-84.
C crystals were obtained.

Specific rotation [α] _D ²⁵ −139 ° (C = 0.55, CHCl ₃ ) Infrared absorption spectrum ν _max (KBr) cm ⁻¹ : 3260, 2250,
1618, 1598, 1520 NMR spectrum (CDCl ₃ ) δppm: 1.22 (3H, d, J = 7Hz), 3.
74 (1H, q, J = 7Hz), 3.90 (2H, s), 4.83 (1H, d, J = 14Hz), 5.0
6 (1H, d, J = 14Hz), 5.76 (1H, s), 6.6-6.9 (2H, m), 7.4-7.5
(1H, m), 7.83 (1H, s), 7.92 (1H, s).

Example 21 (2R, 3R) -2- (2,4-difluorophenyl)
-3- (tetrahydrofuran-3-ylthio) -1-
(1H-1,2,4-triazol-1-yl) -2-
Butanol and its oxalate

[0161]

[Chemical 28]

20 mg (0.46 mmol) of sodium hydroxide (55% w / w of mineral oil suspension) was washed with hexane and suspended in 1.5 ml of dimethylformamide. In this suspension, (2R, 3R) -2- (2,4-difluorophenyl) -3-mercapto-1- (1H-1,2,4-
130 mg of triazol-1-yl) -2-butanol
(0.46 mmol) was added under nitrogen cooling in a nitrogen stream, and the mixture was stirred for 10 minutes. (±)-(Methanesulfonyloxy) in this solution
Tetrahydrofuran 92 mg (0.55 mmol) was added, and 60-
The mixture was stirred at 65 ° C for 2 hours. Ethyl acetate was added to this reaction solution, which was washed with saturated saline, and then the solvent was evaporated under reduced pressure. The residue was subjected to silica gel (15 g) column chromatography, and 139 mg of an oily substance was obtained from the portion eluted with a mixed solvent of ethyl acetate: hexane = 2: 1. This oil was applied to a Rover column, and 85 mg of the desired product was obtained as an oil from the portion eluted with ethyl acetate.

Infrared absorption spectrum ν _max (CHCl ₃ ) c
m ^-1 : 3425, 1615, 1595 NMR spectrum (CDCl ₃ ) δppm: 1.15 (3H, d, J = 7Hz), 1.
57-2.65 (2H, m), 3.33 (1H, q, J = 7Hz), 3.4-4.5 (5H, m), 4.
82 (1H, d, J = 15Hz), 4.94 (1H, s), 5.14 (1H, d, J = 15Hz), 6.
4-7.1 (2H, m), 7.1-7.7 (1H, m), 7.76 (1H, s), 7.87 (1H,
s).

1 molar equivalent of oxalic acid was added to a solution of 73 mg of the obtained oily substance in ethyl acetate. Hexane was added to this solution and the precipitated crystals were collected by filtration to obtain 56 mg of the oxalate salt of the title compound having a melting point of 162-4 ° C.

Example 22 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[(3-oxetanyl) thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butano-
Le

[0166]

[Chemical 29]

8 mg of sodium hydride (55% mineral oil suspension, 0.18 mmol) was added to 0.6 ml of dimethylformamide.
0.1 ml of methanol was added with stirring under ice-cooling.
To this solution, under a nitrogen atmosphere 3- (acetylthio) oxetane 36 mg (0.27 mmol;. 3-tosyloxy oxetane (JAWojtowicz and RJPolak, J.Org.Chem 38, 2061 (1
973)) was obtained by the reaction of potassium thioacetate) in 0.4 ml of dimethylformamide, and
After stirring for 10 minutes, (2R, 3R) -2- (2,4-
Difluorophenyl) -3-mercapto-1- (1H-
1,2,4-triazol-1-yl) -2-butano-
50 mg (0.20 mmol) was added. The reaction mixture was stirred at 60 ° C. for 40 minutes, then cooled and diluted with ethyl acetate. The oily substance obtained by washing with saturated saline and distilling off the solvent was used for preparative thin layer chromatography on silica gel [developing solvent;
Hexane-ethyl acetate (1: 2) mixed solvent] to give the object compound as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.10 (3
H, d, J = 6.6 Hz), 3.27 (1H, brq,
J = 6.6 Hz), 4.49 (1H, quintet,
J = 7.3 Hz), 4.83 (1H, d, J = 14.5)
Hz), 4.97 (1H, d, J = 14.5Hz),
6.65-6.8 (2H, m), 7.3-7.4 (1
H, m), 7.78 (1H, s), 7.79 (1H,
s)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location C07D 405/12 249 8829-4C 409/12 249 8829-4C 413/12 249 8829-4C 417/12 249 9051-4C (72) Inventor Toshiyuki Konosu 1-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) Noriko Takeda 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. In-house (72) Inventor Hiro Yasuda Sanyo Co., Ltd. 1-25-2 Hiromachi, Shinagawa-ku, Tokyo

Claims (1)

What is claimed is: Claims 1 A compound having: or an acid addition salt or alkali metal salt thereof. In the formula, Ar represents a phenyl group which is unsubstituted or substituted with 1 to 3 substituents selected from a halogen atom and trifluoromethyl, R ¹ represents a lower alkyl group, and R ^1
2 is an alkyl group having 1 to 3 carbon atoms having 1 to 3 substituents, a cycloalkyl group having 3 to 6 carbon atoms having 1 to 3 substituents, 1 to 3 substituents A cycloalkylalkyl group having 4 to 8 carbon atoms having 1
˜3 to 6 membered heterocyclic group having at least one nitrogen, oxygen or sulfur atom which may have 3 substituents or 1 to 3
Represents a 3- to 6-membered heterocyclic-substituted alkyl group having at least one nitrogen, oxygen, or sulfur atom which may have 4 substituents, and n represents 0, 1 or 2.