JP2902345B2 - Triazole antifungal agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art Japanese Patent Application Laid-Open No. 61-85369 discloses that

[0003]

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[0004] It is described that analogous compounds of the compound of the present invention, in which the portion corresponding to is an alkyl group, a cycloalkylalkyl group or a cycloalkyl group, have antifungal activity.

[0005]

However, the present inventors have conducted intensive studies to find a more excellent antifungal agent, and have found that the compound of the present invention is an excellent antifungal agent, and have completed the present invention. Reached.

[0006]

The present invention is a compound having the formula (I) or a pharmaceutically acceptable salt thereof.

[0007]

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In the formula, Ar ¹ represents a phenyl group or a phenyl group having 1 to 3 substituents (the substituents represent a halogen atom or a trifluoromethyl group).

Ar ² is a phenyl group, a 5- to 6-membered aromatic heterocyclic group (the aromatic heterocyclic group has at least one nitrogen, oxygen or sulfur atom) or a phenyl group having 1 to 3 substituents Or a 5- to 6-membered aromatic heterocyclic group (the substituent is a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkyl group substituted with a halogen atom, a lower alkoxy group substituted with a halogen atom, a nitro group, a cyano group, Group,
A —S (O) _m R ⁶ group (R ⁶ : a lower alkyl group optionally substituted by a halogen atom; m: represents 0, 1 or 2) or a —NHCOR ⁷ group (R ⁷ represents a lower alkyl group) ),
The aromatic heterocyclic group has at least one nitrogen, oxygen and sulfur atom).

R ⁰ represents a hydrogen atom or a lower alkyl group. R ¹ represents a lower alkyl group. R ² , R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkyl group substituted with a halogen atom. When q and s represent 2, R ² , R ³ , R
⁴ and R ⁵ each independently represent the same or different groups. n represents 0, 1 or 2. p represents 0 or 1. q, r and s represent 0, 1 or 2. A represents a 4- to 7-membered aliphatic carbocyclic group having 4 to 7 carbon atoms or a 4- to 7-membered aliphatic heterocyclic group having at least one nitrogen, oxygen or sulfur atom.

The above halogen atom is, for example, a fluorine, chlorine or bromine atom, preferably a fluorine or chlorine atom.

Lower alkyl groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
It is a c-butyl or tert-butyl group, preferably a methyl, ethyl, propyl or isopropyl group.

Lower alkoxy groups include, for example, methoxy,
An ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy group, preferably a methoxy, ethoxy, propoxy or isopropoxy group.

The 5- to 6-membered aromatic heterocyclic group of Ar ² is, for example, a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl or pyrazyl group, preferably furyl, thienyl, pyrrolyl or pyryl. It is a pyridyl group.

The 4- to 7-membered aliphatic carbocyclic group consisting of 4 to 7 carbon atoms of A is, for example, a cyclobutane, cyclopentane, cyclohexane or cycloheptane ring, preferably a cyclobutane, cyclopentane or cyclohexane ring.

At least one nitrogen, oxygen and sulfur atom of A
The 4- to 7-membered aliphatic heterocyclic group having, for example, azetidine, pyrrolidine, piperidine, homopiperidine, oxetane, tetrahydrofuran, tetrahydropyran, thietane, tetrahydrothiophene, pentamethylene sulfide, 1,4,5,6-tetrahydro Pyrimidine, 1,
3-dioxane, 1,3-dithiane, dihydrooxazine, tetrahydrooxazine, dihydrothiazine or tetrahydrothiazine ring, preferably azetidine, piperidine, 1,3-dioxane, 1,4,5,6
-A tetrahydropyrimidine, tetrahydrooxazine or 1,3 dithiane ring.

In a preferred compound having formula (I), Ar ¹ is a dichlorophenyl, difluorophenyl, chlorophenyl, fluorophenyl, (trifluoromethyl) phenyl or fluoro (trifluoromethyl) phenyl group, preferably 2,4 -Dichlorophenyl, 2,4-difluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4- (trifluoromethyl) phenyl or 2-fluoro-4- (trifluoromethyl) phenyl, and particularly preferably 2, 4-dichlorophenyl, 2,
A compound which is a 4-difluorophenyl or 4- (trifluoromethyl) phenyl group.

Ar ² is fluorophenyl, chlorophenyl, difluorophenyl, dichlorophenyl, (trifluoromethyl) phenyl, (trichloromethyl) phenyl, fluoro- (trifluoromethyl) phenyl, (difluoromethoxy) phenyl, (trifluoromethoxy) phenyl , (2,2,2-trifluoroethoxy)
Phenyl, (1,1,2,2-tetrafluoroethoxy) phenyl, (2,2,3,3-tetrafluoropropoxy) phenyl, fluoro- (2,2,3,3-tetrafluoropropoxy) phenyl, nitro Phenyl, fluoro-nitrophenyl, cyanophenyl, chloro-cyanophenyl, (methylthio) phenyl, (methylsulfinyl) phenyl, (methylsulfonyl) phenyl,
(Trifluoromethylthio) phenyl, (trifluoromethylsulfinyl) phenyl, (trifluoromethylsulfonyl) phenyl, chloropyridyl, (trifluoromethyl) pyridyl, (2,2,3,3-tetrafluoropropoxy) pyridyl, Fluoromethyl) furyl, chlorothienyl or (trifluoromethyl) thienyl group, preferably 4-fluorophenyl, 4-fluorophenyl,
Chlorophenyl, 2,4-difluorophenyl, 2,4
-Dichlorophenyl, 4- (trifluoromethyl) phenyl, 4- (trichloromethyl) phenyl, 2-fluoro-4- (trifluoromethyl) phenyl, 4- (difluoromethoxy) phenyl, 3- (trifluoromethoxy) phenyl, 4- (trifluoromethoxy) phenyl, 4- (2,2,2-trifluoroethoxy) phenyl, 4- (1,1,2,2-tetrafluoroethoxy)
Phenyl, 4- (2,2,3,3-tetrafluoropropoxy) phenyl, 2-fluoro-4- (2,2,3
3-tetrafluoropropoxy) phenyl, 4-nitrophenyl, 2-fluoro-4-nitrophenyl, 4-cyanophenyl, 2-chloro-4-cyanophenyl, 4-
(Methylthio) phenyl, 4- (methylsulfinyl)
Phenyl, 4- (methylsulfonyl) phenyl, 4-
(Trifluoromethylthio) phenyl, 4- (trifluoromethylsulfinyl) phenyl, 4- (trifluoromethylsulfonyl) phenyl, 6-chloro-3-pyridyl, 6- (trifluoromethyl) -3-pyridyl, 5
-Chloro-2-pyridyl, 6- (2,2,3,3-tetrafluoropropoxy) -3-pyridyl, 5- (trifluoromethyl) -2-furyl, 5-chloro-2-thienyl or 5- ( Trifluoromethyl) -2-thienyl group, particularly preferably 4-chlorophenyl, 4- (trifluoromethylthio) phenyl, 4- (trifluoromethylsulfonyl) phenyl, 4- (trifluoromethyl) phenyl, A compound which is a (trifluoromethoxy) phenyl or 4- (2,2,3,3-tetrafluoropropoxy) phenyl group.

Compounds wherein R ⁰ is a hydrogen atom, methyl, ethyl or propyl group, preferably a hydrogen atom, methyl or ethyl group, particularly preferably a hydrogen atom or methyl group. Compounds wherein R ¹ is a methyl, ethyl or propyl group, preferably a methyl or ethyl group, particularly preferably a methyl group.

R ² , R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, methyl, ethyl, propyl or trifluoromethyl, preferably a hydrogen atom, methyl or trifluoromethyl group. And particularly preferably a compound which is a hydrogen atom or a trifluoromethyl group.

A compound wherein n is 0, 1 or 2;
Particularly preferably, the compound wherein n is 0. A compound wherein p is 0 or 1, and particularly preferably p is 0.

Compounds wherein q is 0, 1 or 2, and particularly preferably q is 1.

A compound wherein r is 0, 1 or 2, and particularly preferably r is 0 or 1.

A compound wherein s is 0, 1 or 2, and particularly preferably s is 1.

A is cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, 1,3-dioxane, 1,3-dithiane,
A tetrahydrooxazine or tetrahydrothiazine ring, preferably cyclobutane, cyclohexane, azetidine, piperidine, 1,3-dioxane, 1,3-dithiane, tetrahydrooxazine or tetrahydrothiazine ring, particularly preferably cyclohexane, piperidine , 1,3-dioxane or 1,3-dithiane ring. Examples of suitable compounds (I) include Ar ¹
But 4-chlorophenyl, 2, 4-difluorophenyl,
A 2,4-dichlorophenyl or 4- (trifluoromethyl) phenyl group, R ⁰ is a hydrogen atom or a methyl group, R ¹ is a methyl group,

[0026]

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Compounds having the groups shown in Table 1 can be mentioned.

[0028]

[Table 1]

[0029]

[Table 2]

[0030]

[Table 3]

[0031]

[Table 4]

[0032]

[Table 5]

[0033]

[Table 6]

[0034]

[Table 7]

[0035]

[Table 8]

[0036]

[Table 9]

[0037]

[Table 10]

[0038]

[Table 11]

[0039]

[Table 12]

[0040]

[Table 13]

[0041]

[Table 14]

[0042]

[Table 15]

[0043]

[Table 16]

[0044]

[Table 17]

[0045]

[Table 18]

[0046]

[Table 19]

[0047]

[Table 20]

[0048]

[Table 21]

[0049]

[Table 22]

[0050]

[Table 23]

Preferred compounds in Table 1 are 4, 6, 7, 1
3, 16, 18, 22, 25, 32, 36, 40, 4
3, 44, 47, 52, 53, 61, 63, 71, 7
6, 96, 107, 123, 127, 142, 174,
Compounds having substituents at 176, 177, 178, 181, 182, 183 and 186 are mentioned, and a particularly preferred compound is 2- (2,4-difluorophenyl) -3-[[2-
[2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -1-
(1H-1,2,4-triazol-1-yl) -2-
Butanol (compound corresponding to Example 2), 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[2- [4- (trifluoromethoxy) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -2-butanol (compound corresponding to Example 11), 2- (2,4 -Difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[4- [4- (trifluoromethyl) phenyl] -1,
3-butadien-1-yl] -1,3-dioxane-5
-Yl] thio] -2-butanol (compound corresponding to Example 15), 2- (2,4-difluorophenyl) -3-[[2-
[4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1,3-butadien-1-yl]-
1,3-dioxan-5-yl] thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butano-
(A compound corresponding to Example 16), 2- (2,4-difluorophenyl) -3-[[2-
[4- (4-Chlorophenyl) -4,4,4-trifluoro-1,3-pentadien-1-yl] -1,3-dioxan- 5 -yl] thio] -1- (1H-1,2 , 4
-Triazol-1-yl) -2-butanol (a compound corresponding to Example 18), 2- (2,4-difluorophenyl) -3-[[1-
[(4- (trifluoromethoxy) cinnamoyl] piperidin-4-yl] thio] -1- (1H-1,2,4-
Triazol-1-yl) -2-butanol (Example 2
1), 2- (2,4-difluorophenyl) -3-[[1-
(4-Nitrocinnamoyl) piperidin-4-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol (compound corresponding to Example 23) 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[1-
[5- [4- (trifluoromethoxy) phenyl]-
2,4-pentadienoyl] piperidin-4-yl] thio] -2-butanol (compound corresponding to Example 24), 3-methyl-1- (1H-1,2,4-triazol-
1-yl) -2- [4- (trifluoromethyl) phenyl] -3-[[2- [4-[(trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1,3 −
Dioxan-5-yl] thio] -2-butanol (compound corresponding to Example 31), 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[4- [4- (trifluoromethylthio) phenyl]-
1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol (compound corresponding to Example 32), 3-[[2- [4- [4 -(2,2,3,3-tetrafluoropropoxy) phenyl] -1,3-butadiene-
1-yl] -1,3-dioxan-5-yl] thio]-
1- (1H-1,2,4-triazol-1-yl)-
2- [4- (trifluoromethyl) phenyl] -2-butanol (compound corresponding to Example 33), 1- (1H-1,2,4-triazol-1-yl)-
2- [4- (trifluoromethyl) phenyl] -3-
[[2- [4- [4- (trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol (Example 3
4), 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[4- [4- (trifluoromethylsulfinyl) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol (corresponding to Example 35) Compound), 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[4-
[4- (trifluoromethyl) phenyl] -1,3-butadien-1-yl] cyclohexyl] thio] -2-butanol (compound corresponding to Example 36), 2- (2,4-difluorophenyl) ) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[6- [4- (trifluoromethyl) phenyl] -1,
3,5-Hexatrien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol (Example 37
2- (2,4-difluorophenyl) -3-methyl-1
-(1H-1,2,4-triazol-1-yl) -3
-[[2- [4- [4- (trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol (implemented Example 3
8) and 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[4- [4- (trifluoromethyl) phenyl] -1-
Buten-3-yn-1-yl] -1,3-dioxane-
5-yl] thio] -2-butanol (compound corresponding to Example 39) can be mentioned.

The triazole compound (I) of the present invention has at least two asymmetric carbons, and includes optical isomers and diastereomers. The enantiomers can be obtained as enantiomers by a general optical resolution technique or an asymmetric synthesis technique. Further, diastereomers can be separated by using an ordinary separation method such as fractional recrystallization or chromatography. Compound (I) of the present invention includes one or a mixture of these isomers.

The triazole compound (I) of the present invention can be used as it is or in the form of a pharmacologically acceptable salt as an antifungal agent. Pharmaceutically acceptable salts of compound (I) include, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid A salt of a carboxylic acid such as malic acid, a salt of a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid, or a salt of an amino acid such as glutamic acid or aspartic acid. Salt.

The hydrate of the compound (I) and the hydrate of the salt of the compound (I) are also included in the compounds of the present invention.

The compound (I) of the present invention and a pharmaceutically acceptable salt thereof show excellent antifungal activity. When the compound (I) and a pharmaceutically acceptable salt thereof are used as an antifungal agent, As such or mixed with appropriate pharmacologically acceptable excipients, diluents, etc., and administered orally with tablets, capsules, granules, powders or syrups or parenterally with injections, etc. can do.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxy Cellulose derivatives such as propylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked carboxymethylcellulose sodium; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate; Silicate derivatives such as magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; Agent Gelatin; polyvinylpyrrolidone;
Maglogol, etc.), disintegrants (for example, the above-mentioned excipients; croscarmellose sodium, carboxymethyl starch)
Disodium, chemically modified starch such as crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloidal silica) Luxes such as bee gum and gay wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfate salts such as sodium sulfate; Lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (such as methylparaben and propylparaben) Paraoxybenzoic acid esters; chlorobutanol, Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.), suspending agents (for example, polysorbate 80, sodium carboxymethyl cellulose), diluents, solvents for preparations (for example, Water, ethanol, glycerin and the like) are used and manufactured by a known method. The dosage varies depending on symptoms, age, etc., but for oral administration, once
Lower limit 1mg (preferably 5mg), upper limit 2000m
g (preferably 1000 mg), in the case of intravenous administration, 0.1 mg (preferably 0.5 m
g) The upper limit of 600 mg (preferably 500 mg) is desirably administered to an adult 1 to 6 times per day depending on the symptoms.

[0057]

BEST MODE FOR CARRYING OUT THE INVENTION Among the compounds having the formula (I) of the present invention, the compound (Ia) wherein R ⁰ is a hydrogen atom and n = 0 can be produced by the following method.

[0058]

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(Wherein Ar ¹ and R ¹ have the same meanings as described above, and R ⁸ is the same as defined above.

[0060]

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Represents That is, JP-A-2-191
No. 262 (Hei 2.7.27), a method of reacting mercaptan (3) or its acetic acid ester derivative (4) under basic conditions to produce the desired compound (Ia) It is. As the solvent used for the reaction, alcohols such as methanol, ethanol, and propanol, and aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, and tetrahydrofuran are preferable, and an acetyl derivative (4) is used. When the reaction is carried out in the above aprotic solvent, coexistence of alcohols or water is required. The base used in the reaction is sodium hydride, sodium methoxide, sodium ethoxide, lithium methoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the amount used is the compound (2 ) For 0.1 to 2
It is a molar equivalent. The mercaptan (3) or its acetate derivative (4) is used in an amount of 1 to 3 molar equivalents. The reaction temperature ranges from room temperature to 100 ° C., and the reaction time ranges from 2 to 10 hours. The reaction solution is treated according to a conventional method (an organic solvent is extracted, and an oil obtained by distilling off the solvent is purified by column chromatography or recrystallization) to obtain a compound (Ia).

The R ⁸ SH (3) or R ⁸ SAc (4) used in the above reaction can be obtained by the following method. That is, the compound (3a) or (4a) wherein A in R ⁸ is a 1,3-dioxane ring and p = 0.
Is a known compound (5) (literature: OEvan Lohuizen, P.
E.Verkade, Rec.trav.chim., 78 , 460 (1959)) as a starting material according to the following process chart.

[0063]

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(Wherein R ² , R ³ , R ⁴ , R ⁵ , A
r ² , q, r, and s have the same meanings as described above. (Refer to Reference Examples 3, 4, 5, 6, and 7 for the reaction conditions and isolation method in each step). Among the unsaturated aldehydes (6) used above, the compound (6
a) is generally an unsaturated ester (7) by the following method.
a)) (refer to Reference Examples 8, 9, 10, 20, and 2 for the reaction conditions and isolation method in each step).
1, 22, 23, 33, 49).

[0065]

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(Wherein R ² , R ³ , R ⁴ , R ⁵ , A
r ² , q, and s have the same meanings as described above, and DIBAL
-H represents diisobutylaluminum hydride. ) Among the unsaturated aldehydes (6), the compound (6b) in which r = 1 and 2 can be generally obtained via the unsaturated ester (7b) by the following method (reaction conditions for each step and simple reaction). Reference Examples 44, 45, and 4 for the separation method
6, 47, 48).

[0067]

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(Wherein R ² , R ³ , R ⁴ , R ⁵ ,
q, r, and s have the same meanings as described above, and DIBAL
-H represents diisobutylaluminum hydride. A compound in which A in R ^{8 of} R ⁸ SH (3) or R ⁸ SAc (4) is a 4- to 7-membered nitrogen-containing heterocyclic ring (azetidine, pyrrolidine, piperidine, homopiperidine) and p = 1. (3b) or (4b) can be obtained by the following method (refer to Reference Examples 16 and 17 for the reaction conditions and isolation method in each step).

[0069]

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(Wherein R ² , R ³ , R ⁴ , R ⁵ ,
q, r, and s are as defined above, and t is 3,
Indicate 4,5 or 6, and Boc indicates tert-butoxycarbonyl. The acid chloride (10) used above can be obtained by treating a carboxylic acid obtained by subjecting the above-mentioned unsaturated esters (7a) and (7b) to alkaline decomposition with thionyl chloride.

Among the compounds having the formula (I) of the present invention,
Compound (Ia) wherein R ⁰ is a hydrogen atom and n = 0 can also be produced by the following method.

[0072]

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(In the above formula, Ar ¹ , R ¹ and R ⁸ have the same meanings as described above. X represents a chlorine, bromine or iodine atom, methanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy.) That is, Japanese Unexamined Patent Application Publication No. Hei 3-240778 (Japanese
This is a method for producing the target compound (Ia) by reacting the triazolylmercapto alcohol derivative (11) described in 8) with an alkylating reagent (12) under basic conditions. Solvents used in the reaction include methanol, ethanol, propanol, butanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide,
Examples include acetonitrile, tetrahydrofuran, dioxane, diethyl ether, acetone, benzene, toluene, xylene and the like. The base used for the reaction is triethylamine, diisopropylethylamine, sodium hydride, sodium methoxide, sodium ethoxide, lithium methoxide, potassium tert-butoxide,
Examples thereof include sodium hydroxide and potassium hydroxide, and the amount used is 1 to 3 molar equivalents relative to compound (11).
The alkylating reagent (12) is used in 1 to 3 molar equivalents.
The reaction temperature is −50 to 100 ° C., and the reaction time is 2 to 10 hours. The reaction solution is treated in accordance with a conventional method (an oily substance obtained by extracting with an organic solvent and distilling off the solvent is purified by chromatography or recrystallization) to obtain a compound (Ia).

The alkylating reagent R ⁸ used in the above reaction
-X (12) can be obtained by the following method. The compound (12a) in which A in R ⁸ is a 1,3-dioxane ring and p = 0 is, for example, a diol compound (13) obtained by treating the above-mentioned compound (5) with an acid in methanol. It is obtained by reacting unsaturated aldehyde (6) under acidic conditions (Reference Example No. 56,
57).

[0075]

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(Wherein R ² , R ³ , R ⁴ , R ⁵ , A
r ² , q, r, and s have the same significance as described above. ) In addition, A in R ⁸ is a nitrogen-containing heterocyclic ring having 4 to 7 members (azetidine,
Pyrrolidine, piperidine, homopiperidine) and p =
Compound (12b) which is 1 is obtained, for example, by reacting compound (14) obtained by treating the above-mentioned cyclic amine derivative (8) with HCl with the above-mentioned acid chloride (10) in the presence of a base such as triethylamine. Can be

[0077]

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(Wherein R ² , R ³ , R ⁴ , R ⁵ , A
r ² , q, r, s, and t have the same meanings as described above. ) Among the compounds having the formula (I) of the present invention, the compound (Ib) wherein R ⁰ is a hydrogen atom, n = 0, p = 0, and A is a 1,3-dioxane ring is as follows: Can also be produced.

[0079]

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(Where Ar ¹ , Ar ² , R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , p, q and r have the same meanings as described above. ) That is, the aforementioned epoxide compound (2)
The thioacetic acid derivative (15) obtained by the reaction of the above-mentioned known compound (5) with sodium thioacetate is converted into (2)
The compound (16) is reacted under the same conditions as in the reaction of (4), and the compound (16) is deprotected according to a conventional method such as acid treatment to lead to (17). By reacting the aldehyde compound (6), the desired compound (I
This is a method for producing b). The reaction between (17) and (6) is usually carried out under acidic conditions, and the acid used is, for example, hydrogen chloride, sulfuric acid, nitric acid, boron trifluoride, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid And the amount of the acid used is 1 to 2 molar equivalents relative to (17). Aldehyde (6) is used in 1 to 2 molar equivalents. As the solvent, methylene chloride, chloroform, 1,
2-dichloroethane, benzene, toluene, xylene,
An aprotic solvent such as diethyl ether or tetrahydrofuran is used. The reaction is carried out at a temperature ranging from 0 ° C. to the boiling point of the solvent, and the reaction time is 2 to 10 hours. Water generated by the reaction can be removed by azeotropic distillation, but molecular sieves may be used as a dehydrating agent. The reaction solution is neutralized with an aqueous solution of sodium bicarbonate and the like, and then treated in a conventional manner (extraction with an organic solvent and evaporation of the solvent to obtain an oily product, which is purified by chromatography or crystallization) to obtain a compound (Ib).

In the compounds of the present invention, R ⁰ is a hydrogen atom, n = 0, p = 1, and A is a 4- to 7-membered nitrogen-containing heterocyclic ring (azetidine, pyrrolidine, piperidine, homopiperidine) )) Can also be produced by the following method.

[0082]

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(Wherein Ar ¹ , Ar ² , R ¹ , R ² ,
R ³ , R ⁴ , R ⁵ , q, r, s and t have the same meanings as described above, and Boc represents tert-butoxycarbonyl. That is, the epoxide compound (2) and the mercaptan compound (18) obtained by treating the thioacetic acid derivative (9) with an alkali are represented by (2)
And under the same conditions as in the reaction of (3), the compound (1)
9), (19) is treated with an acid according to a conventional method to deprotect the compound (20), and the compound (20) is reacted with the above-mentioned acid chloride (10) to give the desired compound (Ic). It is a manufacturing method. The reaction between (20) and (10) is performed in an inert solvent such as benzene, toluene, methylene chloride, chloroform or tetrahydrofuran in the presence of a suitable base according to a conventional method. (Reference Example Nos. 13, 14, 18, and 19) Among the compounds (I) of the present invention, the compounds wherein n = 1 or n = 2 can be produced by the methods described below. That is, the compound (I) of the present invention wherein n = 0 obtained by the above-mentioned method.
Is oxidized with one equivalent of an oxidizing agent in a solvent to produce a compound (I) wherein n = 1, and by oxidizing with two or more equivalents of the oxidizing agent, n
= 2 can be produced. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
Halogenated hydrocarbons such as methylene chloride and chloroform can be mentioned. Examples of the oxidizing agent used include peracetic acid and 3-chloroperbenzoic acid. The reaction is carried out at a temperature of 0 to 50 ° C., preferably at room temperature, and the reaction time is usually 30 minutes to 2 hours. The reaction solution is treated according to a conventional method (after washing with aqueous sodium bicarbonate,
The crude product obtained by distilling off the solvent is purified by chromatography or recrystallization) and the compound (I) (n = 1
Or 2) is obtained.

Among the compounds having the formula (I) of the present invention,
Compounds (I) wherein R ⁰ is lower alkyl and n = 0
The production of d) can be performed by the following method.

[0085]

Embedded image

(Wherein Ar ¹ , R ⁰ , R ¹ and R ^1
8 has the same meaning as described above. That is, the above-mentioned mercaptan (3) or its acetic acid ester derivative (4) is added to bromoketone (21) obtained according to the method described in JP-A-7-2802 (Japanese Patent Laid-Open No. 7-2802). Reaction under alkaline conditions leads to the thioether derivative (22), and then (22) is reacted with trimethylsulfoxonium iodide and 1,2,4-triazole in the presence of a base to produce the desired compound (Id). Is the way. Alcohols such as methanol, ethanol and propanol are suitable as the solvent used in the reaction between (21) and (3) or (4), and the alkali used is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium methoxide. Ethoxide and the like. Solvents used in the reaction for converting the thioether derivative (22) to (Id) include alcohols such as methanol, ethanol, propanol, butanol and t-butanol, and non-protons such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran. Nonionic solvents are preferred. The base used for the reaction is sodium hydride, sodium methoxide, sodium ethoxide, lithium methoxide, potassium ter
t-butoxide, lithium hydroxide, sodium hydroxide,
Potassium hydroxide, the amount used is compound (22)
2 to 5 molar equivalents. Trimethylsulfoxonium iodide and 1,2,4-triazole are each used in an amount of 1 to 2 molar equivalents relative to compound (22). The reaction temperature is from room temperature to 100 ° C, and the reaction time is from 2 to 10 hours. The reaction solution is treated according to a conventional method (the crude product obtained by extracting the solvent with an organic solvent and then distilling off the solvent is purified by column chromatography or recrystallization) to obtain a compound (Id) (n = 0). In the compound (Id) obtained by the above method, R ⁸ is

[0087]

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From the compound (23), via the triol (24) by the following method, among the compounds (I), n = 0, p = 0, and A is 1,
The compound (Ie) which is a 3-dioxane ring can be obtained.

[0089]

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(In the above formula, R ⁰ represents lower alkyl;
Ar ¹ , Ar ² , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , q,
r and s have the same meaning as described above. ) The reaction conditions in each of the above-mentioned steps are (16) → (17) → (I
The same as described in the reaction of b).

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

The aldehyde compounds used in the examples are described in parentheses if they are clearly indicated.
Alternatively, it is synthesized by the method described in the cited reference of that document.
Aldehyde compounds whose literature is not specified are commercially available or described in parentheses in the Examples or described in the synthesis method of aldehydes specified in the references cited in the references or Reference Examples in this specification. It can be obtained by a method according to the synthesis method of aldehyde.

[0093]

【Example】

Example 1 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(E) -1-methyl-2-
[4- (trifluoromethyl) phenyl] vinyl]-
1,3-dioxan-5-yl] thio] -2-butanol

[0094]

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166 mg of trans-4- (acetylthio) -2-[(E) -1-methyl-2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane described in Reference Example 7 (0.48 mmol) and (2R, 3S) -2-
(2,4-difluorophenyl) -3-methyl-2-
110 mg (0.44 mmol) of [(1H-1,2,4-triazol-1-yl) methyl] oxirane was dissolved in 2 ml of dimethylformamide, and 0.15 ml (0.24 mmol) of a 1.6 M sodium methoxide-methanol solution was added under a nitrogen atmosphere. After the addition, the mixture was stirred at 55 ° C. for 6 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with saturated saline. The oil obtained by distilling off the solvent was subjected to column chromatography using 15 g of silica gel, and eluted with a mixed solvent of hexane-ethyl acetate (2: 1) to give 180 mg of the desired compound (74% yield) as an oil. Obtained.

NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.
19 (3H, d, J = 7Hz), 1.90 (3H, d, J = 1.5Hz), 3.34 (1H, q, J = 7H
z), 3.0-3.9 (3H, m), 4.1-4.6 (2H, m), 4.80 (1H, d, J = 14Hz),
4.94 (1H, s), 5.02 (1H, d, J = 1Hz), 5.05 (1H, d, J = 14Hz), 6.4-
7.0 (3H, m), 7.1-7.6 (1H, m), 7.40 (2H, d, J = 9Hz), 7.62 (2H,
d, J = 9 Hz), 7.80 (2H, s). Example 2 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(E) -2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2 , 4-Triazol-1-yl) -2-butanol

[0097]

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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] oxirane and trans-5- (acetylthio)-
By reacting with 2-[(E) -2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane and treating, the target compound having a melting point of 73-75 ° C. is obtained in a yield of 70. %.

Specific rotation [α] _D ²⁵ -73.8 ° (C = 1.00, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.19 (3H, d, J = 7.
3Hz), 3.34 (1H, q, J = 7.3Hz), 3.43 (H, tt, J = 11.2, 4.6Hz), 3.
65 (1H, t, J = 11.2Hz), 3.67 (1H, t, J = 11.2Hz), 4.33 (1H, ddd,
J = 11.2,4.6,2.0Hz), 4.46 (1H, ddd, J = 11.2,4.6,2.0Hz), 4.
82 (1H, d, J = 13.8Hz), 5.03 (1H, d, J = 13.8Hz), 5.04 (1H, br
s), 5.14 (1H, d, J = 4.6Hz), 6.25 (1H, dd, J = 15.8,4.6Hz), 6.7
-7.8 (2H, m), 6.83 (1H, d, J = 15.8Hz), 7.3-7.45 (1H, m), 7.49
(2H, d, J = 8.6Hz), 7.58 (2H, d, J = 8.6Hz), 7.79 (2H, s). Example 3 (2R, 3R) -3-[[trans-4-[(E) -2]
-(4-chlorophenyl) vinyl] cyclohexyl] thio] -2- (2,4-difluorophenyl) -1- (1
H-1,2,4-triazol-1-yl) -2-butanol

[0100]

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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] oxirane and trans-1- (acetylthio)-
By reacting with 4-[(E) -2- (4-chlorophenyl) vinyl] cyclohexane and treating, the target compound having a melting point of 64-66 ° C. was obtained in a yield of 31%.

Specific rotation [α] _D ²⁵ -84.1 ° (C = 2.69, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.16 (3
H, d, J = 7.3 Hz), 1.2-1.6 (4H,
m), 1.9-2.0 (2H, m), 2.1-2.25
(3H, m), 2.70 (1H, tt, J = 11.2,
4.0 Hz), 3.36 (1H, q, J = 7.3H)
z), 4.60 (1H, s), 4.83 (1H, d, J
= 13.9 Hz), 5.10 (1H, d, J = 13.9)
Hz), 6.11 (1H, dd, J = 15.8, 7.3)
Hz), 6.32 (1H, d, J = 15.8 Hz),
6.74 (2H, t-like, J = 9 Hz), 7.2
6 (4H, s), 7.37 (1H, td, J = 8.6,
6.5 Hz), 7.76 (1H, s), 7.83 (1
H, s). Example 4 (2R, 3R) -3-[[trans-2-[(E) -2]
-(4-Chlorophenyl) vinyl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole-1-
Yl) -2-butanol

[0103]

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(2R, 3R) -2-described in Reference Example 2
(2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -1- (1H-1,
2,4-triazol-1-yl) -2-butanol 2
94 mg (0.82 mmol) and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde (Bull. Chem. So
c. Japan 52 555 (1979)) in 14 ml of methylene chloride and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate.
l) and 1.5 g of Molecular Sieves 4A were added and stirred for 1 hour and 15 minutes. After adding a sodium bicarbonate solution to the reaction solution and stirring for 10 minutes, molecular sieves were removed by filtration, the organic layer was collected and dried, and the solvent was distilled off under reduced pressure. The obtained oil was subjected to column chromatography using 15 g of silica gel, and eluted with a mixed solvent of hexane-ethyl acetate (3: 2) to give 280 mg of the trans-isomer (A) as the title compound.
(67% yield) as an oil. Hexane-
Elution with a mixed solvent of ethyl acetate (1: 1) yielded 35 mg of the cis isomer (B) (8% yield) as an oil.

[0105] NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: (A), 1.19 (3H, d,
J = 7.3Hz), 3.34 (1H, q, J = 7.3Hz), 3.41 (1H, tt, J = 11.2,4.6H
z), 3.64 (1H, t, J = 11.2Hz), 3.66 (1H, t, J = 11.2Hz), 4.32 (1
H, ddd, J = 11.2,4.6,2.6Hz), 4.44 (1H, ddd, J = 11.2,4.6,2.6
Hz), 4.82 (1H, d, J = 13.9Hz), 5.01 (1H, s), 5.04 (1H, d, J = 13.
9Hz), 5.11 (1H, d, J = 4.6Hz), 6.15 (1H, dd, J = 15.8,4.6Hz),
6.7-6.8 (2H, m), 6.76 (1H, d, J = 15.8Hz), 7.25-7.45 (5H, m),
7.78 (2H, s); (B), 1.21 (3H, d, J = 7.3Hz), 3.11 (1H, s-like),
3.50 (1H, q, J = 7.3Hz), 4.2-4.4 (4H, m), 4.88 (1H, J = 14.5H
z), 4.93 (1H, s), 5.16 (1H, d, J = 14.5Hz), 5.23 (1H, d, J = 4.6H
z), 6.21 (1H, dd, J = 16.5,4.6Hz), 6.65-6.8 (2H, m), 6.76 (1
H, d, J = 16.5Hz), 7.25-7.45 (5H, m), 7.77 (1H, s), 7.80 (1H,
s). (A) 54 mg was dissolved in ethyl acetate, 19 mg of oxalic acid was added, and then hexane was added.
65 mg of oxalate having a temperature of 2 ° C. were obtained. The oxalate of (B), melting point 94-98 ° C, was obtained in the same manner.

Example 5 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(E) -2- (3-pyridyl) vinyl] -1,3-dioxan-5-yl] thio]
-1- (1H-1,2,4-triazol-1-yl)
-2-butanol

[0107]

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(2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -1-[(1H-1,2,4-triazole -1-yl) -2-butanol 120 mg (0.33 mmol)
And trans-β- (3-pyridyl) acrolein 60mg
(0.45 mmol) (J. Med. Chem. 18 839 (1975)) was dissolved in 5 ml of methylene chloride, and p-toluenesulfonic acid monohydrate 19 was dissolved.
0 mg (1.00 mmol) and 1.2 g of molecular sieves 4A are added,
Stir for 1 hour and 15 minutes. After adding aqueous sodium bicarbonate to the reaction solution and stirring for 10 minutes, molecular sieves were removed by filtration.
Extracted with chloroform. After drying, the solvent obtained by evaporating the solvent was subjected to column chromatography using 15 g of silica gel to give hexane-ethyl acetate (1: 4-1: 1).
5) The residue was eluted with a mixed solvent to obtain 82 mg (yield: 52%) of the title compound, trans isomer (A) as an oil. Further, elution was carried out with ethyl acetate to 5% methanol-ethyl acetate to give 28 mg of the cis isomer (B) (yield 15%), melting point 118
Obtained as a solid having -125 ° C.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm:
(A), 1.20 (3H, d, J = 7.3Hz), 3.34 (1H, q, J = 7.3Hz), 3.43 (1H,
tt, J = 11.2,4.6Hz), 3.65 (1H, t, J = 11.2Hz), 3.68 (1H, t, J = 1
1.2Hz), 4.33 (1H, m), 4.46 (1H, m), 4.83 (1H, d, J = 13.9Hz),
5.04 (1H, s), 5.04 (1H, d, J = 13.9Hz), 5.14 (1H, d, J = 4.0Hz),
6.25 (1H, dd, J = 16.5,4.0Hz), 6.7-6.8 (2H, m), 6.81 (1H, d, J
= 16.5Hz), 7.29 (1H, dd, J = 7.9,4.6Hz), 7.3-7.45 (1H, m), 7.
73 (1H, dt, J = 7.9,1Hz), 8.51 (1H, dd, J = 4.6,1Hz), 8.62 (1H,
d, J = 1Hz); (B), 1.22 (3H, d, J = 7.3Hz), 3.13 (1H, br s), 3.50
(1H, q, J = 7.3Hz), 4.2-4.4 (4H, m), 4.88 (1H, d, J = 13.9Hz),
4.94 (1H, s), 5.17 (1H, d, J = 13.9Hz), 5.26 (1H, d, J = 4.6Hz),
6.31 (1H, dd, J = 16.5,4.6Hz), 6.65-6.8 (2H, m), 6.81 (1H, d,
J = 16.5Hz), 7.26 (1H, dd, J = 7.9,4.6Hz), 7.74 (1H, td, J = 7.
2,6.6Hz), 7.74 (1H, br d, J = 7.9Hz), 7.77 (1H, s), 7.80 (1H,
s), 8.50 (1H, br d, J = 4.6 Hz), 8.63 (1H, brs). Example 6 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(E) -2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2 , 4-Triazol-1-yl) -2-butanol

[0110]

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In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1-[(1H
By reacting -1,2,4-triazol-1-yl) -2-butanol with trans-4- (trifluoromethyl) cinnamaldehyde described in Reference Example 22, the target compound is converted into a main product. (62% yield). Physical data and spectral data were obtained in Example 2.
This was consistent with the compound described in.

Example 7 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(E) -2- (4-fluorophenyl) vinyl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,4-triazole −
1-yl) -2-butanol

[0113]

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In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1-[(1H
-1,2,4-triazol-1-yl) -2-butanol and trans-4-fluorocinnamaldehyde (Arc
h. Pharm. 316 574 (1983)) and the title compound was obtained as an oil in 66% yield by treatment.

NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 1.
20 (3H, d, J = 7Hz), 3.1-3.9 (4H, m), 4.1-4.6 (2H, m), 4.78 (1
H, d, J = 14Hz), 4.99 (1H, d, J = 1.5Hz), 5.06 (1H, d, J = 14Hz),
5.09 (1H, d, J = 4Hz), 6.07 (1H, dd, J = 16.4Hz), 6.79 (1H, d, J =
16Hz), 6.5-7.6 (7H, m), 7.78 (2H, s). This compound was mixed with 1 equivalent of oxalic acid in a mixed solvent of ethyl acetate-hexane to obtain oxalate crystals having a melting point of 132-135 ° C.

Example 8 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(E) -2- [2-fluoro-4- (trifluoromethyl) phenyl] vinyl]-
1,3-dioxan-5-yl] thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol

[0117]

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In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
By reacting 1,2,4-triazol-5-yl) -2-butanol with trans-2-fluoro-4- (trifluoromethyl) cinnamaldehyde, the title compound, which is the main product, is obtained. Yield 6 as an oil
Obtained at 6%.

Specific rotation [α] _D ²⁵ -72 ° (C = 0.63, CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.20 (3H, d, J = 7.
0Hz), 3.34 (1H, q, J = 7.0Hz), 3.43 (1H, tt, J = 11.3,4.6Hz),
3.65 (1H, t, J = 11.3Hz), 3.68 (1H, t, J = 11.3Hz), 4.34 (1H,
m), 4.46 (1H, m), 4.83 (1H, d, J = 14.0Hz), 5.04 (d, J = 14.0H
z), 5.04 (1H, d, J = 1.1Hz), 5.15 (1H, d, J = 4.2Hz), 6.36 (1
H, dd, J = 16.3,4.2Hz), 6.7-6.8 (2H, m), 6.97 (1H, d, J = 16.0H
z), 7.3-7.45 (3H, m), 7.58 (1H, t, J = 7.6Hz), 7.79 (2H, s). Example 9 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(E) -2- [4- (methylsulfonyl) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2, 4-triazol-1-yl) -2-butanol

[0120]

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In the same manner as in Example 4, (2R, 3R) -2
-(2,4-difluorophenyl) -3-[(1,3-
Dihydroxy-2-propyl) thio] -1- (1H-
The title compound, which is the main product, is obtained as an oil by reacting 1,2,4-triazol-1-yl) -2-butanol with trans-4- (methylsulfonyl) cinnamaldehyde and treating the resulting product. Obtained at 58%.

NMR spectrum (60 MHz, CDCl ₃ + D ₂ O) δ ppm
: 1.20 (3H, d, J = 7Hz), 3.00 (3H, s), 3.33 (1H, q, J = 7Hz), 3.
5-4.0 (3H, m), 4.2-4.8 (2H, m), 4.80 (1H, d, J = 14Hz), 5.08 (1
H, d, J = 14Hz), 5.15 (1H, d, J = 4Hz), 6.30 (1H, dd, J = 17,4Hz),
6.90 (1H, d, J = 17Hz), 6.55-7.0 (2H, m), 7.2-7.6 (1H, m), 7.5
8 (2H, d, J = 8Hz), 7.80 (2H, s), 7.94 (2H, d, J = 8Hz). Example 10 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(E) -2- (4-nitrophenyl) vinyl] -1,3-dioxan-5-yl]
Thio] -1- (1H-1,2,4-triazole-1-
Yl) -2-butanol

[0123]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
By reacting and treating 1,2,4-triazol-5-yl) -2-butanol with trans-4-nitrocinnamaldehyde, the main product, the title compound, is obtained as an oil in 40% yield. Obtained.

Specific rotation [α] _D ²⁵ -64.1 ° (C = 2.43, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.19 (3H, d, J = 7.
3Hz), 3.35 (1H, q, J = 7.3Hz), 3.44 (1H, tt, J = 11.2,4.6Hz),
3.66 (1H, t, J = 11.2Hz), 3.68 (1H, t, J = 11.2Hz), 4.34 (1H,
m), 4.46 (1H, m), 4.83 (1H, d, J = 13.9Hz), 5.04 (1H, d, J = 13.9
Hz), 5.04 (1H, s), 5.16 (1H, d, J = 4.0Hz), 6.32 (1H, dd, J = 1
6.5,4.0Hz), 6.7-6.8 (2H, m), 6.87 (1H, d, J = 16.5Hz), 7.36
(1H, m), 7.53 (2H, d, J = 8.6Hz), 7.79 (1H, s), 7.80 (1H, s), 8.
19 (2H, d, J = 8.6Hz). This compound was mixed with 1 equivalent of oxalic acid in a mixed solvent of ethyl acetate-hexane to obtain oxalate crystals having a melting point of 103-105 ° C.

Example 11 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[[trans-2-[(E) -2- [4- (trifluoromethoxy) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -2-butanol

[0127]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-Triazol-5-yl) -2-butanol is reacted with trans-4- (trifluoromethoxy) cinnamaldehyde described in Reference Example 33 and treated to give the main product, the title compound Was obtained as an oil in 43% yield.

Specific rotation [α] _D ²⁵ -77 ° (C = 0.52, CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.20 (3H, d, J = 7.
3Hz), 3.34 (1H, q, J = 2.3Hz), 3.42 (1H, tt, J = 11.2,4.6Hz),
3.65 (1H, t, J = 11.2Hz), 3.67 (1H, t, J = 11.2Hz), 4.32 (1H, dd
d, J = 11.2,4.6,2.0Hz), 4.45 (1H, ddd, J = 11.2,4.6,2.0Hz),
4.83 (1H, d, J = 14.5Hz), 5.01 (1H, s), 5.03 (1H, d, J = 14.5H
z), 5.12 (1H, d, J = 4.0Hz), 6.15 (1H, dd, J = 16.5,4.0Hz), 6.
7-6.8 (2H, m), 6.79 (1H, d, J = 16.5Hz), 7.17 (2H, d, J = 8.6H
z), 7.3-7.45 (1H, m), 7.42 (2H, d, J = 8.6Hz), 7.79 (2H, s). Example 12 (2R, 3R) -3-[[trans-2-[(E) -2]
-(4-cyanophenyl) vinyl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole-1-
Yl) -2-butanol

[0130]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-Triazol-5-yl) -2-butanol and trans-4-cyanocinnamaldehyde (Mol. Cry.
Cryst. 123 257 (1985)) to give the title compound as the main product as an oil in 66% yield.

Specific rotation [α] _D ²⁵ -78 ° (C = 0.52, CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.20 (3
H, d, J = 7.0 Hz), 3.34 (1H, br)
q, J = 7.0 Hz), 3.43 (1H, tt, J = 1)
1.3, 4.8 Hz), 3.65 (1H, t, J = 1)
1.3Hz), 3.67 (1H, t, J = 11.3H)
z), 4.33 (1H, m), 4.46 (1H, m),
4.83 (1H, d, J = 14.2 Hz), 5.03
(1H, d, J = 1.2 Hz), 5.04 (1H, d, J = 1.2 Hz)
d, J = 14.2 Hz), 5.14 (1H, d, J =
4.1 Hz), 6.28 (1H, dd, J = 16.1,
4.1 Hz), 6.7-6.8 (2H, m), 6.82
(1H, d, J = 16.1 Hz), 7.36 (1H,
m), 7.49 (2H, d, J = 8.3 Hz), 7.6
2 (2H, d, J = 8.3 Hz), 7.79 (2H,
s). This compound was mixed with 1 equivalent of oxalic acid in a mixed solvent of ethyl acetate-hexane to obtain oxalate crystals having a melting point of 164-165 ° C.

Example 13 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(E) -2-methyl-2-
[4- (trifluoromethyl) phenyl] vinyl]-
1,3-dioxan-5-yl] thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol

[0134]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1-[(1H
By reacting -1,2,4-triazol-1-yl) -2-butanol with trans-β-methyl-4- (trifluoromethyl) cinnamaldehyde and treating the resulting product, the main product, title purpose The compound was obtained as an oil in 73% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm
： 1.20 (3H, d, J = 7.1Hz), 2.16 (3H, s), 3.36 (1H, q, J = 7.1H
z), 3.41 (1H, tt, J = 11.3,4.6Hz), 3.66 (1H, t, J = 11.3Hz), 3.
68 (1H, t, J = 11.3Hz), 4.32 (1H, m), 4.44 (1H, m), 4.83 (1H, d,
J = 13.9Hz), 5.03 (1H, s), 5.04 (1H, d, J = 13.9Hz), 5.33 (1
H, d, J = 6.0Hz), 5.83 (1H, br d, J = 6.0Hz), 6.7-6.8 (2H, m),
7.3-7.45 (1H, m), 7.51 (2H, d, J = 8.3Hz), 7.59 (2H, d, J = 8.3H
z), 7.79 (2H, s). Example 14 (2R, 3R) -3-[[trans-2-[(E) -2]
-(5-Chloro-2-thienyl) vinyl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole- 1-yl) -2-butanol

[0137]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
Reaction of 1,2,4-triazol-5-yl) -2-butanol with trans-β- (5-chloro-2-thienyl) acrolein (Chem. Abst. 51 1284h (1941))
By the treatment, the title compound was obtained as an oil in a yield of 5%.
Obtained at 0%.

Specific rotation [α] _D ²⁵ -75.7 ° (C = 0.56, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.19 (3H, d, J = 7.
3Hz), 3.33 (1H, q, J = 7.3Hz), 3.40 (1H, tt, J = 11.2,4.6Hz),
3.62 (1H, t, J = 11.2Hz), 3.64 (1H, t, J = 11.2Hz), 4.36 (1H,
m), 4.42 (1H, m), 4.82 (1H, d, J = 13.8Hz), 5.02 (1H, br s),
5.03 (1H, d, J = 13.8Hz), 5.06 (1H, d, J = 4.6Hz), 5.88 (1H, d
d, J = 15.8,4.6Hz), 6.7-6.85 (3H, m), 6.78 (2H, s), 7.36 (1H,
m), 7.87 (2H, s). This compound was mixed with 1 equivalent of oxalic acid in a mixed solvent of ethyl acetate-hexane to obtain oxalate crystals having a melting point of 53-57 ° C.

Example 15 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[[trans-2-[(1E, 3E) -4- [4
-(Trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol

[0141]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1-[(1H
-1,2,4-triazol-5-yl) -2-butanol and (2E, 4E) -5- [4-
(Trifluoromethyl) phenyl] -2,4-pentadienal, and the reaction was carried out to give the title compound as a main product as an oil in a yield of 67%.

Specific rotation [α] _D ²⁵ -69.8 ° (C = 1.00, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.19 (3H, d, J = 7.
3Hz), 3.33 (1H, q, J = 7.3Hz), 3.40 (1H, tt, J = 11.2,4.6Hz),
3.62 (1H, t, J = 11.2Hz), 3.64 (1H, t, J = 11.2Hz), 4.30 (1H,
m), 4.42 (1H, m), 4.82 (1H, d, J = 13.9Hz), 5.01 (1H, s), 5.03
(1H, d, J = 13.9Hz), 5.06 (1H, d, J = 4.6Hz), 5.84 (1H, dd, J = 1
5.2,4.6Hz), 6.60 (1H, dd, J = 15.2,10.6Hz), 6.73 (1H, d, J = 1
5.8Hz), 6.7-6.8 (2H, m), 6.85 (1H, dd, J = 15.8,10.6Hz), 7.3
-7.45 (1H, m), 7.49 (2H, d, J = 8.6Hz), 7.56 (2H, d, J = 8.6Hz),
7.78 (2H, s). Example 16 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(1E, 3E) -4- [4
-(2,2,3,3-tetrafluoropropoxy) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,2 4
-Triazol-1-yl) -2-butanol

[0144]

Embedded image

As in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1-[(1H
-1,2,4-triazol-5-yl) -2-butanol and (2E, 4E) -5- [4-
(2,2,3,3-tetrafluoropropoxy) phenyl] -2,4-pentadienal and treated to give the main product, the title compound, with a melting point of 75-8.
A powder having a temperature of 5 ° C. (crystallized from a mixed solvent of hexane and ether) was obtained in a yield of 60%.

Specific rotation [α] _D ²⁵ -69 ° (C = 0.56, CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.18 (3H, d, J = 7.
0Hz), 3.33 (1H, q, J = 7.0Hz), 3.39 (1H, tt, J = 11.3,4.8Hz),
3.62 (1H, t, J = 11.3Hz), 3.64 (1H, t, J = 11.3Hz), 4.30 (1H,
m), 4.35 (2H, brt, J = 11.8Hz), 4.41 (1H, m), 4.82 (1H, d, J = 1
4.1Hz), 4.99 (1H, d, J = 1.6Hz), 5.03 (1H, d, J = 14.1Hz), 5.
04 (1H, d, J = 4.6Hz), 5.75 (1H, dd, J = 15.7,4.6Hz), 6.06 (1H,
tt, J = 53.0,5.1Hz), 6.56 (1H, dd, J = 15.7,10.2Hz), 6.57 (1
H, d, J = 15.0Hz), 6.68 (1H, dd, J = 15.0,10.2Hz), 6.7-6.8 (2
H, m), 6.88 (2H, d, J = 8.7Hz), 7.3-7.4 (1H, m), 7.37 (2H, d, J =
8.7Hz), 7.79 (2H, s). Example 17 (2R, 3R) -3-[[trans-2-[(1E, 3
E) -4- (6-Chloro-3-pyridyl) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2- (2,4-difluorophenyl)- 1
-(1H-1,2,4-triazol-1-yl) -2
-Butanol

[0147]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-triazol-5-yl) -2-butanol was reacted with (2E, 4E) -5- (6-chloro-3-pyridyl) -2,4-pentadienal described in Reference Example 38, This gave the title compound as the main product as crystals with a melting point of 88-90 ° C. in 69% yield.

Specific rotation [α] _D ²⁵ -74 ° (C = 0.59, CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.19 (3H, d, J = 7.
1Hz), 3.33 (1H, q, J = 7.1Hz), 3.40 (1H, tt, J = 11.3,4.7Hz),
3.62 (1H, t, J = 11.3Hz), 3.64 (1H, t, J = 11.3Hz), 4.30 (1H,
m), 4.42 (1H, m), 4.82 (1H, d, J = 14.3Hz), 5.00 (1H, s), 5.03
(1H, d, J = 14.3Hz), 5.05 (1H, d, J = 4.2Hz), 5.84 (1H, dd, J = 1
5.1,4.2Hz), 6.56 (1H, d, J = 15.5Hz), 6.58 (1H, dd, J = 15.1,1
0.5Hz), 6.7-6.8 (2H, m), 6.80 (1H, dd, J = 15.5,10.5Hz), 7.2
8 (1H, d, J = 8.3Hz), 7.3-7.4 (1H, m), 7.70 (1H, dd, J = 8.3,2.5
Hz), 7.79 (2H, s), 8.37 (1H, d, J = 2.5Hz). Example 18 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(1E, 3Z) -4- (4
-Chlorophenyl) -5,5,5-trifluoro-1,
3-pentadien-1-yl] -1,3-dioxane-
5-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol

[0150]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-Triazol-5-yl) -2-butanol and (2E, 4Z) -5- (4-chlorophenyl) -6,6,6-trifluoro-2,4-described in Reference Example 52.
The title compound as a main product was obtained as an oil in a yield of 31% by reacting with hexadienal and treating.

Specific rotation [α] _D ²⁵ -59.4 ° (C = 0.90, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.19 (3H, d, J = 7.
3Hz), 3.33 (1H, br q, J = 7.3Hz), 3.40 (1H, tt, J = 11.2,4.6H
z), 3.61 (1H, t, J = 11.2Hz), 3.64 (1H, t, J = 11.2Hz), 4.31 (1
H, m), 4.43 (1H, m), 4.82 (1H, d, J = 13.9Hz), 5.02 (1H, s), 5.
03 (1H, d, J = 13.9Hz), 5.09 (1H, d, J = 4.6Hz), 5.96 (1H, dd, J
= 15.2,4.6Hz), 6.50 (1H, d, J = 11.9Hz), 6.7-6.8 (2H, m), 6.9
-7.1 (1H, m), 7.25-7.4 (5H, m), 7.79 (2H, s). Example 19 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(1E, 3E) -2-methyl-4- [4- (trifluoromethyl) phenyl]-
1,3-Butadien-1-yl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol

[0153]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-triazol-5-yl) -2-butanol and (2E, 4E) -3-methyl- described in Reference Example 10.
5- [4- (trifluoromethyl) phenyl] -2,4
By reacting with pentadienal and treating
The main product, the title compound, was obtained as an oil in a yield of 70%.

Specific rotation [α] _D ²⁵ -68 ° (C = 0.50, CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.27 (3H, d, J = 7.
1Hz), 1.99 (3H, s), 3.34 (1H, q, J = 7.1Hz), 3.39 (1H, tt, J = 1
1.3,4.8Hz), 3.64 (1H, t, J = 11.3Hz), 3.66 (1H, t, J = 11.3H
z), 4.30 (1H, m), 4.41 (1H, m), 4.83 (1H, d, J = 14.1Hz), 5.01
(1H, s), 5.04 (1H, d, J = 14.1Hz), 5.32 (1H, d, J = 6.2Hz), 5.
66 (1H, d, J = 6.2Hz), 6.66 (1H, d, J = 16.1Hz), 6.7-6.8 (2H,
m), 6.86 (1H, d, J = 16.1Hz), 7.3-7.4 (1H, m), 7.51 (2H, d, J =
8.4Hz), 7.57 (2H, d, J = 8.4Hz), 7.78 (2H, s). Example 20 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(1E, 3E) -3-methyl-4- [4- (trifluoromethyl) phenyl]-
1,3-Butadien-1-yl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol

[0156]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
Reacting 1,2,4-triazol-5-yl) -2-butanol with (2E, 4E) -4-methyl-5- [4- (trifluoromethyl) phenyl] -2,4-pentadienal, By treatment, the main product, the title compound, was obtained as an oil in a yield of 69%.

Specific rotation [α] _D ²⁵ -63.4 ° (C = 1.07, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.19 (3H, d, J = 7.
0Hz), 2.00 (3H, s), 3.33 (1H, q, J = 7.0Hz), 3.41 (1H, tt, J = 1
1.2,4.6Hz), 3.64 (1H, t, J = 11.2Hz), 3.66 (1H, t, J = 11.2H
z), 4.31 (1H, m), 4.43 (1H, m), 4.83 (1H, d, J = 14.2Hz), 5.01
(1H, s), 5.04 (1H, d, J = 14.2Hz), 5.09 (1H, d, J = 4.6Hz), 5.
81 (1H, dd, J = 16.0,4.6Hz), 6.60 (1H, s), 6.63 (1H, d, J = 16.0
Hz), 6.7-6.8 (2H, m), 7.3-7.4 (1H, m), 7.38 (2H, d, J = 8.2H
z), 7.59 (2H, d, J = 8.2 Hz), 7.79 (2H, s). Example 21 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[1-[(E) -4- (trifluoromethoxy) cinnamoyl] piperidin-4-yl] thio] -1
-(1H-1,2,4-triazol-1-yl) -2
-Butanol

[0159]

Embedded image

[Production Method A] Reference Example 14 (2R, 3
R)-(2,4-Difluorophenyl) -3- (1H-
1,2,4-triazol-1-yl) -3-[(piperidin-4-yl) thio] -2-butanol dihydrochloride 1
To a mixture of 50 mg (0.340 mmol) and 3 ml of dichloromethane,
142 μl of triethylamine (1.02 m
mol) Then, 5 minutes later, 128 mg (0.510 mmol) of (E) -4- (trifluoromethoxy) cinnamoyl chloride was added. After stirring at the same temperature for 30 minutes, the solvent was distilled off, and ethyl acetate was added to the obtained residue, which was washed with brine. The solvent was distilled off, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate to give 160 mg of the title compound (81% yield).
Was obtained as a colorless foam.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
19 (3H, d, J = 7.0Hz), 1.6-1.8 (2H, m), 2.0-2.1 (2H, m), 3.0-
3.2 (2H, m), 3.35 (1H, q, J = 7.0Hz), 3.2-3.4 (1H, m), 4.0-4.1
(1H, m), 4.2-4.3 (1H, m), 4.83 (1H, s), 4.83 (1H, d, J = 14.0H
z), 5.09 (1H, d, J = 14.0Hz), 6.7-6.8 (2H, m), 6.87 (1H, d, J =
15.5Hz), 7.22 (2H, d, J = 8.5Hz), 7.3-7.4 (1H, m), 7.55 (2H,
d, J = 8.5Hz), 7.65 (1H, d, J = 15.5Hz), 7.78 (1H, s), 7.82 (1H,
s). IR spectrum ν _max ^KBr cm ^-1 : 3421,1695,1686,1617,1591. Mass spectrum m / e: 582,563,522,500,427,359,299,258,
215,187,144,101,82. [Production Method B] 4- (acetylthio)-described in Reference Example 16
327 mg (0.875 mmol) of 1-[(E) -4- (trifluoromethoxy) cinnamoyl] piperidine and (2R, 3
S) -2- (2,4-Difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane (200 mg, 0.796 mmol) was dissolved in 4 ml of dimethylformamide. 129 μl of a 28% sodium methoxide-methanol solution (0.613 mm
ol), and the mixture was stirred at 50 ° C. for 3 hours. After cooling, the reaction solution was diluted by adding ethyl acetate, and washed with water and then with a saturated saline solution. The oil obtained by evaporating the solvent was subjected to silica gel column chromatography, and eluted with ethyl acetate to obtain 275 mg (yield 59%) of the title compound as a colorless foam. This compound is composed of the compound obtained in [Production Method A] and NM
It was identified by various spectra of R, IR and MS.

Example 22 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[1-((E) -4-Methylcinnamoyl) piperidin-4-yl] thio] -1- (1H-1,2,4
-Triazol-1-yl) -2-butanol

[0163]

Embedded image

(E) -4-Colorless foam obtained from 4-methylcinnamoyl chloride (Can. J. Chem. 45 1001 (1967)) according to Example 21 [Preparation A].

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
19 (3H, d, J = 7.0Hz), 1.6-1.8 (2H, m), 2.0-2.2 (2H, m), 2.37
(3H, s), 3.0-3.2 (2H, m), 3.2-3.4 (1H, m), 3.35 (1H, q, J = 7.0
Hz), 4.0-4.2 (1H, m), 4.4-4.6 (1H, m), 4.83 (1H, d, J = 13.9H
z), 4.84 (1H, s), 5.09 (1H, d, J = 13.9Hz), 6.7-6.8 (2H, m), 6.
85 (1H, d, J = 15.5Hz), 7.18 (2H, d, J = 8.3Hz), 7.3-7.4 (1H,
m), 7.43 (2H, d, J = 8.3Hz), 7.65 (1H, d, J = 15.5Hz), 7.77 (1H,
s), 7.82 (1H, s). IR spectrum ν _max ^KBr cm ^-1 : 3333,1645,1599. Mass spectrum m / e: 512,510,452,430,425,367,357,289,
229,224,188,145,117,82. Example 23 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[1-((E) -4-nitrocinnamoyl) piperidin-4-yl] thio] -1- (1H-1,2,4
-Triazol-1-yl) -2-butanol

[0166]

Embedded image

(E) A pale yellow foam obtained from 4-nitrocinnamoyl chloride according to Example 21 [Preparation A].

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
26 (3H, d, J = 6.6Hz), 1.6-1.9 (2H, m), 2.1-2.3 (2H, m), 3.1-
3.3 (2H, m), 3.3-3.5 (1H, m), 3.42 (1H, q, J = 6.6Hz), 4.0-4.2
(1H, m), 4.4-4.6 (1H, m), 4.89 (1H, d, J = 13.9Hz), 4.92 (1H,
s), 5.15 (1H, d, J = 13.9Hz), 6.7-6.9 (2H, m), 7.10 (1H, d, J = 1
5.5Hz), 7.4-7.5 (1H, m), 7.73 (2H, d, J = 8.9Hz), 7.75 (1H, d,
J = 15.5Hz), 7.86 (2H, d, J = 8.9Hz), 8.29 (1H, s), 8.32 (1H,
s). IR spectrum ν _max ^KBr cm ⁻¹ : 3361,1649,1612,1518,1345. Mass spectrum m / e: 544,525,513,483,461,388,365,284,
260,224,219,176,144,130,82. Example 24 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[[1-[((2E, 4E) -5- [4- (trifluoromethoxy) phenyl] -2,4-pentadienoyl] piperidin-4-yl] thio] -2-butanol

[0169]

Embedded image

(2E, 4E) -5- [4- (trifluoromethoxy) phenyl] -2,4-pentadienoyl
Colorless foam obtained from chloride according to Example 21 [Production Method A].

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
19 (3H, d, J = 6.6Hz), 1.5-1.8 (2H, m), 2.0-2.2 (2H, m), 3.0-
3.3 (3H, m), 3.34 (1H, q, J = 6.6Hz), 3.9-4.1 (1H, m), 4.3-4.5
(1H, m), 4.83 (1H, d, J = 13.9Hz), 4.82 (1H, s), 5.08 (1H, d, J =
13.9Hz), 6.50 (1H, d, J = 14.5Hz), 6.7-6.8 (2H, m), 6.8-6.9
(2H, m), 7.20 (2H, d, J = 8.9Hz), 7.3-7.5 (2H, m), 7.47 (2H, d,
J = 8.9Hz), 7.78 (1H, s), 7.82 (1H, s). IR spectrum ν _max ^KBr cm ^-1 : 3395,1639,1616,1596. Mass spectrum m / e: 608,589,548,526,453,433,385,325,
241,224,213,144,127,82. Example 25 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[[1-[((E) -3- (pyridin-4-yl) -acryloyl] piperidin-4-yl] thio]-
2-butanol

[0172]

Embedded image

4- (acetylthio) -1-[((E)-
Colorless foam obtained from 3- (pyridin-4-yl) -acryloyl] piperidine according to Example 21 [Preparation B].

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
20 (3H, d, J = 6.6Hz), 1.6-1.8 (2H, m), 2.0-2.2 (2H, m), 3.0-
3.2 (2H, m), 3.35 (1H, q, J = 6.6Hz), 3.2-3.4 (1H, m), 3.9-4.1
(1H, m), 4.3-4.5 (1H, m), 4.83 (1H, d, J = 14.5Hz), 4.86 (1H, m
s), 5.09 (1H, d, J = 14.5Hz), 6.7-6.8 (2H, m), 7.06 (1H, d, J = 1
5.2Hz), 7.3-7.4 (1H, m), 7.37 (2H, d, J = 5.9Hz), 7.57 (1H, d,
J = 15.2Hz), 7.78 (1H, s), 7.81 (1H, s), 8.64 (2H, d, J = 5.9H
z). IR spectrum ν _max ^KBr cm ^-1 : 3420,1651,1615,1598. Mass spectrum m / e: 499,439,417,410,365,344,307,275,
247,216,144,132,104,82. Example 26 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[1- (E) -4- (trifluoromethoxy)
Cinnamoyl] azetidin-3-yl] thio] -1-
(1H-1,2,4-triazol-1-yl) -2-
Butanol

[0175]

Embedded image

(2R, 3R) -2-described in Reference Example 19
(2,4-difluorophenyl) -1- (1H-1,
Light yellow foam obtained from 2,4-triazol-1-yl) -3-[(azetidin-3-yl) thio] -2-butanol dihydrochloride according to Example 21 [Production Method A].

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
17 (3H, d, J = 7.1Hz), 3.32 (1H, q, J = 7.1Hz), 4.0-4.3 (3H, m),
4.5-4.6 (1H, m), 4.6-4.7 (1H, m), 4.86 (1H, d, J = 14.2Hz), 5.
05 (1H, d, J = 14.2Hz), 5.09 (1H, s), 6.43 (1H, d, J = 15.7Hz),
6.7-6.8 (2H, m), 7.22 (2H, d, J = 8.2Hz), 7.3-7.4 (1H, m), 7.5
6 (2H, d, J = 8.2Hz), 7.65 (1H, d, J = 15.7Hz), 7.79 (1H, s), 7.8
1 (1H, s). IR spectrum ν _max ^KBr cm ^-1 : 3376,1656. Mass spectrum m / e: 554,535,472,384,331,271,224,215,
187,127,87. Example 27 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(1E, 3E) -4-
(2,4-Difluorophenyl) -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio]
-1- (1H-1,2,4-triazol-1-yl)
-2-butanol

[0178]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-Triazol-5-yl) -2-butanol is reacted with (2E, 4E) -5- (2,4-difluorophenyl) -2,4-pentadienal to give the main product, title The compound was obtained as an oil in 61% yield.

Specific rotation [α] _D ²⁵ -79.1 ° (c = 1.04,
CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.18 (3H, d, J =
7.0Hz), 3.33 (1H, q, J = 7.0Hz), 3.39 (1H, tt, J = 11.3,4.6H
z), 3.62 (1H, t, J = 11.3Hz), 3.64 (1H, t, J = 11.3Hz), 4.30
(1H, m), 4.41 (1H, m), 4.82 (1H, d, J = 14.0Hz), 5.00 (1H,
s), 5.03 (1H, d, J = 14.0Hz), 5.05 (1H, d, J = 4.6Hz), 5.79
(1H, dd, J = 15.2,4.6Hz), 6.58 (1H, dd, J = 15.2,9.5Hz), 6.
65-6.9 (6H, m), 7.3-7.5 (2H, m), 7.79 (2H, s).

Example 28 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(1E, 3E) -4- [6
-(2,2,3,3-tetrafluoropropoxy) -3
-Pyridyl] -1,3-butadien-1-yl] -1,
3-dioxan-5-yl] thio] -1- (1H-1,
2,4-triazol-5-yl) -2-butanol

[0182]

Embedded image

(2R, 3R) -2- (2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -1- (1H-1,2,4-triazole- 1-yl) -2-butanol 404 mg (1.12
mmol) and (2E, 4E) -5 described in Reference Example 37.
[6- (2,2,3,3-tetrafluoropropoxy)
-3-pyridyl] -2,4-pentadienal 501mg
(1.73 mmol) was dissolved in 11 ml of methylene chloride, and 320 mg of p-toluenesulfonic acid monohydrate (1.
68 mmol) and 4 g of molecular sieves 4A
Stirred at room temperature for 1 hour. The reaction solution was cooled with ice and 3% aqueous sodium bicarbonate 20
After stirring for 5 minutes, the molecular sieves were removed by filtration, the organic layer was separated and dried, and the solvent was distilled off under reduced pressure. 908 mg of the obtained oil was subjected to column chromatography using 19 g of silica gel, and eluted with a mixed solvent of hexane-ethyl acetate (1: 1) to give 448 mg (yield 63%) of the title compound as an oil.

Specific rotation [α] _D ²⁵ -58.6 ° (c = 0.52,
CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.19 (3H, J = 7.
0Hz), 3.33 (1H, q, J = 7.0Hz), 3.39 (1H, tt, J = 11.2,4.8H
z), 3.62 (1H, t, J = 11.2Hz), 3.64 (1H, t, J = 11.2Hz), 4.30
(1H, ddd, J = 11.2,4.7,2.1Hz), 4.42 (1H, ddd, J = 11.2,4.7,
2.1Hz), 4.74 (2H, brt, J = 12.8Hz), 4.82 (1H, d, J = 13.9H
z), 5.01 (1H, s), 5.03 (1H, d, J = 13.9Hz), 5.05 (1H, d, J =
4.5Hz), 5.78 (1H, d, J = 15.5,4.5Hz), 6.01 (1H, tt, J = 53.
1,4.6Hz), 6.51-6.62 (2H, m), 6.65-6.78 (3H, m), 6.81 (1
H, d, J = 8.6Hz), 7.35 (1H, m), 7.74 (1H, dd, J = 8.6,2.3Hz),
7.79 (2H, s), 8.11 (1H, d, J = 2.3Hz).

Example 29 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[trans-2-[(1E, 3E) -1-methyl-4- [4- (trifluoromethyl) phenyl]-
1,3-Butadien-1-yl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,3-triazol-1-yl) -2-butanol

[0186]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-diphenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -1- (1H-1,2,2
4-triazol-5-yl) -2-butanol and (2
E, 4E) -2-Methyl-5- [4- (trifluoromethyl) phenyl] -2,4-pentadienal was reacted to give the title compound as the main product as an oil in 31% yield. .

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm:
1.19 (3H, d, J = 7.3Hz), 1.94 (3H, s), 3.34 (1H, q, J = 7.3Hz),
3.39 (1H, tt, J = 11.2,4.6Hz), 3.36 (1H, t, J = 11.2Hz), 3.
65 (1H, t, J = 11.2Hz), 4.33 (1H, m), 4.44 (1H, m), 4.83 (1
H, d, J = 13.9Hz). 4.89 (1H, s), 5.02 (1H, s), 5.04 (1H, d, J =
13.9Hz), 6.41 (1H, d, J = 11.2Hz), 6.62 (1H, d, J = 15.8Hz),
6.7-6.8 (2H, m), 7.09 (1H, dd, J = 15.8,11.2Hz), 7.36 (1
H, m), 7.50 (2H, d, J = 8.6Hz), 7.56 (2H, d, J = 8.6Hz), 7.79
(1H, s), 7.80 (1H, s).

Example 30 (RS) -3-Methyl-1- (1H-1,2,4-triazol-1-yl) -2- [4- (trifluoromethyl) phenyl] -3-[[trans -2-[(E) -2
-[4- (trifluoromethyl) phenyl] vinyl]-
1,3-dioxan-5-yl] thio] -2-butanol

[0190]

Embedded image

In the same manner as in Example 4, (RS) -3-[(1,3-dihydroxy-2-propyl) thio] -3-methyl-2- [4- (trifluoromethyl ) Phenyl] -1- (1H-1,2,4-triazol-1-yl) -2-butanol was reacted with trans-4- (trifluoromethyl) cinnamaldehyde described in Reference Example 22 to give the title compound. Was obtained as a colorless foam.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm:
1.36 (3H, s), 1.37 (3H, s), 3.5-3.7 (3H, m), 4.2-4.3 (1H,
m), 4.4-4.5 (1H, m), 5.02 (2H, s), 5.11 (1H, d, J = 4.1Hz),
5.44 (1H, s), 6.25 (1H, dd, J = 16.2,4.1Hz), 6.84 (1H, d, J
= 16.2Hz), 7.4-7.6 (8H, m), 7.70 (1H, s), 7.93 (1H, s).

IR spectrum ν _max (KBr) cm ⁻¹ : 3404, 1
618, 1508, 1328.

Mass spectrum m / e: 587, 568, 331, 298,
256, 201, 159, 131.

Example 31 (RS) -3-Methyl-1- (1H-1,2,4-triazol-1-yl) -2- [4- (trifluoromethyl) phenyl] -3-[[trans -2-[(1E, 3
E) -4-[(Trifluoromethyl) phenyl] -1,
3-butadien-1-yl] -1,3-dioxane-5
-Yl] thio] -2-butanol

[0196]

Embedded image

In the same manner as in Example 4, (RS) -3-[(1,3-dihydroxy-2-propyl) thio] -3-methyl-2- [4- (trifluoromethyl ) Phenyl] -1- (1H-1,2,4-triazol-1-yl) -2-butanol and (2E, 4E) -5- [4- (trifluoromethyl) phenyl]-described in Reference Example 25. The 2,4-pentadienal was reacted to obtain the main product, the title compound, as a colorless foam.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm:
1.36 (3H, s), 1.37 (3H, s), 3.4-3.7 (3H, m), 4.2-4.3 (1H,
m), 4.4-4.5 (1H, m), 5.01 (2H, s), 5.02 (1H, d, J = 4.3Hz),
5.39 (1H, s), 5.83 (1H, dd, J = 15.2,4.3Hz), 6.59 (1H, dd,
J = 15.2,10.7Hz), 6.63 (1H, d, J = 15.8Hz), 6.85 (1H, dd, J =
15.8,10.7Hz), 7.4-7.6 (8H, m), 7.73 (1H, s), 7.93 (1H,
s).

IR spectrum ν _max (KBr) cm ⁻¹ : 3398, 1
679, 1619, 1328, 1126.

Mass spectrum m / e: 614, 541, 494, 478,
406, 348, 256, 211.

Example 32 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[[trans-2-[(1E, 3E) -4- [4
-(Trifluoromethylthio) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol

[0202]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-Triazol-5-yl) -2-butanol is allowed to react with (2E, 4E) -5- [4- (trifluoromethylthio) phenyl] -2,4-pentadienal to give a main product. Certain title compounds were obtained as a colorless foam.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm:
1.19 (3H, d, J = 7.1Hz), 3.3-3.5 (2H, m), 3.62 (1H, t, J = 11.
4Hz), 3.64 (1H, t, J = 11.4Hz), 4.31 (1H, ddd, J = 11.4,4.7,
2.1Hz), 4.42 (1H, ddd, J = 11.4,4.7,2.1Hz), 4.83 (1H, d, J
= 14.1Hz), 5.01 (1H, s), 5.03 (1H, d, J = 14.1Hz), 5.06 (1
H, d, J = 4.5Hz), 5.83 (1H, dd, J = 15.7,4.5Hz), 6.60 (1H, d
d, J = 15.7,10.3Hz), 6.62 (1H, d, J = 15.7Hz), 6.7-6.8 (2H,
m), 6.84 (1H, dd, J = 15.7,10.3Hz), 7.3-7.4 (1H, m), 7.44
(2H, d, J = 8.3Hz), 7.60 (2H, d, J = 8.3Hz), 7.79 (2H, s).

IR spectrum ν _max (KBr) cm ⁻¹ : 3389, 1
621, 1680, 1621, 1501, 1117.

Mass spectrum m / e: 599, 580, 557, 530,
500, 438, 388, 376, 346, 284, 258, 224, 183.

Example 33 (2R ^* , 3R ^* )-3-[[trans-2-[(1
E, 3E) -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1,3-butadiene-1
-Yl] -1,3-dioxan-5-yl] thio] -1
-(1H-1,2,4-triazol-1-yl) -2
-[4- (trifluoromethyl) phenyl] -2-butanol

[0208]

Embedded image

In the same manner as in Example 4, (2R ^* , 3
R ^* )-3-[(1,3-dihydroxy-2-propyl) thio] -1- (1H-1,2,4-triazole-
5-yl) -2- [4- (trifluoromethyl) phenyl] -2-butanol and Reference Example 32 (2E, 4
E) Reaction of 5- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2,4-pentadienal gave the title compound as the main product as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
22 (3H, d, J = 6.6Hz), 3.16 (1H, q, J = 6.6Hz), 3.34 (1H, tt, J
= 11.2,4.6Hz), 3.58 (1H, t, J = 11.2Hz), 3.61 (1H, t, J = 11.
2Hz), 4.27 (1H, m), 4.35 (2H, brt, J = 11.9Hz), 4.39 (1H, m
m), 4.57 (1H, d, J = 13.9Hz), 4.77 (1H, s), 5.02 (1H, d, J =
4.6Hz), 5.03 (1H, d, J = 13.9Hz), 5.72 (1H, dd, J = 15.8,4.6
Hz), 6.05 (1H, tt, J = 52.8,5.3Hz), 6.5-6.75 (3H, m), 6.8
8 (2H, d, J = 8.6Hz), 7.36 (2H, d, J = 8.6Hz), 7.39 (2H, d, J =
8.6Hz), 7.54 (2H, d, J = 8.6Hz), 7.71 (1H, s), 7.83 (1H,
s).

Example 34 (2R ^* , 3R ^* )-1- (1H-1,2,4-triazol-1-yl) -2- [4- (trifluoromethyl) phenyl] -3-[[trans -2-[(1E, 3
E) -4- [4- (Trifluoromethyl) phenyl]-
1,3-Butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol

[0212]

Embedded image

In the same manner as in Example 1, (2R ^* , 3
R ^* )-3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane and trans-
5- (acetylthio) -2-[(1E, 3E) -4-
[4- (Trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1,3-dioxane was reacted to obtain the title compound as an oil in a yield of 71%.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
22 (3H, d, J = 7.0Hz), 3.17 (1H, q, J = 7.0Hz), 3.36 (1H, tt, J
= 11.3,4.7Hz), 3.59 (1H, t, J = 11.3Hz), 3.62 (1H, t, J = 11.
3Hz), 4.27 (1H, ddd, J = 11.3, 4.7, 2.2Hz), 4.39 (1H, dd
d, J = 11.3, 4.7,2.2Hz), 4.57 (1H, d, J = 14.0Hz), 4.80 (1
H, s), 5.03 (1H, d, J = 14.0Hz), 5.05 (1H, d, J = 4.5Hz), 5.8
3 (1H, dd, J = 15.3,4.5Hz), 6.59 (1H, dd, J = 15.3,10.7Hz),
6.64 (1H, d, J = 15.3Hz), 6.85 (1H, dd, J = 15.3,10.7Hz),
7.39 (2H, d, J = 8.4Hz), 7.49 (2H, d, J = 8.3Hz), 7.54 (2H, d, J
J = 8.3Hz), 7.57 (2H, d, J = 8.4Hz), 7.71 (1H, s), 7.83 (1H,
s).

Example 35 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[[trans-2-[(1E, 3E) -4- [4
-(Trifluoromethylsulfinyl) phenyl]-
1,3-Butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol

[0216]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1-[(1H
-1,2,4-Triazol-5-yl) -2-butanol is reacted with (2E, 4E) -5- [4- (trifluoromethylsulfinyl) phenyl] -2,4-pentadienal to form a main product The title compound was obtained as a colorless foam.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm:
1.19 (3H, d, J = 7.0Hz), 3.3-3.5 (2H, m), 3.62 (1H, t, J = 11.
3Hz), 3.64 (1H, t, J = 11.3Hz), 4.30 (1H, ddd, J = 11.3,4.8,
2.3Hz), 4.42 (1H, ddd, J = 11.3,4.8,2.3Hz), 4.83 (1H, d, J
= 14.1Hz), 5.01 (1H, s), 5.03 (1H, d, J = 14.1Hz), 5.06 (1
H, d, J = 4.5Hz), 5.83 (1H, dd, J = 15.9,4.5Hz), 6.60 (1H, d
d, J = 15.9,10.6Hz), 6.62 (1H, d, J = 15.9Hz), 6.7-6.8 (2H,
m), 6.84 (1H, dd, J = 15.9,10.6Hz), 7.3-7.4 (1H, m), 7.44
(2H, d, J = 8.3Hz), 7.60 (2H, d, J = 8.3Hz), 7.79 (2H, s).

Mass spectrum m / e: 616, 600, 547, 400,
370, 342, 284, 252, 224, 183.

Example 36 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[[trans-4-[(1E, 3E) -4- [4
-(Trifluoromethyl) phenyl] -1,3-butadien-1-yl] cyclohexyl] thio] -2-butanol

[0221]

Embedded image

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] oxirane and trans-1-described in Reference Example 43
(Acetylthio) -4-[(1E, 3E) -4- [4-
(Trifluoromethyl) phenyl] -1,3-butadien-1-yl] cyclohexane to give a melting point of 74.
The title compound having -76 ° C was obtained in 59% yield.

Specific rotation [α] _D ²⁵ -83 ° (c = 0.90, CH
Cl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.1-1.6 (4H, m),
1.17 (3H, d, J = 7Hz), 1.8-2.0 (2H, m), 2.0-2.2 (2H, m),
2.69 (1H, tt, J = 12,3Hz), 3.35 (1H, q, J = 7Hz), 4.64 (1H, s,
O H ), 4.83 (1H, d, J = 15Hz), 5.10 (1H, d, J = 15Hz), 5.83 (1
H, dd, J = 15,7Hz), 6.22 (1H, dd, J = 15,10Hz), 6.48 (1H, d, J =
15Hz), 6.74 (1H, t, J = 8Hz), 6.81 (1H, dd, J = 15,10Hz), 7.
1-7.5 (2H, m), 7.45 (2H, d, J = 8Hz), 7.54 (2H, d, J = 8Hz),
7.76 (1H, s), 7.84 (1H, s).

IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 1615,
1500, 1325, 1125, 1068.

Mass spectrum m / e: 563, 544, 340, 310,
277, 224, 159, 127.

Example 37 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[[trans-2-[(1E, 3E, 5E) -6
-[4- (trifluoromethyl) phenyl] -1,3,
5-hexatrien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol

[0227]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol and (2E, 4E ,, 6E) -7- described in Reference Example 28.
[4- (trifluoromethyl) phenyl] -2,4,6
-Heptatrienal was reacted to give the main product, the title compound, as an oil in 65% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
18 (3H, d, J = 6.6Hz), 3.33 (1H, q, J = 6.6Hz), 3.38 (1H, tt, J
= 11.2,4.6Hz), 3.61 (1H, t, J = 11.2Hz), 3.63 (1H, t, J = 11.
2Hz), 4.29 (1H, m), 4.40 (1H, m), 4.83 (1H, d, J = 14.5Hz),
5.00 (1H, s), 5.02 (1H, d, J = 14.5Hz), 5.03 (1H, d, J = 4.6H
z), 5.74 (1H, dd, J = 15.2, 4.6Hz), 6.35-6.55 (3H, m), 6.5
9 (1H, d, J = 15.2Hz), 6.7-6.8 (2H, m), 6.89 (1H, dd, J = 15.
2,9.9Hz), 7.35 (1H, m), 7.48 (2H, d, J = 8.6Hz), 7.56 (2H, m
d, J = 8.6Hz), 7.78 (1H, s), 7.79 (1H, s).

Example 38 (RS) -2- (2,4-Difluorophenyl) -3-
Methyl-1- (1H-1,2,4-triazole-1-
Yl) -3-[[trans-2-[(1E, 3E) -4
-[4- (trifluoromethyl) phenyl] -1,3-
(Butadien-1-yl) -1,3-dioxan-5-yl] thio] -2-butanol

[0231]

Embedded image

In the same manner as in Example 4, (RS) -2-
(2,4-difluorophenyl) -3-[(1,3-dihydroxy-2-propyl) thio] -3-methyl-1-
(1H-1,2,4-triazol-1-yl) -2-
Butanol and (2E, 4E) -5 described in Reference Example 25
[4- (Trifluoromethyl) phenyl] -2,4-pentadienal was reacted to obtain the title compound as a main product as a colorless foam.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm:
1.36 (6H, s), 3.5-3.6 (2H, m), 3.6-3.8 (2H, m), 4.2-4.4
(1H, m), 4.4-4.6 (1H, m), 4.93 (1H, d, J = 14.1Hz), 5.03 (1
(H, d, J = 4.3Hz), 5.23 (1H, d, J = 14.1Hz), 5.56 (1H, s), 5.8
4 (1H, dd, J = 15.4,4.3Hz), 6.5-6.7 (3H, m), 6.7-6.9 (2H,
m), 7.50 (2H, d, J = 8.4Hz), 7.57 (2H, d, J = 8.4Hz), 7.6-7.
7 (1H, m), 7.74 (1H, s), 8.05 (1H, s).

Example 39 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[[trans-2-[(E) -4- [4- (trifluoromethyl) phenyl] -1-buten-3-yn-
1-yl] -1,3-dioxan-5-yl] thio]-
2-butanol

[0235]

Embedded image

In the same manner as in Example 4, (2R, 3R)-
2- (2,4-difluorophenyl) -3-[(1,3
-Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-Triazol-1-yl) -2-butanol was reacted with (E) -5- [4- (trifluoromethyl) phenyl] -2-penten-4-inal described in Reference Example 48. The main product, the title compound, was obtained as an oil in a yield of 70%. Specific rotation [α] _D ²⁵ −65.1 ° (c = 0.97, CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.19 (3H, d, J = 7.
0Hz), 3.33 (1H, q, J = 7.0Hz), 3.39 (1H, tt, J = 11.4,4.9H
z), 3.60 (1H, t, J = 11.4Hz), 3.62 (1H, t, J = 11.4Hz), 4.30
(1H, m), 4.42 (1H, m), 5.0-5.1 (2H, m), 5.04 (1H, d, J = 3.2
Hz), 6.12 (1H, d, J = 16.0Hz), 6.18 (1H, dd, J = 16.0,3.2H
z), 6.7-6.8 (2H, m), 7.36 (1H, m), 7.54 (2H, d, J = 8.5Hz),
7.58 (2H, d, J = 8.5Hz), 7.79 (2H, s).

Example 40 (2R, 3R) -2- (2,4-difluorophenyl)
-3-[[Trans-2-phenyl-1,3-dioxan-5-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol

[0238]

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(2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4
-Triazol-1-yl) methyl] oxirane 1.65 g
(6.57 mmol) and 2.00 g of trans-4- (acetylthio) -2-phenyl-1,3-dioxane described in Reference Example 1.
(8.40 mmol) in 20 ml of dimethylformamide,
Under a nitrogen atmosphere, 2.5 ml (4.00 mmol) of a 1.6 M sodium methoxide-methanol solution was added, and the mixture was heated with stirring at 65 ° C. for 2 hours. After cooling, ethyl acetate was added to the reaction solution, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure. The obtained crude product was subjected to column chromatography using 60 g of silica gel, and eluted with a benzene-ethyl acetate (5: 1) mixed solvent to obtain 2.53 g (yield 91%) of the title compound as a solid. Recrystallization was performed from ethyl acetate-hexane to obtain a pure product having a melting point of 58-60 ° C.

Specific rotation [α] _D ²⁵ -88 ° (C = 1.07, CHCl ₃ ) Infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3400,1615,1500,
1139. NMR spectrum (270 MHz, CHCl ₃ ) δ ppm: 1.21 (3H, d, J = 7.
3Hz), 3.36 (1H, q, J = 7.3Hz), 3.48 (1H, tt, J = 11.2, 4.6Hz),
3.75 (1H, t, J = 11.2Hz), 3.77 (1H, t, J = 11.2Hz), 4.40 (1H, dd
d, J = 11.2,4.6,2.6Hz), 4.51 (1H, ddd, J = 11.2,4.6,2.6Hz),
4.84 (1H, d, J = 13.9Hz), 5.02 (1H, s), 5.05 (1H, d, J = 13.9H
z), 5.49 (1H, s), 7.7-7.8 (2H, m), 7.3-7.45 (4H, m), 7.45-7.
53 (2H, m), 7.79 (2H, s). Reference Example 1 trans-4- (acetylthio) -2-phenyl-1,
3-dioxane

[0241]

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Cis-2-phenyl-4- (p-toluenesulfonyloxy) -1,3-dioxane 29.0 g
(86.8 mmol) and sodium thioacetate 17.0.
g (149 mmol) in dimethylformamide 200m
and heated under a nitrogen atmosphere at 115-120 ° C. for 1 hour. After cooling, benzene was added to the reaction solution, and after washing with water, the solvent was distilled off. The resulting brown residue was subjected to column chromatography using silica gel, and the fraction eluted with a benzene-hexane (2: 1) mixed solvent was collected.
Recrystallization from a mixed solvent of hexane gave a melting point of 95-96.
8.99 g (43% yield) of the title compound having a temperature of ° C. were obtained.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.
37 (3H, s), 3.79 (2H, t, J = 11.2Hz), 4.03 (1H, tt, J = 11.2,
4.6Hz), 4.31 (2H, dd, J = 11.2,4.6Hz), 5.47 (1H, s), 7.35
-7.5 (5H, m).

IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 1690,
1383, 1146, 1084.

Mass spectrum m / e: 238 (M ⁺ ), 237, 19
5, 162 (100%), 149, 116, 107, 73.

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

[0247]

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(2R, 3R) -2- described in Example 40
(2,4-difluorophenyl) -3-[[trans-
2-phenyl-1,3-dioxan-5-yl] thio]
-1- (1H-1,2,4-triazol-1-yl)
253 mg of 2-butanol was dissolved in 3.5 ml of methanol, and 0.35 ml of a 4N HCl dioxane solution was added.
Stirred for minutes. After adding 250 mg of NaHCO ₃ powder and stirring for 10 minutes, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The obtained oil was subjected to column chromatography using 5 g of silica gel, and eluted with 10% methanol-ethyl acetate to obtain 179 mg (88% yield) of the title compound as a viscous oil.

Specific rotation [α] _D ²⁵ -61 ° (C = 1.05, CHCl ₃ ) Infrared absorption spectrum ν _max (CHCl ₃ ) cm ^-1 : 3400,1618,1500. NMR spectrum (60 MHz, CDCl ₃ + D ₂ O) δppm: 1.20 (3H, d,
J = 6.5Hz), 3.0-4.0 (6H, m), 4.80 (1H, d, J = 14Hz), 5.16 (1H,
d, J = 14Hz), 6.6-7.0 (2H, m), 7.43 (1H, td, J = 9,8Hz), 7.74 (1H
H, s), 7.86 (1H, s). Reference Example 3 trans-5-[(4-chlorobenzyl) thio] -2-
Phenyl-1,3-dioxane

[0250]

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240 mg of 55% sodium hydride (5.50 mmo
After l) was washed with hexane, it was suspended in 15 ml of dimethylformamide, and 903 mg (5.70 mmol) of 4-chlorobenzylmercaptan was added while stirring under a nitrogen atmosphere. After 15 minutes, cis-5- (p-toluenesulfonyloxy) -2
1.66 g (4.96 mmol) of -phenyl-1,3-dioxane was added, and the mixture was stirred at 75 ° C. for 1 hour. After cooling, benzene was added, and the mixture was washed with water and then with a saline solution. After the solvent was distilled off, the obtained crystalline residue was recrystallized from a benzene-hexane mixed solvent to give the title compound 670 having a melting point of 95-99 ° C.
mg (42% yield) were obtained as scaly crystals.

NMR spectrum (60 MHz, CDCl ₃ ) δ ppm:
3.02 (1H, tt, J = 11.5 Hz), 3.67
(2H, t, J = 11 Hz), 3.72 (2H, s),
4.21 (2H, dd, J = 11.5 Hz), 5.39
(1H, s), 7.30 (5H, s), 7.38 (4
H, s). Reference Example 4 2-[(4-chlorobenzyl) thio] -1,3-propanediol

[0253]

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Trans-5-[(4-chlorobenzyl)
Thio] -2-phenyl-1,3-dioxane 750 mg
Was dissolved in 10 ml of methanol, 1 ml of a 4N hydrogen chloride-dioxane solution was added, and the mixture was stirred at room temperature for 1 hour. After adding 750 mg of sodium hydrogen carbonate (powder) and stirring for 15 minutes, the solid was removed by filtration and the solvent was distilled off. Ethyl acetate was added to the residue, and insolubles were removed by filtration. The crystals obtained by distilling off the solvent were recrystallized from a benzene-hexane mixed solvent to give the title compound 46 having a melting point of 70-75 ° C.
8 mg (86% yield) were obtained.

Reference Example 5 trans-5-[(4-chlorobenzyl) thio] -2-
[(E) -1-methyl-2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane

[0256]

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2-[(4-chlorobenzyl) thio]-
341 mg (1.46 mmol) of 1,3-propanediol and (E)
375 mg (1.75 mmol) of 4- (trifluoromethyl) -α-methylcinnamaldehyde are dissolved in 12 ml of benzene, 3 mg of p-toluenesulfonic acid is added, and the mixture is dissolved under nitrogen atmosphere.
Heated to reflux for an hour. After cooling, the mixture was washed with aqueous sodium hydrogen carbonate and the residue obtained by evaporating the solvent was subjected to column chromatography using 15 g of silica gel. The fraction eluted with a hexane-ethyl acetate (9: 1) mixed solvent was collected, and the obtained solid was washed with hexane to obtain 370 mg (yield: 59%) of the title compound having a melting point of 93-95 ° C.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
87 (3H, s), 2.99 (1H, tt, J = 11.2,4.6Hz), 3.58 (2H, dd, J = 11.
9,11.2Hz), 3.73 (2H, s), 4.15 (2H, dd, J = 11.9,4.6Hz), 4.87
(1H, s), 6.68 (1H, br s), 7.25-7.3 (4H, m), 7.36 (2H, d, J = 7.
9Hz), 7.57 (2H, d, J = 7.9Hz). Reference Example 6 trans-5-[(4-chlorobenzyl) sulfinyl] -2-[(E) -1-methyl-2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane

[0259]

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Trans-5-[(4-chlorobenzyl)
Dissolve 382 mg (0.89 mmol) of thio] -2-[(E) -1-methyl-2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane in 10 ml of methylene chloride and at 0 ° C. 188 chloroperbenzoic acid (85% purity)
mg (0.92 mmol) was added and stirred for 15 minutes. The reaction solution was washed with aqueous sodium bicarbonate, and the solid obtained by evaporating the solvent was evaporated with ethyl acetate
The residue was washed with a mixed solvent of hexane to obtain 328 mg (yield: 83%) of the title compound having a melting point of 192-194 ° C.

NMR spectrum (60 MHz, CDCl ₃ ) δ ppm:
1.88 (3H, d, J = 1.5 Hz), 2.8-3.
3 (1H, m), 3.8-4.5 (4H, m), 4.0
1 (2H, s), 4.95 (1H, s), 6.73 (1
H, br s), 7.15-7.75 (8H, m). Reference Example 7 trans-4- (acetylthio) -2-[(E) -1-
Methyl-2- [4- (trifluoromethyl) phenyl]
Vinyl] -1,3-dioxane

[0262]

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Trans-5-[(4-chlorobenzyl)
Sulfinyl] -2-[(E) -1-methyl-2- [4
-(Trifluoromethyl) phenyl] vinyl] -1,3
309 mg (0.696 mmol) of -dioxane was dissolved in 8 ml of a mixed solvent of tetrahydrofuran-acetonitrile (1: 1), and 500 mg (4.67 mmol) of 2,6-lutidine was added. Trifluoroacetic anhydride 5 while stirring at 0 ° C.
00 mg (2.4 mmol) was added dropwise in about 5 minutes. After 10 minutes, about 5 ml of aqueous sodium bicarbonate was added, stirred for 5 minutes, and extracted with ethyl acetate. An oily residue obtained after distilling off the solvent (about 350 m
g) was dissolved in 5 ml of methylene chloride, and at 0 ° C., 210 mg of triethylamine was added, followed by 109 mg of acetyl chloride. After 5 minutes, the reaction solution was washed with water and the solvent was distilled off. The residue was subjected to column chromatography using 10 g of silica gel. Elution with a mixed solvent of hexane-benzene (1: 1 to 1: 2) gave 186 mg (yield 77%) of the title compound as crystals. Recrystallization was performed from a benzene-hexane mixed solvent to obtain plate crystals having a melting point of 128 to 129 ° C.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
92 (3H, s), 2.36 (3H, s), 3.70 (2H, t, J = 11.2Hz), 3.96 (1H, t
t, J = 11.2,4.6Hz), 4.25 (2H, dd, J = 11.2,4.6Hz), 4.94 (1H,
s), 6.70 (1H, br s), 7.39 (2H, d, J = 8.2Hz), 7.59 (2H, d, J = 8.
2Hz). Reference Example 8 Ethyl (2E, 4E) -3-methyl-5- [4- (trifluoromethyl) phenyl] -2,4-pentadienoate

[0265]

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45 mg (1.03 mmol) of 55% sodium hydride
Was washed with hexane, and suspended in 3 ml of 1,2-dimethoxyethane.
273 mg of 3-methyl-4-phosphonocrotonate (1.03 m
mol) was added. After 15 minutes, 4- (trifluoromethyl)
100 mg (0.57 mmol) of benzaldehyde was added and stirred for 10 minutes. Ice-water was added to the reaction solution, which was extracted with ethyl acetate. The crude product obtained by distilling off the solvent is silica gel 5
g, and eluted with a mixed solvent of ethyl acetate-hexane (4:96) to give the (2E, 4E) isomer as the title compound and its (2Z, 4E)
159 mg (97% yield) of a 5: 1 mixture with the isomers were obtained as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: (2
E, 4E) -isomer, 1.31 (3H, t, J = 6.6 Hz), 2.41 (3H, s), 4.20 (2
H, q, J = 6.6Hz), 5.95 (1H, s), 6.86 (1H, dJ = 16.5Hz), 6.95 (1
H, d, J = 16.5Hz), 7.5-7.65 (4H, m): (2E, 4E) -isomer (main signal), 2.14 (3H, s), 5.82 (1H, s), 6.92 (1H , d, J = 16.5H
z), 8.49 (1H, d, J = 16.5Hz). Reference Example 9 (2E, 4E) -3-methyl-5- [4- (trifluoromethyl) phenyl] -2,4-pentadien-1-ol

[0268]

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Ethyl (4E) -3-methyl-5- [4- (trifluoromethyl) phenyl]-described in Reference Example 8
2,4-pentadienoate ((2E) / (2Z) = 5
/ 1) While stirring a solution of 150 mg (0.53 mmol) in 2 ml of toluene at 0 ° C, 0.7 ml (1.06 mmol) of a 1.5 M diisobutylaluminum hydride-toluene solution was added. After 20 minutes, ice-water was added and the mixture was stirred for 10 minutes, and insoluble materials were removed by filtration using Celite. After extraction with ethyl acetate, the solvent was distilled off after drying to obtain an oil. Silica gel 5
g, column chromatography using 30 g
Elution with a 0% ethyl acetate-hexane mixed solvent gave 90 mg of the title compound as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
34 (1H, br s), 1.93 (3H, s), 4.37 (2H, d, J = 6.5Hz), 5.87 (1H,
t, J = 6.5Hz), 6.58 (1H, dJ = 16.1Hz), 6.88 (1H, d, J = 16.1H
z), 7.50 (2H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz). Reference Example 10 (2E, 4E) -3-Methyl-5- [4- (trifluoromethyl) phenyl] -2,4-pentadienal

[0271]

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(2E, 4E) -3-methyl-5- [4-
(Trifluoromethyl) phenyl] -2,4-pentadien-1-ol (460 mg, 1.90 mmol) was treated with methylene chloride 1
The mixture was dissolved in 0 ml, and 5 g of activated manganese dioxide was added, followed by stirring at room temperature for 30 minutes. The solid was removed by filtration, and the filtrate was concentrated and purified by silica gel chromatography (elution solvent: 4%
Ethyl acetate-hexane) gave 460 mg of the title compound as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.
41 (3H, s), 6.13 (1H, dJ = 8.0Hz), 6.96 (1H, d, J = 16.1Hz), 7.
09 (1H, d, J = 16.1Hz), 7.55-7.7 (4H, m), 10.19 (1H, d, J = 8.0H
z). Reference Example 11 4- (acetylthio) -1- (tert-butoxycarbonyl) piperidine

[0274]

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1- (tert-butoxycarbonyl) -4-
(Methanesulfonyloxy) piperidine 4.12g (14.7mmo
l) was dissolved in 40 ml of dimethylformamide, and 2.53 g (2.21 mmol) of potassium thioacetate was added thereto.
Stirred at C for 4 hours. After cooling, the mixture was diluted with ethyl acetate, washed with water and then with saturated saline, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, and the fraction eluted with a hexane-ethyl acetate (5: 1) mixed solvent was collected to give 5.19 g of the title compound as an oil (81% yield).
I got

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
46 (9H, s), 1.5-1.6 (2H, m), 1.9-2.0 (2H, m), 2.33 (3H, s), 3.
0-3.1 (2H, m), 3.5-3.7 (1H, m), 3.8-3.9 (2H, m). Mass spectrum m / e: 259,244,216,202,186,183,160,144,
127,116,97,84,57. Reference Example 12 1- (tert-butoxycarbonyl) -4-mercaptopiperidine

[0277]

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520 mg (2 mmol) of 4- (acetylthio) -1- (tert-butoxycarbonyl) piperidine was dissolved in dry methanol, and 420 μl of a 28% sodium methoxide-methanol solution (2 mmol) was added under ice-cooling and a nitrogen atmosphere.
l) was added and stirred for 40 minutes. Then 173 μl of acetic acid
After the solvent was distilled off at room temperature, the residue was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, and the solvent was distilled off to obtain 430 mg of a red-orange oil. This was used for the next reaction without purification.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
46 (9H, s), 1.5-1.6 (2H, m), 1.9-2.0 (2H, m), 2.8-3.0 (3H,
m), 3.9-4.1 (2H, m). Mass spectrum m / e: 217,202,184,161,144,127,117,84,8
2. Reference Example 13 (2R, 3R) -2- (2,4-difluorophenyl)
-3- (1H-1,2,4-triazol-1-yl)
-3-[[1- (tert-butoxycarbonyl) piperidin-4-yl] thio] -2-butanol

[0280]

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1- (tert-butoxycarbonyl) -4-mercaptopiperidine (2 mmol) described in Reference Example 12 was dissolved in 6 ml of dimethylformamide, and 86 mg (1.97 mmol) of 55% sodium hydride was added at 0 ° C. under a nitrogen atmosphere. After the addition, the mixture was stirred at the same temperature for 20 minutes. Then (2R,
3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazole-1-
After adding 503 mg (2.00 mmol) of yl) methyl] oxirane, the mixture was stirred at 60 ° C for 3 hours. After cooling, the reaction solution was diluted by adding ethyl acetate, and washed with water and saturated saline in this order. The oil obtained by evaporating the solvent was subjected to silica gel column chromatography and eluted with ethyl acetate to obtain 557 mg (yield 53%) of the desired compound as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
17 (3H, d, J = 6.6Hz), 1.47 (9H, s), 1.4-1.6 (2H, m), 1.9-2.1
(2H, m), 2.9-3.1 (3H, m), 3.34 (1H, q, J = 6.6Hz), 3.9-4.1 (2
H, m), 4.77 (1H, s), 4.82 (1H, d, J = 14.2Hz), 5.09 (1H, d, J = 1
4.2Hz), 6.7-6.8 (2H, m), 7.3-7.4 (1H, m), 7.77 (1H, s), 7.82
(1H, s). IR spectrum ν _max ^KBr cm ^-1 : 3401,1691. Mass spectrum m / e: 468,408,395,365,321,284,253,224,
188,166,144,127. Reference Example 14 (2R, 3R)-(2,4-difluorophenyl) -3
-(1H-1,2,4-triazol-1-yl) -3
-[(Piperidin-4-yl) thio] -2-butanol dihydrochloride

[0283]

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(2R, 3R) -2- (2,4-difluorophenyl) -3- (1H-1,2,4-triazol-1-yl) -3-[[1- (tert-butoxycarbonyl) Piperidin-4-yl] thio] -2-butanol 5
57 mg (1.05 mmol) was dissolved in 20 ml of ethyl acetate, and 4N
After adding 2.63 ml (10.5 mmol) of a hydrogen chloride-ethyl acetate solution, the mixture was stirred at 40 ° C. for 8 hours. After cooling, the precipitated solid was collected by filtration and washed with hexane to obtain 460 mg (yield: 100%) of the target compound as a colorless powder.

NMR spectrum (270 MHz, DMSO-d6 + CDCl ₃ ) δ
ppm ： 1.23 (3H, d, J = 6.6Hz), 1.8-2.0 (2H, m), 2.3-2.5 (2H,
m), 3.1-3.4 (3H, m), 3.74 (1H, q, J = 6.6Hz), 4.79 (1H, d, J = 1
4.2Hz), 5.05 (1H, d, J = 14.2Hz), 5.3-5.6 (1H, br s), 6.8-6.
9 (1H, m), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m), 7.79 (1H, s), 8.2
8 (1H, s). IR spectrum ν _max ^KBr cm ^-1 : 3366,3094,2725,2483. Mass spectrum m / e: 368,308,286,284,253,224,213,183,
165,144,116,113,84. Reference Example 15 4- (acetylthio) piperidine hydrochloride

[0286]

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4- (acetylthio) described in Reference Example 11
1.25 g of -1- (tert-butoxycarbonyl) piperidine
(4.82 mmol) was dissolved in 45 ml of ethyl acetate, and 12.0 ml (48.2 mmol) of a 4N hydrogen chloride-ethyl acetate solution was added.
Stirred at C for 4 hours. After cooling, the precipitated solid was collected by filtration and washed with hexane to give 885 mg (yield 94%) of the desired compound as a slightly yellow powder.

NMR spectrum (270 MHz, CD ₃ OD) δ ppm: 1.
8-2.0 (2H, m), 2.1-2.3 (2H, m), 2.35 (3H, s), 3.1-3.3 (2H, m
m), 3.3-3.5 (2H, m), 3.6-3.8 (1H, m). Reference Example 16 4- (acetylthio) -1-[(E) -4- (trifluoromethoxy) cinnamoyl] -piperidine

[0289]

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4- (acetylthio) piperidine hydrochloride 1.
28 g (6.53 mmol) were suspended in 17 ml of dichloromethane, and 2.27 ml (16.3 mmol) of triethylamine was added dropwise with stirring under ice cooling. Then, a solution of 1.80 g (7.18 mmol) of (E) -4- (trifluoromethoxy) cinnamoyl chloride dissolved in 6 ml of dichloromethane was added dropwise, and the mixture was stirred at the same temperature for 1 hour.
The reaction mixture was subjected to silica gel column chromatography, and eluted with a mixed solvent of hexane-ethyl acetate (2: 1 to 1: 1) to obtain 2.32 g (yield 95%) of the desired compound as a slightly yellow solid.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
5-1.7 (2H, m), 1.9-2.1 (2H, m), 2.34 (3H, s), 3.1-3.3 (1H,
m), 3.3-3.5 (1H, m), 3.7-3.8 (1H, m), 3.9-4.0 (1H, m), 4.2-
4.4 (1H, m), 6.85 (1H, d, J = 15.5Hz), 7.21 (2H, d, J = 8.6Hz),
7.54 (2H, d, J = 8.6Hz), 7.63 (1H, d, J = 15.5Hz). Mass spectrum m / e: 373,330,298,256,228,215,187,158,
136,116,101. Reference Example 17 3- (acetylthio) -1- (tert-butoxycarbonyl) azetidine

[0292]

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1- (tert-butoxycarbonyl) -3-
Reference Example 11 from (methanesulfonyloxy) azetidine
Orange oil obtained according to 1.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
44 (9H, s), 2.33 (3H, s), 3.81 (2H, dd, J = 9.0,5.5Hz), 4.1-4.
2 (1H, m), 4.37 (2H, t, J = 9.0Hz). Reference Example 18 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[[1- (tert-butoxycarbonyl) azetidin-3-yl] thio] -2-butanol

[0295]

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Reference examples 12 and 13 were obtained from 3- (acetylthio) -1- (tert-butoxycarbonyl) azetidine.
Pale yellow foam obtained according to 1.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
13 (3H, d, J = 7.1Hz), 1.45 (9H, s), 3.27 (1H, q, J = 7.1Hz), 3.7
-3.9 (2H, m), 3.9-4.0 (1H, m), 4.2-4.4 (2H, m), 4.84 (1H, d, J
= 14.1Hz), 4.98 (1H, s), 5.04 (1H, d, J = 14.1Hz), 6.7-6.9 (2
H, m), 7.3-7.4 (1H, m), 7.78 (1H, s), 7.80 (1H, s). IR spectrum ν _max ^KBr cm ^-1 : 3405,1701. Mass spectrum m / e: 441,425,385,367,341,311,284,252,
224,199,183,165,141,127,88. Reference Example 19 (2R, 3R) -2- (2,4-difluorophenyl)
-1- (1H-1,2,4-triazol-1-yl)
-3-[(azetidin-3-yl) thio] -2-butanol dihydrochloride

[0298]

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(2R, 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -3-[[1- (tert-butoxycarbonyl) A pale yellow powder obtained from azetidin-3-yl] thio] -2-butanol according to Reference Example 14.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
16 (3H, d, J = 6.6Hz), 3.52 (1H, q, J = 6.6Hz), 3.9-4.3 (3H, m),
4.3-4.6 (2H, m), 4.98 (1H, d, J = 14.2Hz), 5.43 (1H, d, J = 14.2
Hz), 6.6-6.9 (2H, m), 7.2-7.4 (1H, m), 8.40 (1H, s), 8.95 (1
H, s), 9.0-9.6 (1H, br). Reference Example 20 ethyl trans-4- (trifluoromethyl) cinnamate

[0301]

Embedded image

903 mg of 55% sodium hydride (2
0.7 mmol) was washed with hexane, suspended in 60 ml of 1,2-dimethoxyethane, and stirred under a nitrogen atmosphere at 0 ° C. while triethyl phosphonoacetate 4.63 was added.
g (20.7 mmol) was added dropwise. After 15 minutes, at the same temperature, 4- (trifluoromethyl) benzaldehyde 2.0
0 g (11.5 mmol) was added and stirred for 15 minutes.
Ethyl acetate was added to the reaction solution, which was washed with water. After drying, the oily residue obtained by distilling off the solvent was subjected to column chromatography on silica gel and eluted with 4% ethyl acetate-hexane to give the title compound having a melting point of 31-32.5 ° C in a yield of 98. %.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
35 (3H, t, J = 7.3Hz), 4.48 (2H, q, J = 7.3Hz), 6.51 (1H, d, J =
16.2Hz), 7.66 (4H, s), 7.69 (1H, d, J = 16.2Hz).

Reference Example 21 trans-4- (trifluoromethyl) cinnamyl alcohol

[0305]

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Ethyl trans-4- (trifluoromethyl) cinnamate (3.00 g, 12.3 mmol) was dissolved in toluene (15 ml) and stirred at 0 ° C. for 1.5 times.
M diisobutylaluminum hydride-toluene solution 1
6.4 ml (24.6 mmol) were added. 20 minutes later,
Ice-water was added and the mixture was stirred for 10 minutes, and the insoluble matter was removed by filtration using Celite. After extraction with ethyl acetate and drying, the solvent was distilled off to obtain a crystalline residue. Recrystallization from a benzene-hexane mixed solvent gave 2.36 g (96% yield) of the title compound having a melting point of 53-55 ° C.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
55 (1H, t, J = 5.9Hz), 4.37 (2H, br t), 6.46 (1H, dt, J = 16.2,
5.3Hz), 6.67 (1H, d, J = 16.2Hz), 7.46 (2H, d, J = 8.3Hz),
7.57 (2H, d, J = 8.3Hz).

Reference Example 22 trans-4- (trifluoromethyl) cinnamaldehyde

[0309]

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Trans-4- (trifluoromethyl) cinnamyl alcohol (2.15 g) was added to methylene chloride (30 ml).
And add 14 g of active manganese dioxide at 0 ° C.
The mixture was stirred for 5 minutes and then at room temperature for 2 hours. The solid was removed by filtration and the filtrate was concentrated to give a crystalline residue. Recrystallization from a benzene-hexane mixed solvent was performed, and the melting point was 60-6.
The title compound having 1 ° C. was obtained in 90% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 6.
78 (1H, dd, J = 16.2,7.3Hz), 7.53 (1H, d, J = 16.2Hz), 7.69
(4H, s), 9.76 (1H, d, J = 7.3Hz).

IR spectrum ν _max (KBr) cm ^-1 : 1680,16
30,1321,1173,1123,1066.

Mass spectrum m / e: 200 (M ⁺ ), 199, 17
1, 151, 145, 131 (100%), 103, 102.

Reference Example 23 Ethyl (2E, 4E) -5- [4- (trifluoromethyl) phenyl] -2,4-pentadienoate

[0315]

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4.51 g of 55% sodium hydride (10%
3 mmol) was washed with hexane, suspended in 70 ml of 1,2-dimethoxyethane, and 25.9 g of triethyl phosphonocrotonate (1
03 mmol) was added dropwise. 15 minutes later, at the same temperature 4-
10.0 g of (trifluoromethyl) benzaldehyde
(57.4 mmol) and stirred for 10 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The oily residue obtained by evaporating the solvent was subjected to column chromatography using silica gel, and eluted with 6% ethyl acetate-hexane to obtain 11.2 g (yield 72%) of the title compound as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
32 (3H, t, J = 7.3Hz), 4.24 (2H, q, J = 7.3Hz), 6.05 (1H, d, J =
15.2Hz), 6.85-7.0 (2H, m), 7.44 (1H, ddd, J = 15.2,7.9,2.
6Hz), 7.55 (2H, d, J = 8.6Hz), 7.61 (2H, d, J = 8.6Hz).

Reference Example 24 (2E, 4E) -5- [4- (Trifluoromethyl) phenyl] -2,4-pentadien-1-ol

[0319]

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In the same manner as in Reference Example 21, ethyl (2
E, 4E) -5- [4- (Trifluoromethyl) phenyl] -2,4-pentadienoate was treated with diisobutylaluminum hydride to give the title compound in quantitative yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
47 (1H, t, J = 5.9Hz), 4.28 (2H, t, J = 5.9Hz), 6.04 (1H, dt, J
= 15.2,5.9Hz), 6.45 (1H, dd, J = 15.2,10.6Hz), 6.57 (1H,
d, J = 15.8Hz), 6.87 (1H, dd, J = 15.8,10.6Hz), 7.47 (2H, d,
J = 8.6Hz), 7.56 (2H, d, J = 8.6Hz).

Reference Example 25 (2E, 4E) -5- [4- (Trifluoromethyl) phenyl] -2,4-pentadienal

[0323]

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In the same manner as in Reference Example 22, (2E, 4E)
-5- [4- (trifluoromethyl) phenyl] -2,
Treatment of 4-pentadien-1-ol with activated manganese dioxide gave the title compound in 92% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 6.
33 (1H, dd, J = 15.2,7.3Hz), 7.0-7.35 (3H, m), 7.60 (2H, d,
J = 8.6Hz), 7.64 (2H, d, J = 8.6Hz), 9.65 (1H, d, J = 7.3Hz).

Reference Example 26 Ethyl (2E, 4E, 6E) -7- [4- (trifluoromethyl) phenyl] -2,4,6-heptatrienoate

[0327]

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In the same manner as in Reference Example 20, (2E, 4E)
-5- [4- (trifluoromethyl) phenyl] -2,
Reaction of 4-pentadienal with triethyl phosphonoacetate afforded the title compound in 95% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
31 (3H, t, J = 7.3Hz), 4.23 (2H, q, J = 7.3Hz), 5.96 (1H, d, J =
15.2Hz), 6.49 (1H, dd, J = 15.2,11.2Hz), 6.72 (1H, dd, J = 1
5.2,10.6Hz), 6.73 (1H, d, J = 15.8Hz), 6.94 (1H, dd, J = 15.
8,10.6Hz), 7.37 (1H, dd, J = 15.2,11.2Hz), 7.51 (2H, d, J =
8.6Hz), 7.58 (2H, d, J = 8.6Hz).

Reference Example 27 (2E, 4E, 6E) -7- [4- (Trifluoromethyl) phenyl] -2,4,6-heptatrien-1-ol

[0331]

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In the same manner as in Reference Example 21, ethyl (2
E, 4E, 6E) -7- [4- (trifluoromethyl)
Phenyl] -2,4,6-heptatrienoate was treated with diisobutylaluminum hydride to give the title compound in 90% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
41 (1H, t, J = 5.3Hz), 4.25 (2H, t, J = 5.3Hz), 5.95 (1H, dt, J
= 15.0,5.3Hz), 6.3-6.5 (3H, m), 6.57 (1H, d, J = 15.2Hz),
6.90 (1H, m), 7.47 (2H, d, J = 8.6Hz), 7.55 (2H, d, J = 8.6H
z).

Reference Example 28 (2E, 4E, 6E) -7- [4- (trifluoromethyl) phenyl] -2,4,6-heptatrienal

[0335]

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In the same manner as in Reference Example 22, (2E, 4E,
6E) -7- [4- (trifluoromethyl) phenyl]
Treatment of -2,4,6-heptatrien-1-ol with activated manganese dioxide gave the title compound in 88% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 6.
23 (1H, dd, J = 15.2,7.9Hz), 6.62 (1H, dd, J = 14.5,11.2Hz),
6.82 (1H, d, J = 15.8Hz), 6.84 (1H, dd, J = 14.5,9.9Hz), 6.
98 (1H, dd, J = 15.8,9.9Hz), 7.19 (1H, dd, J = 15.2,11.2Hz),
7.54 (2H, d, J = 8.6Hz), 7.61 (2H, d, J = 8.6Hz), 9.62 (1H,
d, J = 7.9Hz).

Reference Example 29 4- (2,2,3,3-tetrafluoropropoxy) benzaldehyde

[0339]

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1.90 g of 55% sodium hydride (4
3.5 mmol) was washed with hexane, and suspended in 25 ml of N, N-dimethylacetamide.
5.3 g of 4-hydroxybenzaldehyde (43 mm
ol) was added slowly. When generation of hydrogen gas was stopped, 11.14 g (39 mmol) of 2,2,3,3-tetrafluoropropyl p-toluenesulfonate was added, and the mixture was heated with stirring at 120 ° C for 2 hours and 15 minutes. After cooling the reaction solution, a mixed solvent of benzene and hexane (1: 1) was added and washed with water. After drying, the solvent was distilled off and 8.85 g of the title compound was obtained.
(96% yield) as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 4.
45 (2H, brt, J = 11.9Hz), 6.06 (1H, tt, J = 53.3,4.6Hz), 7.
06 (2H, d, J = 8.7Hz), 7.88 (2H, d, J = 8.7Hz), 9.93 (1H, s).

Reference Example 30 ethyl (2E, 4E) -5- [4- (2,2,3,3
-Tetrafluoropropoxy) phenyl] -2,4-pentadienoate

[0343]

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In the same manner as in Reference Example 23, 4- (2,2,2
Reaction of 3,3-tetrafluoropropoxybenzaldehyde with triethyl phosphonocrotonate gives a melting point of 6
The title compound with 5-66 ° C was obtained in 74% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
31 (3H, t, J = 7.3Hz), 4.23 (2H, q, J = 7.3Hz), 4.37 (2H, br
t, J = 11.9Hz), 5.95 (1H, d, J = 15.2Hz), 6.06 (1H, tt, J = 53.
5,4.6Hz), 6.77 (1H, dd, J = 15.2,9.9Hz), 6.86 (1H, d, J = 1
5.2Hz), 6.91 (2H, d, J = 8.6Hz), 7.42 (1H, dd, J = 15.2,9.9H
z), 7.44 (2H, d, J = 8.6Hz).

Reference Example 31 (2E, 4E) -5- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2,4-pentadien-1-ol

[0347]

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In the same manner as in Reference Example 21, ethyl (2
E, 4E) -5- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2,4-pentadienoate treated with diisobutylaluminum hydride and has a melting point of 95-97 ° C. The compound was obtained in 95% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
39 (1H, t, J = ~ 5Hz), 4.25 (2H, t, J = 5.9Hz), 4.34 (2H, br
t, J = 11.9Hz), 5.94 (1H, dt, J = 15.1,5.9Hz), 6.06 (1H, tt,
J = 53.2,4.8Hz), 6.40 (1H, dd, J = 15.1,10.3Hz), 6.50 (1H,
d, J = 15.5Hz), 6.69 (1H, dd, J = 15.5,10.3Hz), 6.88 (2H, d,
J = 8.7Hz), 7.36 (2H, d, J = 8.7Hz).

Reference Example 32 (2E, 4E) -5- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2,4-pentadienal

[0351]

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In the same manner as in Reference Example 22, ethyl (2
E, 4E) -5- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -2,4-pentadiene-
1-ol is treated with activated manganese dioxide to give a melting point of 53-.
The title compound having a temperature of 55 ° C. was obtained in a 96% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 4.
38 (2H, brt, J = 11.9Hz), 6.06 (1H, tt, J = 52.8,4.6Hz), 6.
25 (1H, dd, J = 15.2,7.9Hz), 6.90 (1H, dd, J = 15.8,9.2Hz),
6.94 (2H, d, J = 8.6Hz), 6.97 (1H, d, J = 15.8Hz), 7.25 (1H, d
d, J = 15.2,9.2Hz), 7.48 (2H, d, J = 8.6Hz), 9.61 (1H, d, J =
7.9Hz).

Reference Example 33 trans-4- (trifluoromethoxy) cinnamaldehyde

[0355]

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570 mg (3.0 mmol) of 4- (trifluoromethoxy) benzaldehyde and 913 mg of (triphenylphosphoranylidene) acetaldehyde (3.
0 mmol) in 7.5 ml of toluene under a nitrogen atmosphere.
The mixture was heated under reflux for 45 minutes. The toluene was distilled off under reduced pressure, and the obtained residue was purified by column chromatography using 20 g of silica gel. Acetic acid-hexane (1:10)
The fraction eluted with the mixed solvent was collected and 387 mg of the title compound
(60% yield) as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 6.
70 (1H, dd, J = 15.8,7.3Hz), 7.29 (2H, d, J = 8.6Hz), 7.47 (1
H, d, J = 15.8Hz), 7.61 (2H, d, J = 8.6Hz), 9.72 (1H, d, J = 7.3
Hz).

IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 1680,
1508, 1259.

Mass spectrum m / e: 216 (M ⁺ ), 215, 18
7, 175, 162, 131 (100%), 119, 101.

Reference Example 34 6- (2,2,3,3-tetrafluoropropoxy) nicotinic acid ethyl ester

[0361]

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840 mg of 55% sodium hydride (1
9.3 mmol) was washed with hexane and suspended in 40 ml of dimethylformamide.
3.00 g of 3,3-tetrafluoropropanol (2
(2.7 mmol) was added slowly. If the generation of hydrogen gas stops, 6-chloronicotinic acid ethyl ester 3.40
g (18.3 mmol) in dimethylformamide 15m
1 was added dropwise at the same temperature over about 30 minutes. After the dropwise addition, the mixture was stirred for 30 minutes, poured into ice water, and extracted with benzene. After drying, the solvent was distilled off, and the obtained oil was purified by column chromatography using silica gel [eluted with a benzene-hexane (1: 1) mixed solvent].
4.42 g (86% yield) of the title compound were obtained as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
40 (3H, t, J = 7.2Hz), 4.39 (2H, q, J = 7.2Hz), 4.81 (2H, br
t, J = 12.6Hz), 6.00 (1H, tt, J = 53.0,4.6Hz), 6.87 (1H, d, J
= 8.6Hz), 8.24 (1H, dd, J = 8.6,2.5Hz), 8.83 (1H, d, J = 2.5H
z).

IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 1717,
1604, 1280, 1119.

Mass spectrum m / e: 281 (M ⁺ ), 236 (100
%), 180, 152, 151, 123, 122, 93.

Reference Example 35 2- (2,2,3,3-tetrafluoropropoxy)-
5- (hydroxymethyl) pyridine

[0367]

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In the same manner as in Reference Example 21, 6- (2,2,2
Ethyl 3,3-tetrafluoropropoxy) nicotinate was reduced with diisobutylaluminum hydride to give the title compound as an oil in 100% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
69 (1H, t, J = 5.8Hz), 4.66 (2H, d, J = 5.8Hz), 4.74 (2H, brt,
J = 12.8Hz), 6.01 (1H, tt, J = 53.1,4.6Hz), 6.84 (1H, d, J =
8.5Hz), 7.69 (1H, dd, J = 8.5,2.5Hz), 8.12 (1H, d, J = 2.5H
z).

Mass spectrum m / e: 239 (M ⁺ ), 210, 18
8, 168, 138 (100%), 109, 108, 78.

Reference Example 36 6- (2,2,3,3-tetrafluoropropoxy) nicotinaldehyde

[0372]

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In the same manner as in Reference Example 22, 2- (2,2,2
3,3-Tetrafluoropropoxy) -5- (hydroxymethyl) pyridine was treated with activated manganese dioxide to give the title compound as an oil in 96% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 4.
86 (2H, brt, J = 12.8Hz), 6.01 (1H, tt, J = 53.3,4.4Hz), 6.
97 (1H, d, J = 8.6Hz), 8.15 (1H, dd, J = 8.6,2.3Hz), 8.65 (1
H, d, J = 2.3Hz).

Mass spectrum m / e: 237 (M ⁺ ), 186, 16
6, 136 (100%), 107, 106, 78.

Reference Example 37 (2E, 4E) -5- [6- (2,2,3,3-tetrafluoropropoxy) -3-biridyl] -2,4-pentadienal

[0377]

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According to Reference Examples 23, 24 and 25, 6-
(2,2,3,3-tetrafluoropropoxy) nicotinaldehyde gave the title compound in 3 steps with a melting point of 88-89 ° C.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 4.
78 (2H, brt, J = 12.6Hz), 6.01 (1H, tt, J = 53.3,4.5Hz), 6.
28 (1H, dd, J = 15.2,7.9Hz), 6.87 (1H, d, J = 8.7Hz), 6.85-
7.0 (2H, m), 7.25 (1H, ddd, J = 15.2,7.8,2.5Hz), 7.85 (1
H, dd, J = 8.7,2.5Hz), 8.23 (1H, d, J = 2.5Hz), 9.63 (1H, d, J =
7.9Hz). IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 1677, 1626, 1591,
1488, 1290, 1120.

Mass spectrum m / e: 289 (M ⁺ ), 260, 18
8, 178, 160, 145, 128, 117, 81, 69 (100%).

Reference Example 38 (2E, 4E) -5- [6-Chloro-3-pyridyl)-
2,4-Pentadienal

[0382]

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According to Reference Examples 23, 24 and 25, the title compound was obtained as an oil from 6-chloronicotinaldehyde in three steps.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 6.
32 (1H, dd, J = 15.2,7.8Hz), 6.96 (1H, d, J = 15.4Hz), 7.05
(1H, dd, J = 15.4,9.8Hz), 7.26 (1H, dd, J = 15.2,9.8Hz), 7.
36 (1H, d, J = 8.3Hz), 7.80 (1H, dd, J = 8.3,2.5Hz), 8.48 (1
(H, d, J = 2.5Hz), 9.66 (1H, d, J = 7.8Hz) Reference Example 39 [4- [4-chlorobenzyl] thio] cyclohexylidene] methyl methyl ether

[0385]

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146 mg of 55% sodium hydride (3.
34 mmol) was washed with hexane, suspended in 18 ml of dimethyl sulfoxide, and stirred at 55 ° C. for 2 hours. The mixture was cooled to room temperature and 1.26 g (3.34 mmol) of methoxymethyltriphenylphosphonium chloride was added.
Further, a solution of 426 mg (1.67 mmol) of 4-[(4-chlorobenzyl) thio] cyclohexanone dissolved in 5 ml of dimethyl sulfoxide was added. Water was added to the mixture and extracted with toluene. After drying, the solvent was distilled off, and the crude product obtained was subjected to column chromatography using 20 g of silica gel to give methylene chloride-hexane (1: 1).
4) Elution with a mixed solvent gave 370 mg (yield 78%) of the title compound as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
2-1.5 (2H, m), 1.7-2.0 (3H, m), 2.0-2.2 (1H, m), 2.5-2.8
(2H, m), 3.53 (3H, s), 3.71 (2H, s), 5.77 (1H, s), 7.27 (4
H, s).

IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 2935,
1689, 1491, 1443, 1123.

Mass spectrum m / e: 282, 157, 124, 109.

Reference Example 40 trans-4-[(4-chlorobenzyl) thio] cyclohexanecarboxaldehyde

[0391]

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[4-[(4-chlorobenzyl) thio] cyclohexylidene] methyl methyl ether 955 mg
(3.4 mmol) dissolved in 20 ml of acetone and 5 m of water
1 ml of 5N hydrochloric acid was added to the mixture. Mix 5
Stirred at 5 ° C for 20 minutes. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. After drying, the solvent was distilled off, and the crude product obtained was subjected to column chromatography using 15 g of silica gel to give methylene chloride-hexane (1: 1).
3) Elution with a mixed solvent gave 865 mg (95% yield) of a 1: 1 mixture of the title compound, the trans isomer and its cis isomer, as an oil.

The product was stirred in 15 ml of a 0.07 N sodium methoxide-methanol solution at room temperature for 2.3 hours. Add 0.2 ml of acetic acid, dilute with ethyl acetate,
Washed with saline. After drying, the solvent was distilled off to obtain 865 mg of a 4: 1 mixture of the title trans form and the cis isomer as a solid. Recrystallized from an ether-hexane mixed solvent,
220 mg of the title trans form having a melting point of 44-46 ° C. were obtained.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
2-1.5 (4H, m), 1.9-2.15 (2H, m), 2.15-2.35 (1H, m), 2.35
-2.55 (1H, m), 3.73 (2H, s), 7.27 (5H, s), 9.61 (1H, s) The cis isomers are δ3.67 (2H, s) and δ9.64 (1H, s) Signal.

IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 2927,
1732, 1493, 1448, 1092.

Mass spectrum m / e: 268, 240, 127, 125,
110.

Reference Example 41 4-chlorobenzyl trans-4-[(1E, 3E)
-4- [4- (trifluoromethyl) phenyl] -1,
3-butadienyl] cyclohexyl sulfide

[0398]

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50% of 55% sodium hydride (1.1 mg)
4 mmol) was washed with hexane, suspended in 7 ml of dimethyl sulfoxide, and stirred at 55 ° C. for 2.5 hours. The mixture was cooled to room temperature and [(E) -4- (trifluoromethyl) cinnamyl] triphenylphosphonium chloride 607
mg (1.26 mmol) was added. Further, 170 mg (0.63 mmol) of trans-4-[(4-chlorobenzyl) thio] cyclohexanecarboxaldehyde was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was diluted with toluene and washed with water and brine. After drying, the solvent was distilled off, and the crude product obtained was subjected to column chromatography using 5 g of silica gel to give methylene chloride-hexane (1: 1).
2) Elution was carried out with a mixed solvent. The eluate was recrystallized from hexane to give 86 mg of the title compound having a melting point of 142-144 ° C
(Yield 31%) was obtained.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
1-1.3 (2H, m), 1.3-1.5 (2H, m), 1.7-2.0 (2H, m), 2.0-2.2
(2H, m), 2.64 (1H, tt, J = 12,4Hz), 3.74 (2H, s), 5.81 (1H,
dd, J = 15,7Hz), 6.20 (1H, dd, J = 15,10Hz), 6.47 (1H, d, J = 1
6Hz), 6.81 (1H, dd, J = 16,10Hz), 7.29 (4H, s), 7.46 (2H,
d, J = 8 Hz), 7.55 (2H, d, J = 8 Hz).

IR spectrum ν _max (KBr) cm ⁻¹ : 1641,
1612, 1490, 1326, 1167, 1127, 1069.

Mass spectrum m / e: 436, 417, 403, 311,
277, 235, 159, 125.

Reference Example 42 4-chlorobenzyl trans-4-[(1E, 3E)
-4- [4- (trifluoromethyl) phenyl] -1,
3-butadienyl] cyclohexyl sulfoxide

[0404]

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4-Chlorobenzyl trans-4-
[(1E, 3E) -4- [4- (trifluoromethyl)
Phenyl] -1,3-butadienyl] cyclohexyl
211 mg (0.48 mmol) of sulfide was dissolved in 20 ml of methylene chloride, 104 mg (0.48 mmol) of m-chloroperbenzoic acid (purity 80%) was added at 0 ° C., and the mixture was stirred for 5 minutes. An aqueous solution of sodium sulfite and ethyl acetate were added, and the organic layer was washed with aqueous sodium bicarbonate and brine. After drying, the solvent was distilled off, and the obtained crude product was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain 168 mg (yield 77%) of the title compound having a melting point of 212-214 ° C.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
1-1.3 (2H, m), 1.5-1.8 (2H, m), 1.9-2.3 (5H, m), 2.42 (1
H, tt, J = 12,4Hz), 3.87 (1H, d, J = 13Hz), 3.97 (1H, d, J = 13H
z), 5.80 (1H, dd, J = 15,7Hz), 6.22 (1H, dd, J = 15,10Hz),
6.48 (1H, d, J = 16Hz), 6.80 (1H, dd, J = 16,10Hz), 7.25 (2H,
d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.45 (2H, d, J = 8Hz), 7.55
(2H, d, J = 8Hz).

The IR spectrum ν _max (KBr) cm ⁻¹ : 1612,
1492, 1325, 1168, 1128, 1069.

Mass spectrum m / e: 452, 436, 327, 278,
277, 159, 125.

Reference Example 43 trans-1- (acetylthio) -4-[(1E, 3
E) -4- [4- (Trifluoromethyl) phenyl]-
1,3-Butadien-1-yl] cyclohexane

[0410]

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4-Chlorobenzyl trans-4-
[(1E, 3E) -4- [4- (trifluoromethyl)
Phenyl] -1,3-butadienyl] cyclohexyl
178 mg (0.39 mmol) of sulfoxide was mixed with tetrahydrofuran-acetonitrile (8: 3) mixed solvent 11
168 mg of 2,6-lutidine (1.57
mmol). While stirring at 0 ° C., 165 mg (0.79 mmol) of trifluoroacetic anhydride was added.
After 3 minutes, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The oily residue obtained after evaporating the solvent was diluted with 10 ml of methylene chloride.
At 0 ° C. and 119 mg of triethylamine (1.1 mg).
7 mmol) and then 62 mg of acetyl chloride
(0.79 mmol) was added. One hour later, the reaction solution was diluted with ethyl acetate, and washed with an aqueous solution of sodium bicarbonate and brine. After drying, the solvent was distilled off, and the crude product obtained was subjected to column chromatography using 5 g of silica gel, eluted with a mixed solvent of methylene chloride-hexane (1: 1), and further subjected to a rover column (GroβeB, ethyl acetate). -Hexane (1: 1
9) (mixed solvent) to give 98 mg (yield 70%) of the title compound having a melting point of 113-115 ° C.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
2-1.5 (4H, m), 1.7-1.9 (2H, m), 2.0-2.2 (3H, m), 2.31 (3
H, s), 3.37 (1H, tt, J = 12,4Hz), 5.82 (1H, dd, J = 15,7Hz),
6.20 (1H, dd, J = 15,10Hz), 6.47 (1H, d, J = 16Hz), 6.81 (1H,
dd, J = 16,10Hz), 7.45 (2H, d, J = 8Hz), 7.54 (2H, d, J = 8H
z).

IR spectrum ν _max (KBr) cm ^-1 : 1688,
1613, 1326, 1157, 1117, 1068.

Mass spectrum m / e: 354, 335, 311, 277,
235, 159.

Reference Example 44 3- [4- (trifluoromethyl) phenyl] -2-propyn-1-ol

[0416]

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4-Bromo-α, α, α-trifluorotoluene (5.0 g, 22 mmol) and propargyl alcohol (1.25 g, 22 mmol) were added to diethylamine 50.
and then added with 80 mg (0.11 mmol) of bis (triphenylphosphine) palladium (II) chloride and 40 mg (0.22 mmol) of copper (I) iodide.
Stirred at 0 ° C. for 35 minutes. Bis (triphenylphosphine) palladium (II) chloride 40 mg (0.06 mmol)
1) was added, and the mixture was further stirred for 35 minutes. After cooling to room temperature, the mixture was diluted with benzene, filtered and the filtrate was washed with water. After drying, the solvent was distilled off, and the crude product obtained was subjected to column chromatography using 50 g of silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (3:17) to give 2.21 g of the title compound (yield). (50%) as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
8 (1H, br, O H ), 4.52 (2H, s), 7.54 (2H, d, J = 9Hz), 7.57 (2
H, d, J = 9Hz).

The IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 3610,
1618, 1324, 1172, 1133, 1069 1019, 844 Mass spectrum m / e: 200, 183, 171, 151, 131.

Reference Example 45 3- [4- (trifluoromethyl) phenyl] -2-propynal

[0421]

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2.21 g of 3- [4- (trifluoromethyl) phenyl] -2-propyn-1-ol (11.0 g)
mmol) was dissolved in 20 ml of methylene chloride, and D
7.43 g of ess-Martin reagent (17.5 mmol
l) was added over 1.7 hours. Benzene was added, insolubles were removed by filtration, and the filtrate was concentrated to give the title compound 1.
83 g (84% yield) were obtained as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 7.
68 (2H, d, J = 9Hz), 7.71 (2H, d, J = 9Hz), 9.45 (1H, s).

IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 2197,
1664, 1324, 1175, 1138.

Mass spectrum m / e: 198, 197, 170, 151,
120.

Reference Example 46 Ethyl (E) -5- [4- (trifluoromethyl) phenyl] -2-pentene-4-inoate

[0427]

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181 mg of 55% sodium hydride (4.
After washing with hexane, the suspension was suspended in 1,2-dimethoxyethane (10 ml) and triethyl 4-phosphonoacetate (1.02 g) was stirred under a nitrogen atmosphere at 0 ° C.
(4.54 mmol) was added. After 20 minutes, 3- [4-
Trifluoromethyl) phenyl] -2-propynal 5
00 mg (2.52 mmol) was added, and the mixture was stirred for 20 minutes. The reaction solution was diluted with ethyl acetate, ice was added, and the organic layer was washed with water. The crude product obtained by evaporating the solvent was subjected to column chromatography using 15 g of silica gel,
Elution with benzene gave 488 mg of the title compound (yield 72
%) As an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
32 (3H, t, J = 7Hz), 4.25 (2H, q, J = 7Hz), 6.35 (1H, d, J = 16H
z), 6.97 (1H, d, J = 16 Hz), 7.5-7.7 (4H, m).

The IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 1712,
1622, 1316, 1174, 1134.

Mass spectrum m / e: 268, 240, 223, 195,
183, 175.

Reference Example 47 (E) -5- [4- (Trifluoromethyl) phenyl]
-2-penten-4-yn-1-ol

[0433]

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Ethyl (E) -5- [4- (trifluoromethyl) phenyl] -2-pentene-4-inoate (480 mg, 1.79 mmol) was dissolved in toluene (4 ml), and the mixture was stirred at 0 ° C. and stirred at 1.5 M. 2.38 ml of diisobutylaluminum hydride-toluene solution (3.5
8 mmol) was added. After 10 minutes, ice was added, and insolubles were removed by filtration using Celite. The organic layer was dried, and the solvent was distilled off. The crude product obtained was subjected to column chromatography using 15 g of silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (3:17) to give the title compound 35
3 mg (87% yield) was obtained as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
60 (1H, br, O H ), 4.31 (2H, br), 5.99 (1H, d, J = 16Hz), 6.40
(1H, dt, J = 16,5Hz), 7.54 (2H, d, J = 9Hz), 7.57 (2H, d, J = 9H
z).

Reference Example 48 (E) -5- [4- (Trifluoromethyl) phenyl]
-2-pentene-4-enal

[0437]

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(E) -5- [4- (Trifluoromethyl) phenyl] -2-penten-4-yn-1-ol (350 mg, 1.56 mmol) was added to methylene chloride (4 ml).
, And 3.5 g of activated manganese dioxide was added, followed by stirring at room temperature for 30 minutes. The solid was removed by filtration, and the filtrate was concentrated and subjected to column chromatography using 10 g of silica gel, eluting with a mixed solvent of ethyl acetate-hexane (1:24) to give 245 mg (yield 70%) of the title compound as an oil. Obtained.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 6.
58 (1H, dd, J = 16.8Hz), 6.82 (1H, d, J = 16Hz), 7.63 (4H, s),
9.65 (1H, d, J = 8Hz).

IR spectrum ν _max (CHCl ₃ ) cm ^-1 : 1670,
1325, 1132, 1119, 1107, 1072, 845 Mass spectrum m / e: 224, 196, 195, 175, 170, 146.

Reference Example 49 Methyl (Z) -4-chloro-β- (trifluoromethyl) cinnamate

[0442]

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Bis (2,2,2-trifluoroethyl)
(Methoxycarbonylmethyl) phosphonate 150mg
(0.47 mmol) was dissolved in 10 ml of tetrahydrofuran, and 0.54 potassium hexamethyldisilazide-toluene solution 0.94 was stirred in a nitrogen stream at −78 ° C.
ml (0.47 mmol) was added dropwise. Then, 622 mg (2.36 mmol) of 18-crown-6 was added and 2
After stirring for 0 minutes, a solution of 98 mg (0.47 mmol) of 4'-chloro-2,2,2-trifluoroacetophenone dissolved in 1 ml of tetrahydrofuran was added. The reaction solution was slowly raised to room temperature, an aqueous saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The crude product obtained by distilling off the solvent was purified by column chromatography on silica gel (eluted with 4% ethyl acetate-hexane) to give 89 mg of the title compound (70% yield, about 1% of the (E) -isomer). / 10 contained) as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.
85 (3H, s), 6.34 (1H, s), 7.34 (2H, d, J = 8.6Hz), 7.39 (2H,
d, J = 8.6Hz).

Reference Example 50 (Z) -4-Chloro-β- (trifluoromethyl) cinnamaldehyde

[0446]

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According to Reference Examples 21 and 22, methyl
The title compound was obtained as an oil in two steps from (Z) -4-chloro-β- (trifluoromethyl) cinnamate in a yield of 8
Obtained at 1%.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 6.
36 (1H, d, J = 7.3Hz), 7.38 (2H, d, J = 8.6Hz), 7.44 (2H, d, J =
8.6Hz), 10.21 (1H, dq, J = 7.3, 2.0Hz).

Reference Example 51 Methyl (2E, 4Z) -5- (4-chlorophenyl)
-6,6,6-trifluoro-2,4-hexadienoate

[0450]

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In the same manner as in Reference Example 23, the reaction of (Z) -4-chloro-β- (trifluoromethyl) cinnamaldehyde with trimethyl phosphonocrotonate gave
The title compound was obtained as an oil in a yield of about 90% (separated and purified by column chromatography).

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.
81 (3H, s), 6.15 (1H, d, J = 15.2Hz), 6.59 (1H, d, J = 11.9H
z), 7.31 (2H, d, J = 8.6Hz), 7.38 (1H, d, J = 8.6Hz), 7.78 (1H
H, ddq, J = 15.2,11.9,2.0Hz).

Reference Example 52 (2E, 4Z) -5- (4-Chlorophenyl) -6
6,6-trifluoro-2,4-hexadienal

[0454]

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According to Reference Examples 21 and 22, methyl (2
E, 4Z) -5- (4-Chlorophenyl) -6,6,6
The title compound was obtained in two steps from -trifluoro-2,4-hexadienoate in 71% yield as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 6.
37 (1H, dd, J = 15.2,7.3Hz), 6.72 (1H, d, J = 11.9Hz), 7.33
(2H, d, J = 8.6Hz), 7.40 (2H, d, J = 8.6Hz), 7.64 (1H, ddq, J =
15.2,11.9,2Hz), 9.74 (1H, d, J = 7.3Hz).

Reference Example 53 2-methyl-2-[(trans-2-phenyl-1,3
-Dioxan-5-yl) thio] -4 '-(trifluoromethyl) propiophenone

[0458]

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619 mg of 2-bromo-2-methyl-4 '-(trifluoromethyl) propiophenone (2.10
mmol) in 3.8 ml of dimethylformamide, and stirring at room temperature under a nitrogen atmosphere, 0.44 ml of a 28% sodium methoxide-methanol solution (2.10 mmol).
mmol). After 30 minutes, water was added, and the mixture was extracted with ethyl acetate. After distilling off the solvent, 860 mg of the title compound (yield ~
100%) as a solid.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
61 (6H, s), 4.42 (1H, tt, J = 11.6,5.0Hz), 3.64 (2H, t, J = 1
1.6Hz), 4.12 (2H, dd, J = 11.6,5.0Hz), 5.38 (1H, s), 7.3-
7.5 (5H, m), 7.68 (2H, d, J = 8.2Hz), 8.19 (2H, d, J = 8.2H
z).

Reference Example 54 (RS) -3-Methyl-3-[(trans-2-phenyl-1,3-dioxan-5-yl) thio] -1- (1
H-1,2,4-triazol-1-yl) -2-butanol

[0462]

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2-Methyl-2-[(trans-2-phenyl-1,3-dioxan-5-yl) thio] -4'-
(Trifluoromethyl) propiophenone 680mg
(1.66 mmol), 547 mg (2.49 mmol) of trimethylsulfoxonium iodide, 381 mg (6.79 mmol) of potassium hydroxide, and 264 mg (3.82 mmol) of 1,2,4-triazole in 5.7 ml of t-butanol. At 80 ° C. for 6 hours. After cooling, the mixture was partitioned between chloroform and water, the chloroform layer was separated, and the solvent was distilled off after drying. The obtained oil was subjected to column chromatography using silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (1: 1) to give the title compound (605 m).
g (74% yield) as a foam.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
38 (3H, s), 1.39 (3H, s), 3.55-3.8 (3H, m), 4.33 (1H, m),
4.54 (1H, m), 5.02 (2H, s), 5.37 (1H, s), 5.44 (1H, s), 7.
3-7.6 (5H, m), 7.73 (1H, s), 7.94 (1H, s).

Reference Example 55 (RS) -3-[(1,3-dihydroxy-2-propyl) thio] -3-methyl-2- [4- (trifluoromethyl) phenyl] -1- (1H-1 , 2,4-Triazol-1-yl) -2-butanol

[0466]

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In the same manner as in Reference Example 2, (RS) -3-methyl-3-[(trans-2-phenyl-1,3-dioxan-5-yl) thio] -1- (1H-1,2 , 4-
Treatment of triazol-1-yl) -2-butanol with HCl in methanol provided the title compound as a foam.

NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.
30 (3H, s), 1.42 (3H, s), 3.35 (1H, m), 3.55-3.8 (3H, m),
3.96 (1H, dd, J = 10.9,5.4Hz), 4.83 (3H, s), 5.26 (1H, d, J =
14.6Hz), 5.34 (1H, d, J = 14.6Hz), 7.53 (2H, d, J = 8.3Hz),
7.70 (1H, s), 7.75 (2H, d, J = 8.3Hz), 8.26 (1H, s).

Reference Example 56 2- (p-toluenesulfonyloxy) -1,3-propanediol

[0470]

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5.00 g of cis-2-phenyl-4- (p-toluenesulfonyloxy) -1,3-dioxane was dissolved in 50 ml of methanol, 5 ml of a 4N HCl dioxane solution was added, and the mixture was stirred at room temperature for 2 hours. NaHCO ₃
After adding 3.5 g of powder and stirring for 10 minutes, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained oil was subjected to column chromatography using silica gel, and eluted with ethyl acetate to give the title compound (3.70 g, yield 100%) as an oil.

NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 2.
40 (3H, s), 3.30 (2H, s), 3.73 (4H, d, J = 4.5Hz), 4.55 (1H,
quintet, J = 4.5Hz), 7.33 (2H, d, J = 8Hz), 7.84 (2H, d, J = 8H
z).

Reference Example 57 cis-4- (p-toluenesulfonyloxy) -2-
[(1E, 3E) -4- [4- (trifluoromethyl)
Phenyl] -1,3-butadien-1-yl] -1,3
-Dioxane

[0474]

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2- (p-toluenesulfonyloxy)-
1,3-propanediol 200 mg (0.81 mmol
l) and (2E, 4E) -5- [4- (trifluoromethyl) phenyl] -2,4-pentadienal 206 mg
(0.91 mmol) was dissolved in 4.5 ml of methylene chloride, 15 mg of p-toluenesulfonic acid and 0.8 g of molecular sieves 4A were added, and the mixture was stirred at 0 ° C. for 1 hour. After adding aqueous sodium bicarbonate to the reaction solution and stirring for 10 minutes, the molecular sieves were removed by filtration and extracted with methylene chloride. The oil obtained by distilling off the solvent was separated by preparative thin-layer chromatography on silica gel (developing solvent: 20% ethyl acetate-hexane), and the less polar trans isomer 107 was obtained.
mg (29% yield) of the more polar cis isomer 153
mg (42% yield) were each obtained as an oil.

The NMR spectrum of the cis isomer (270 MHz, CD
Cl ₃ ) δppm: 2.45 (3H, s), 3.99 (2H, brd, J = 13.2Hz), 4.19
(2H, br d, J = 13.2Hz), 4.45 (1H, br s), 5.09 (1H, d, J = 4.6
Hz), 5.82 (1H, dd, J = 15.2,4.6Hz), 6.57 (1H, dd, J = 15.2,1
0.5Hz), 6.63 (1H, d, J = 15.2Hz), 6.82 (1H, dd, J = 15.2,10.
5Hz), 7.36 (2H, d, J = 8.6Hz), 7.48 (2H, d, J = 8.6Hz), 7.56
(2H, d, J = 8.6Hz), 7.85 (2H, d, J = 8.6Hz) Test Example 1 Candida albicans 4 ~ 9 × 1
0 to ^six mice inoculated (10 animals per group), 1,4,2
Four hours later, 20 mg / kg of the drug was orally administered and 21 days after infection.
The survival rate by day was determined. Table 2 shows the results of comparison between the compound (I) of the present invention and commercially available fluconazole. From these results, it is clear that compound (I) exhibits excellent antifungal activity.

Table 2: Compound viability% 14 days 21 days Example 2 100 100 11 100 100 15 100 100 16 100 100 18 100 100 100 21 100 60 30 100 100 32 100 100 35 100 100 37 100 100 Fluconazole 70 60 Formulation Example 1 Capsule Compound of Example 15 or 16 50 mg Lactose 128 mg Corn Starch 70 mg Magnesium stearate 2 mg 250 mg After mixing the powder of the above formulation and passing through a 60 mesh sieve, the powder is mixed with 250 mg of No. 3 gelatin capsule. Into a capsule.

Formulation Example 2 Tablets Compound of Example 15 or 16 50 mg Lactose 126 mg Corn starch 23 mg Magnesium stearate 1 mg 200 mg The powder of the above formulation was mixed, wet-granulated using corn starch paste, dried, and then pressed into a tableting machine. Tableting with 1
Tablets 200 mg tablets. The tablets can be sugar-coated as needed.

[0479]

The compound of the present invention having the general formula (I) or a pharmaceutically acceptable salt thereof has excellent antifungal activity and is useful as an antifungal agent.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 31/535 A61K 31/535 C07D 401/12 249 C07D 401/12 249 401/14 205 401/14 205 207 207 239 239 239 403 / 12 205 403/12 205 207 207 239 239 405 249/249 405 405/12 249 405/14 205 405/14 205 207 207 207 211 211 213 213 239 239 249 249 409 409/12 249 409/12 249 409/14 205 409 / 14 205 207 207 207 211 211 239 239 249 249 411/12 411/12 411/14 411/14 413/12 249 413/12 249 413/14 213 413/14 213 249 249 (72) Inventor Toshiyuki Konosu Shinagawa, Tokyo 1-58, Hiromachi, Ward Sankyo Co., Ltd. (72) Inventor Atsushi Somada 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Takeo Miyaoka 1-258, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Invention Person Hiroshi Yasuda 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (56) References JP-A-5-4975 (JP, A) JP-A-5-230038 (JP, A) JP-A-5 −194429 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 249/08 A61K 31/41 A61K 31/44 A61K 31/445 A61K 31/505 A61K 31/535 C07D 401 / 14 C07D 401/12 C07D 403/12 C07D 405/12 C07D 405/14 C07D 409/12 C07D 409/14 C07D 411/12 C07D 411/14 C07D 413/12 C07D 413/14 CA (STN) REGISTRY (STN)

Claims (26)

(57) [Claims] (1) Formula (1) Or a pharmacologically acceptable salt thereof. Where:
Ar ¹ represents a phenyl group or a phenyl group having 1 to 3 substituents (the substituents represent a halogen atom or a trifluoromethyl group), and Ar ² represents phenyl, a 5- to 6-membered aromatic heterocyclic group ( The aromatic heterocyclic group has at least one nitrogen, oxygen or sulfur atom) or a phenyl group having 1 to 3 substituents or a 5- to 6-membered aromatic heterocyclic group (the substituent is a lower alkyl group; A lower alkoxy group, a halogen atom, a lower alkyl group substituted with a halogen atom, a lower alkoxy group substituted with a halogen atom, a nitro group, a cyano group, a —S (O) _m R ⁶ group (R ⁶ : substituted with a halogen atom M represents 0, 1 or 2) or -NHCOR ⁷ (R ⁷ represents a lower alkyl group), and the aromatic heterocyclic group is a nitrogen, oxygen, sulfur atom Has at least one
R ⁰ represents a hydrogen atom or a lower alkyl group; R ¹ represents a lower alkyl group; R ² , R ³ , R ⁴ and R ⁵ may be the same or different and represent a hydrogen atom, a lower alkyl group or a halogen atom; R ² , R ³ , R ⁴ and R ⁵ each independently represent the same or different groups when n represents 0, 1 or 2, wherein q and s each represent a substituted lower alkyl group; p represents 0 or 1, q, r and s represent 0, 1 or 2, and A represents a 4- to 7-membered aliphatic carbocyclic group having 4 to 7 carbon atoms or at least nitrogen, oxygen and sulfur atoms. 4 to have one
Shows a 7-membered aliphatic heterocyclic group. 2. The triazole compound according to claim 1, wherein Ar ¹ is a phenyl group having ¹ to 3 substituents (the substituents represent a halogen atom or a trifluoromethyl group) or a pharmaceutically acceptable salt thereof. Salt. 3. The triazole compound according to claim 1, wherein Ar ¹ is a phenyl group having ¹ to 2 substituents, wherein the substituent represents a fluorine atom, a chlorine atom or a trifluoromethyl group. Above acceptable salts. 4. Ar ² has a phenyl group, a 5- to 6-membered aromatic heterocyclic group (the aromatic heterocyclic group has at least one nitrogen, oxygen or sulfur atom) or 1 to 3 substituents. A phenyl group or a 5- to 6-membered aromatic heterocyclic group (the substituent is a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom, a lower alkoxy group substituted with a halogen atom, a nitro group, a cyano group or —S (O) _m R ⁶ group (R ⁶ is a lower alkyl group optionally substituted with a halogen atom; m represents 0, 1 or 2), and the aromatic heterocyclic group is nitrogen, oxygen, 4. The triazole compound according to claim 1, which has at least one sulfur atom, or a pharmaceutically acceptable salt thereof. Wherein Ar ² is a phenyl group, a phenyl having 5-6 membered aromatic Hajime Tamaki (said aromatic heterocyclic group nitrogen, oxygen, sulfur atom one have a) or 1 to 3 substituents Or a 5- or 6-membered aromatic heterocyclic group (the substituent is a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom, a lower alkoxy group substituted with a halogen atom, a nitro group, a cyano group or- S (O) _m R ⁶ group (R ⁶ : a lower alkyl group optionally substituted by a halogen atom;
m: 0, 1 or 2), and the aromatic heterocyclic group has one nitrogen, oxygen or sulfur atom).
Or a pharmacologically acceptable salt thereof. 6. Ar ² is a phenyl group, a 5- to 6-membered aromatic heterocyclic group (the aromatic heterocyclic group has one nitrogen or sulfur atom) or a phenyl group having 1 to 2 substituents. A 5- to 6-membered aromatic heterocyclic group (the substituent is a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom, a lower alkoxy group substituted with a halogen atom,
A nitro group, a cyano group or a —S (O) _m R ⁶ group (R ⁶ : a lower alkyl group optionally substituted by a halogen atom; m:
0, 1 or 2), wherein the aromatic heterocyclic group has one nitrogen or sulfur atom) or a pharmacologically acceptable salt thereof. 7. Ar ² is a phenyl group having a phenyl or pyridyl group or one to two substituents, a pyridyl group or a thienyl group (the substituent is a lower alkyl group, a halogen atom, a lower substituted with a halogen atom Alkyl group,
Substituted lower alkoxy group a halogen atom, a nitro group, a cyano group or a -S (O) _m R ⁶ group (R ^6: a lower alkyl group which may be substituted with a halogen atom; m: 0, 1 or 2 The triazole compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. 8. The triazole compound according to claim 1, wherein R ⁰ is a hydrogen atom, a methyl group, an ethyl group or a propyl group, or a pharmaceutically acceptable salt thereof. 9. The triazole compound according to claim 1, wherein R ⁰ is a hydrogen atom, a methyl group or an ethyl group, or a pharmaceutically acceptable salt thereof. 10. The triazole compound according to claim 1, wherein R ⁰ is a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. 11. The triazole compound according to claim 1, wherein R ¹ is a methyl group, an ethyl group or a propyl group, or a pharmaceutically acceptable salt thereof. 12. The triazole compound according to claim 1, wherein R ¹ is a methyl group or an ethyl group, or a pharmaceutically acceptable salt thereof. 13. The method according to claim 1, wherein R ¹ is a methyl group.
Or a pharmacologically acceptable salt thereof. 14. The method according to claim 1, wherein R ² , R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by a fluorine or chlorine atom.
Or a pharmacologically acceptable salt thereof. 15. A methyl, ethyl or propyl group in which R ² , R ³ , R ⁴ and R ⁵ are the same or different and are substituted with a hydrogen atom, a methyl group, an ethyl group or a propyl group or a fluorine or chlorine atom. Certain claims 1 to 1
3. The triazole compound or a pharmacologically acceptable salt thereof. 16. A method according to claim 1, wherein R ² , R ³ , R ⁴ and R ⁵ are the same or different and are each a hydrogen atom, a methyl group or an ethyl group or a methyl or ethyl group substituted by a fluorine or chlorine atom. Or a pharmacologically acceptable salt thereof. 17. The triazole compound according to claim 1, wherein R ² , R ³ , R ⁴ and R ⁵ are the same or different and each is a hydrogen atom or a methyl group or a methyl group substituted with a fluorine atom. Above acceptable salts. 18. The triazole compound according to claim 2, wherein n is 0, 1 or 2, or a pharmacologically acceptable salt thereof. 19. The triazole compound according to claim 1, wherein n is 0, or a pharmacologically acceptable salt thereof. 20. The method according to claim 2, wherein p is 0 or 1.
Or a pharmacologically acceptable salt thereof. 21. The triazole compound according to claim 2, wherein q, r and s are 0, 1 or 2, or a pharmacologically acceptable salt thereof. 22. A is a 5- to 6-membered aliphatic carbocyclic group having 5 to 6 carbon atoms or a 4- to 6-membered aliphatic heterocyclic group having at least one nitrogen, oxygen and sulfur atom. Or a pharmacologically acceptable salt thereof. 23. A is a 5- to 6-membered aliphatic carbocyclic group having 5 to 6 carbon atoms or a 4- to 6-membered aliphatic heterocyclic group having 1 to 2 nitrogen, oxygen and sulfur atoms. 1 to 21 triazole compounds or pharmacologically acceptable salts thereof. (24) A is cyclohexane, piperidine, 1,
22. The triazole compound according to claim 1, which is a 3-dioxane or 1,3-dithiane ring, or a pharmacologically acceptable salt thereof. 25. 2- (2,4-difluorophenyl)-
3-[[2- [2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,4-triazol- 1-yl) -2-butanol, 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[2- [4- (trifluoromethoxy) phenyl] vinyl] -1,3-dioxan-5-yl] thio] -2-butanol, 2- (2,4-difluorophenyl) -1- (1H −
1,2,4-triazol-1-yl) -3-[[2-
[4- [4- (trifluoromethyl) phenyl] -1,
3-butadien-1-yl] -1,3-dioxane-5
-Yl] thio] -2-butanol, 2- (2,4-difluorophenyl) -3-[[2-
[4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -1,3-butadien-1-yl]-
1,3-dioxan-5-yl] thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butano-
2- (2,4-difluorophenyl) -3-[[2-
[4- (4-Chlorophenyl) -4,4,4-trifluoro-1,3-pentadien-1-yl] -1,3-dioxan- 5 -yl] thio] -1- (1H-1,2 , 4
-Triazol-1-yl) -2-butanol, 2- (2,4-difluorophenyl) -3-[[1-
[(4- (trifluoromethoxy) cinnamoyl] piperidin-4-yl] thio] -1- (1H-1,2,4-
Triazol-1-yl) -2-butanol, 2- (2,4-difluorophenyl) -3-[[1-
(4-Nitrocinnamoyl) piperidin-4-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol, 2- (2,4-difluoro Phenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[1-
[5- [4- (trifluoromethoxy) phenyl]-
2,4-pentadienoyl] piperidin-4-yl] thio] -2-butanol, 3-methyl-1- (1H-1,2,4-triazol-
1-yl) -2- [4- (trifluoromethyl) phenyl] -3-[[2- [4-[(trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1,3 −
Dioxan-5-yl] thio] -2-butanol, 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[4- [4- (trifluoromethylthio) phenyl]-
1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol, 3-[[2- [4- [4- (2,2,3,3 -Tetrafluoropropoxy) phenyl] -1,3-butadiene-
1-yl] -1,3-dioxan-5-yl] thio]-
1- (1H-1,2,4-triazol-1-yl)-
2- [4- (trifluoromethyl) phenyl] -2-butanol, 1- (1H-1,2,4-triazol-1-yl)-
2- [4- (trifluoromethyl) phenyl] -3-
[[2- [4- [4- (trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol, 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[4- [4- (trifluoromethylsulfinyl) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol, 2- (2, 4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[4-
[4- (trifluoromethyl) phenyl] -1,3-butadien-1-yl] cyclohexyl] thio] -2-butanol, 2- (2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[6- [4- (trifluoromethyl) phenyl] -1,
3,5-hexatrien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol, 2- (2,4-difluorophenyl) -3-methyl-1
-(1H-1,2,4-triazol-1-yl) -3
-[[2- [4- [4- (trifluoromethyl) phenyl] -1,3-butadien-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol or 2 -(2,4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[2-
[4- [4- (trifluoromethyl) phenyl] -1-
Buten-3-yn-1-yl] -1,3-dioxane-
5-yl] thio] -2-butanol or a pharmacologically acceptable salt thereof. 26. An antifungal agent comprising the triazole compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.