JPH08333350A - Triazole antifungal agent - Google Patents

Abstract

PURPOSE: To obtain a triazole antifungal agent excellent in antifungal activity, useful for human and animal nosomycosis. CONSTITUTION: A compound of formula I [Ar<1> is phenyl, a 5-membered to 6-membered aromatic heterocyclic group (the heterocyclic group contains at least one N, O or S), phenyl containing one to three substituent groups, etc.; R<0> is H or a lower alkyl; R<1> is a lower alkyl; R<2> to R<5> are each H, a lower alkyl or a halogen-substituted lower alkyl with the proviso that R<2> to R<5> are each independently the same or different when (q) and (s) are each 2; (n) is 0, 1 or 2; (p) is 0 or 1; (q), (r) or (s) are each 0, 1 or 2; A is a 4-7C 4-membered to 7-membered ring aliphatic carbon ring group, etc.] or its pharmacologically acceptable salt such as a compound of formula II. The compound of formula I, for example, is obtained by reacting an epoxide compound of formula III with mercaptan or its acetic acid ester derivative in the presence of a base to give a compound in which R<0> is H and (n) is 0 in the compound of formula I.

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 61-85369 discloses an equation (1).

[0003]

Embedded image

It is described that the analogs of the compounds of the present invention in which the moiety corresponding to is an alkyl group, a cycloalkylalkyl group or a cycloalkyl group have antifungal activity.

[0005]

However, the present inventors have conducted diligent studies to find out more excellent antifungal agents, found that the compounds of the present invention are excellent antifungal agents, and completed the present invention. I arrived.

[0006]

The present invention is a compound having the formula (1) or a pharmaceutically acceptable salt thereof.

[0007]

Embedded image

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- or 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- or 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 Base,
Shows the:;: (0, 1 or 2 indicating the R ⁶ m halogenated lower alkyl group which may be substituted by atoms) or -NHCOR ⁷ group (R ⁷ represents a lower alkyl group -S (O) _m R ⁶ group ),
The aromatic heterocyclic group has at least one nitrogen, oxygen or 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 each represents a hydrogen atom, a lower alkyl group or a lower alkyl group substituted with a halogen atom. When q and s are 2, R ² , R ³ , R
⁴ and R ⁵ each independently represent the same or different group. 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-mentioned 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.

The lower alkoxy group is, for example, methoxy,
It is an ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy group, preferably a methoxy, ethoxy, propoxy or isopropoxy group.

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

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

At least 1 nitrogen, oxygen and sulfur atom of A
Examples of the 4- to 7-membered aliphatic heterocyclic group having a group include 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, a tetrahydrooxazine or a 1,3 dithiane ring.

Preferred compounds of formula (1) are those wherein 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 group, 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, (tri A fluoromethyl) furyl, chlorothienyl or (trifluoromethyl) thienyl group, preferably 4-fluorophenyl, 4-
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, 4- A compound which is a (trifluoromethoxy) phenyl or a 4- (2,2,3,3-tetrafluoropropoxy) phenyl group.

Compounds in which R ⁰ is a hydrogen atom, a methyl, ethyl or propyl group, preferably a hydrogen atom, a methyl or ethyl group, and particularly preferably a hydrogen atom or a methyl group. Compounds in which 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 each is a hydrogen atom, methyl, ethyl, propyl or trifluoromethyl, preferably a hydrogen atom, methyl or trifluoromethyl group. , Particularly preferably a compound which is a hydrogen atom or a trifluoromethyl group.

A compound in which n is 0, 1 or 2,
Particularly preferably, n is 0. A compound in which p is 0 or 1, and particularly preferably p is 0.

A compound in which q is 0, 1 or 2, and particularly preferably q is 1.

Compounds in which r is 0, 1 or 2, particularly preferably r is 0 or 1.

A compound in which 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,
Tetrahydrooxazine or tetrahydrothiazine ring, preferably cyclobutane, cyclohexane, azetidine, piperidine, 1,3-dioxane, 1,3-dithiane, tetrahydrooxazine or tetrahydrothiazine ring, particularly preferably cyclohexane, piperidine. A compound which is a 1,3-dioxane or a 1,3-dithiane ring. Examples of suitable compound (1) include Ar ¹
Is 4-chlorophenyl, 4-difluorophenyl, 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]

[Chemical 4]

Compounds in which is a group as 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,
Examples thereof include compounds having a substituent of 176, 177, 178, 181, 182, 183 and 186, and a particularly preferable 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-butadiene-
1-yl] -1,3-dioxan-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-butadiene-1-yl] -1,3
-Dioxan-5-yl] thio] -1- (1H-1,
2,4-Triazol-1-yl) -2-butanol (the compound corresponding to Example 16), 2- (2,4-difluorophenyl) -3-[[2- [4- (4 -Chlorophenyl) -4,4,4-trifluoro-1,3-pentadiene-1-yl] -1,3-dioxan-1-yl]
Thio] -1- (1H-1,2,4-triazol-1-
Yl) -2-butanol (the 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 (the compound corresponding to Example 21), 2- (2,4-difluorophenyl) -3-[[1- (4-nitrocinna Moyl) piperidin-4-yl] thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butano-
(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
-Butadin-1-yl] -1,3-dioxan-5-
Il] thio] -2-butanol (the compound corresponding to Example 31), 2- (2,4-difluorophenyl) -1-
(1H-1,2,4-triazol-1-yl) -3-
[[2- [4- (trifluoromethylthio) phenyl]]
-1,3-Butadiene-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-butadiene-1-yl]-
1,3-dioxan-5-yl] thio] -2-butano-
(A compound corresponding to Example 34), 2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -3-[[2- [4 -[4- (Trifluoromethylsulfinyl) phenyl] -1,3-butadiene-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol (Compound corresponding to Example 35 ), 2- (2,4-difluorophenyl) -1-
(1H-1,2,4-triazol-1-yl) -3-
[[4- [4- (trifluoromethyl) phenyl]-
1,3-Butadiene-1-yl] cyclohexyl] thio] -2-butanol (compound corresponding to Example 36), 2- (2,4-difluorophenyl) -1- (1
H-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 (the compound corresponding to Example 37), 2- (2,4-difluorophenyl) -3-methyl-1- (1H-1,2,2.
4-triazol-1-yl) -3-[[2- [4-
[4- (trifluoromethyl) phenyl] -1,3-butadiene-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol (compound corresponding to Example 38) 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-dioxan-5-yl] thio] -2-butanol The compound of (Compound corresponding to Example 39) may be mentioned.

The triazole compound (1) of the present invention has at least two asymmetric carbon atoms, and optical isomers and diastereomers exist. Optical enantiomers can be obtained as both antipodes by a general optical resolution method or an asymmetric synthesis method. The diastereomers can be separated by using a usual separation method such as fractional recrystallization or chromatography. The compound (1) of the present invention includes one of these isomers or a mixture.

The triazole compound (1) of the present invention can be used as it is or in the form of a pharmacologically acceptable salt as an antifungal agent. The pharmacologically acceptable salt of the compound (1) includes, 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, and toluenesulfonic acid, or a salt of an amino acid such as glutamic acid and aspartic acid, preferably a carboxylic acid. It is salt.

The hydrate of compound (1) and the hydrate of the salt of compound (1) are also included in the compound of the present invention.

The compound (1) and the pharmacologically acceptable salt thereof of the present invention exhibit excellent antifungal activity, and when the compound (1) and its pharmacologically acceptable salt are used as an antifungal agent, As such or in admixture with an appropriate pharmacologically acceptable excipient, diluent, etc., and administered orally by tablets, capsules, granules, powders or syrups, or parenterally by injection, etc. can do.

These formulations include excipients such as lactose,
Sugar derivatives such as sucrose, glucose, mannitol and sorbitol; corn starch, potato starch, α-starch, dextrin, starch derivatives such as carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxy. Cellulose derivatives such as propylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked carboxymethylcellulose sodium; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate, Silicate derivatives such as magnesium aluminometasilicate; Phosphate derivatives such as calcium phosphate; Carbonate derivatives such as calcium carbonate; Sulfate derivatives such as calcium sulfate, etc.), binders (for example, the above-mentioned shaping agents) Agent Gelatin; polyvinylpyrrolidone;
Maglogol, etc.), disintegrating agent (for example, the above-mentioned excipients; croscarmellose sodium, carboxymethyl star)
Tisodium, chemically modified starches such as cross-linked polyvinylpyrrolidone, starch, cellulose derivatives, etc., lubricants (eg, talc; stearic acid; metal stearates such as calcium stearate, magnesium stearate; colloidal silica) Lux, such as bean gum and gallow; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; carboxylic acid sodium salts such as sodium benzoate; sulfuric acid salts such as sodium sulfate; leucine Lauryl sulphates such as sodium lauryl sulphate and magnesium lauryl sulphate; silicic acid anhydrides, silicic acids such as hydrated silicic acid; starch derivatives in the above excipients), stabilizers (eg methylparaben, propyl paraben etc.) Paraoxybenzoates; chlorobutanol, Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.), flavoring Flavoring agents (eg, commonly used sweeteners, acidulants, flavors, etc.), suspending agents (eg, polysorbate 80, sodium carboxymethylcellulose, etc.), diluents, formulation solvents (eg, It is produced by a well-known method using additives such as water, ethanol, glycerin, etc.). The amount used varies depending on the symptoms, age, etc., but in the case of oral administration, the daily lower limit is 1 mg (preferably 5 mg), and the upper limit is 200.
In the case of intravenous administration, the lower limit of 0.1 mg (preferably 1000 mg) is 0.1 mg (preferably 0.5 m)
g), the upper limit of 600 mg (preferably 500 mg) is preferably 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 represented by the formula (1) of the present invention, compounds in which R ⁰ is a hydrogen atom and n = 0 can be produced by the method shown below.

[0058]

Embedded image

(In the above formula, Ar ¹ and R ¹ have the same meanings as described above, and R ⁸ represents

[0060]

[Chemical 6]

Represents ) That is, JP-A-2-191
262 (Head 2.7.27), the epoxide compound (2) is reacted with a mercaptan (3) or an acetic acid ester derivative (4) thereof under basic conditions to produce the target compound (1). Is. As the solvent used in the reaction, methanol, ethanol, alcohols such as propanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile,
An aprotic solvent such as tetrahydrofuran is suitable, but when the reaction is carried out in the above aprotic solvent using the acetyl derivative (4), 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 and potassium hydroxide are used, and the amount used is 0.1 to 2 molar equivalents relative to compound (2). The mercaptan (3) or its acetic acid ester derivative (4) is used at 1 to 3 molar equivalents. The reaction temperature is room temperature to 100 ° C., and the reaction time is 2 to 10 hours.
The compound (1) is obtained by treating the reaction solution according to a conventional method (extracting with an organic solvent, distilling off the solvent and purifying the resulting oily substance by column chromatography or recrystallization).

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) in which A in R ⁸ is a 1,3-dioxane ring and p = 0
Is a known compound (5) (reference: OE van Lohuizen, P.
E.Verkade, according Rec.trav.chim., 78, 460 (1959 )) process chart shown below as starting material

[0063]

[Chemical 7]

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

[0065]

Embedded image

(In the above formula, 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. Of the unsaturated aldehydes (6), compounds (6b) in which r = 1 and 2 can be generally obtained via the unsaturated ester (7b) by the following method (reaction conditions of each step and simple steps). For the separation method, refer to Reference Examples 44, 45, 4
6, 47, 48).

[0067]

[Chemical 9]

(In the above formula, R ² , R ³ , R ⁴ , R ⁵ ,
q, r, and s have the same meaning as described above, and DIBAL
-H represents diisobutylaluminum hydride. ) Further, 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 heterocycle (azetidine, pyrrolidine, piperidine, homopiperidine) and p = 1 (3b) or (4b) can be obtained by the method described below (see Reference Examples 16 and 17 for the reaction conditions and isolation method of each step).

[0069]

[Chemical 10]

(In the above formula, R ² , R ³ , R ⁴ , R ⁵ ,
q, r, and s have the same meaning as described above, and t is 3,
4, 5 or 6 is shown, and Boc is tert-butoxycarbonyl. ) The acid chloride (10) used above can be obtained by treating the carboxylic acid obtained by alkali-decomposing the unsaturated ester (7a), (7b) described above with thionyl chloride.

Among the compounds of formula (1) of the present invention,
A compound in which R ⁰ is a hydrogen atom and n = 0 can also be produced by the following method.

[0072]

[Chemical 11]

(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 Patent Application Laid-Open No. 3-240778 (Hair 3.10.2)
This is a method for producing the target compound (1) by reacting the triazolyl mercapto alcohol derivative (11) described in 8) with an alkylating reagent (12) under basic conditions. Examples of the solvent used in the reaction include methanol, ethanol, propanol, butanol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, acetone, benzene, toluene, xylene and the like. The base used in the reaction is triethylamine, diisopropylethylamine, sodium hydride, sodium methoxide, sodium ethoxide,
It is lithium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or the like, and the amount used is 1 to 3 molar equivalents relative to compound (11). The alkylating reagent (12) is used at 1 to 3 molar equivalents. The reaction temperature is −50 to 100 ° C., and the reaction time is 2 to 10 hours. The compound (1) is obtained by treating the reaction solution according to a conventional method (extracting with an organic solvent, purifying an oil obtained by distilling off the solvent by chromatography or recrystallization).

Alkylation reagent R ⁸ used in the above reaction
-X (12) can be obtained by the method shown below. The compound (12a) in which A in R ⁸ is a 1,3-dioxane ring and p = 0 is the same as the above-mentioned diol compound (13) obtained by subjecting the above-mentioned compound (5) to acid treatment in methanol. Obtained by reacting unsaturated aldehyde (6) under acidic conditions (Reference Example No. 56,
57).

[0075]

[Chemical 12]

(In the above formula, R ² , R ³ , R ⁴ , R ⁵ , and A
r ² , q, r, and s have the same meanings as described above. ) Further, A in R ⁸ is a 4- to 7-membered nitrogen-containing heterocycle (azetidine,
Pyrrolidine, piperidine, homopiperidine) and p =
Compound (12b) which is 1 can be obtained, for example, by reacting compound (14) obtained by treating cyclic amine derivative (8) with HCl with above acid chloride (10) in the presence of a base such as triethylamine. To be

[0077]

[Chemical 13]

(In the above formula, R ² , R ³ , R ⁴ , R ⁵ , A
r ² , q, r, s, and t have the same meaning as described above. ) In the compound having the formula (1) of the present invention, R ⁰ is a hydrogen atom, n = 0, p = 0, and A is 1,3-
The compound having a dioxane ring can also be produced by the following method.

[0079]

Embedded image

(In the above formula, 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 above-mentioned epoxide compound (2)
And the thioacetic acid derivative (15) obtained by the reaction of the above-mentioned known compound (5) with sodium thioacetate, (2)
And (4) are reacted under the same conditions as described above to obtain compound (16), which is deprotected according to a conventional method such as acid treatment to give (17), Target compound (1) is obtained by reacting aldehyde compound (6).
Is a method of manufacturing. The reaction of (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 and p-toluenesulfonic acid,
The amount of acid used is 1-2 molar equivalents with respect to (17). Aldehyde (6) is used at 1 to 2 molar equivalents. As the solvent, aprotic solvents such as methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, diethyl ether, tetrahydrofuran and the like are used. The reaction is performed in the range of 0 ° C to the boiling point of the solvent, and the reaction time is 2 to 10 hours. Water generated in the reaction can be removed by azeotropic distillation, but molecular sieves may be used as a dehydrating agent. The reaction solution is neutralized with aqueous sodium hydrogen carbonate and the like, and then treated by a conventional method (extraction with an organic solvent, purification of an oil obtained by distilling off the solvent by chromatography or crystallization) to obtain the compound (1).

Among 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 heterocycle (azetidine, pyrrolidine, piperidine, homopiperidine). The compound which is) can be manufactured also by the method shown below.

[0082]

[Chemical 15]

(In the above formula, 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 subjecting the thioacetic acid derivative (9) to alkali treatment are treated under the same conditions as in the reaction of (2) and (3). To react with compound (1
9) is obtained, and (19) is treated with an acid according to a conventional method for deprotection to give a compound (20). By reacting (20) with the above-mentioned acid chloride (10), the target compound (1) is obtained. It is a manufacturing method. The reaction of (20) and (10) is carried out in the presence of a suitable base according to a conventional method in an inert solvent such as benzene, toluene, methylene chloride, chloroform or tetrahydrofuran. (Reference example number 1
3, 14, 18, 19) Of the compounds (1) of the present invention, the compound having n = 1 or n = 2 can be produced by the method described below. That is, the compound (1) of n = 1 can be produced by oxidizing the compound (1) of the present invention having n = 0 obtained by the above-described method with 1 equivalent of an oxidizing agent in a solvent. Alternatively, the compound (1) having n = 2 can be produced by oxidizing the compound with 2 equivalents or more of an oxidizing agent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but halogenated hydrocarbons such as methylene chloride and chloroform are preferred. Examples of the oxidizing agent used include peracetic acid and 3-chloroperbenzoic acid. The reaction temperature is 0 to 50 ° C, preferably room temperature, and the reaction time is usually 3
0 minutes to 2 hours. The reaction solution is treated according to a conventional method (after washing with a sodium bicarbonate solution, the solvent is distilled off to obtain a crude product, which is purified by chromatography or recrystallization).
And compound (1) (n = 1 or 2) is obtained.

Of the compounds of formula (1) of the present invention,
A compound in which R ⁰ is lower alkyl and n = 0 can be produced by the method shown below.

[0085]

Embedded image

(In the above formula, Ar ¹ , R ⁰ , R ¹ and R
⁸ has the same meaning as described above. That is, Japanese Patent Laid-Open No. 7-2802 (7.1.6)
The bromketone (21) obtained according to the method described in 1) is reacted with the above-mentioned mercaptan (3) or its acetic acid ester derivative (4) under alkaline conditions to obtain a thioether derivative (22), and then (22) ) In the presence of a base, trimethylsulfoxonium iodide and 1,
This is a method for producing the target compound (1) by reacting 2,4-triazole. (21) and (3) or (4)
Alcohols such as methanol, ethanol and propanol are suitable as the solvent used in the reaction of, and the alkali used is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and the like. Solvents used in the reaction for converting the thioether derivative (22) to (1) include alcohols such as methanol, ethanol, propanol, butanol and t-butanol, dimethylformamide, dimethylacetamide,
Aprotic solvents such as dimethylsulfoxide, acetonitrile, tetrahydrofuran are preferred. 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 (22 ) To 2-5 molar equivalents. Trimethylsulfoxonium iodide and 1,2,4-triazole are used in an amount of 1 to 2 mole equivalent based on the compound (22). The reaction temperature is room temperature to 100 ° C., and the reaction time is 2 to 10 hours. The compound (1) (n = 0) is obtained by treating the reaction solution according to a conventional method (extracting with an organic solvent, and then purifying a crude product obtained by distilling off the solvent by column chromatography or recrystallization). In the compound (1) obtained by the above method, R ⁸ is

[0087]

[Chemical 17]

The compound (23), which is the compound (1), is converted to the compound (1) via the triol (24) by the following method.
Of these, n = 0, p = 0, and A can be led to a compound having a 1,3-dioxane ring.

[0089]

Embedded image

(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 meanings as described above. ) The reaction conditions of the above-mentioned steps are (16) → (17) → (1) described above.
Is the same as that described in the reaction of.

The present invention is described in more detail below with reference to Examples, Reference Examples, Test Examples and Preparation Examples, but the scope of the present invention is not limited thereto.

The aldehyde compounds used in the examples are the documents and / or
Alternatively, it is synthesized by the method described in the references cited therein.
Aldehyde compounds for which literature is not specified are commercially available or are described in parentheses in the Examples or in the methods for synthesizing aldehydes described in the references cited therein or in the Reference Examples herein. It can be obtained by a method similar to the aldehyde synthesis method.

[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]

[Chemical 19]

166 mg (0.48) of trans-4- (acetylthio) -2-[(E) -1-methyl-2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane described in Reference Example 7. 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 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 solution was diluted with ethyl acetate and washed with saturated brine. The oil obtained by distilling off the solvent was subjected to column chromatography using 15 g of silica gel and eluted with a hexane-ethyl acetate (2: 1) mixed solvent to give 180 mg of the target compound (yield 74%) as an oil. Obtained.

NMR spectrum (60 MHz, CDCl ₃ ) δppm: 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 = 9Hz), 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]

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-5- (acetylthio)-
2-[(E) -2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane was reacted and treated to give the target compound having a melting point of 73-75 ° C in a yield of 70. Earned in%.

Specific rotation [α] _D ²⁵ -73.8 ° (C = 1.00, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

[Chemical 21]

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, a target compound having a melting point of 64-66 ° C. was obtained with a yield of 31%.

Specific rotation [α] _D ²⁵ -84.1 ° (C = 2.69, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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 = 15.8Hz),
6.74 (2H, t-like, J = 9Hz), 7.2
6 (4H, s), 7.37 (1H, td, J = 8.6,
6.5 Hz), 7.76 (1 H, 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-
Il) -2-butanol

[0103]

[Chemical formula 22]

Described in 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 2
94 mg (0.82 mmol) and trans-4-chlorocinnamaldehyde 191 mg (1.15 mmol) (Bull.Chem.So.
c.Japan 52 555 (1979)) and dissolved in 14 ml of methylene chloride, and 233 mg (1.23 mmo) of p-toluenesulfonic acid monohydrate.
l) and Molecular Sieves 4A (1.5 g) were added, and the mixture was stirred for 1 hour and 15 minutes. After adding a sodium bicarbonate solution to the reaction solution and stirring for 10 minutes, the molecular sieves were removed by filtration, the organic layers were collected and dried, and the solvent was evaporated under reduced pressure. The obtained oily substance 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.
(Yield 67%) was obtained as an oil. Hexane-
Elution with a mixed solvent of ethyl acetate (1: 1) gave 35 mg (yield 8%) of cis isomer (B) as an oil.

[0105] NMR spectrum (270 MHz, CDCl ₃ ) δppm: (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, hexane was added, and the precipitated crystals were collected by filtration and had a melting point of 89-9.
65 mg of oxalate having a temperature of 2 ° C. are obtained. Similarly, (B) oxalate having a melting point of 94 to 98 ° C was obtained.

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]

[Chemical formula 23]

(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 to prepare p-toluenesulfonic acid monohydrate 19
Add 0 mg (1.00 mmol) and Molecular Sieves 4A 1.2 g,
The mixture was stirred for 1 hour and 15 minutes. After adding sodium bicarbonate water to the reaction solution and stirring for 10 minutes, the molecular sieves were removed by filtration,
It was extracted with chloroform. The oily substance obtained by distilling off the solvent after drying was subjected to column chromatography using 15 g of silica gel, and hexane-ethyl acetate (1: 4 to 1: 1).
5) Elution with a mixed solvent gave 82 mg (yield 52%) of the title compound, trans isomer (A), as an oil. Further, eluting with ethyl acetate to 5% methanol-ethyl acetate to give 28 mg (yield 15%) of cis isomer (B), melting point 118.
Obtained as a solid with -125 ° C.

NMR spectrum (270 MHz, CDCl ₃ ) δppm:
(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 = 4.6Hz), 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]

[Chemical formula 24]

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- (trifluoromethyl) cinnamaldehyde described in Reference Example 22 were reacted and treated to give the desired compound as a main product. (Yield 62%). Physical and spectral data are shown in Example 2.
It was in agreement with that of 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]

[Chemical 25]

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
By reacting with h.Pharm. 316 574 (1983)) and treating, the title compound as a main product was obtained as an oily substance in a yield of 66%.

NMR spectrum (60 MHz, CDCl ₃ ) δppm: 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]

[Chemical formula 26]

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-2-fluoro-4- (trifluoromethyl) cinnamaldehyde are reacted and treated to give the title compound as the main product. Yield 6 as 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]

[Chemical 27]

(2R, 3R) -2 in the same manner as in Example 4.
-(2,4-difluorophenyl) -3-[(1,3-
Dihydroxy-2-propyl) thio] -1- (1H-
1,2,4-triazol-1-yl) -2-butanol was reacted with trans-4- (methylsulfonyl) cinnamaldehyde and treated to give the title compound as a main product as an oily substance. Obtained in 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-
Il) -2-butanol

[0123]

[Chemical 28]

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-nitrocinnamaldehyde were reacted and treated to give the title compound as a main product as an oil in a yield of 40%. Obtained.

Specific rotation [α] _D ²⁵ -64.1 ° (C = 2.43, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

[Chemical 29]

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- (trifluoromethoxy) cinnamaldehyde described in Reference Example 33 are reacted and treated to give the title compound as the main product. Was obtained as an oil in a yield of 43%.

Specific rotation [α] _D ²⁵ -77 ° (C = 0.52, CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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-
Il) -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
st.Liq.Cryst. 123 257 (1985)) and treated to obtain the title compound as a main product as an oily substance in a yield of 66%.

Specific rotation [α] _D ²⁵ -78 ° (C = 0.52, CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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 = 14.2Hz), 5.03
(1H, d, J = 1.2Hz), 5.04 (1H,
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 = 16.1Hz), 7.36 (1H,
m), 7.49 (2H, d, J = 8.3Hz), 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]

[Chemical 31]

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-β-methyl-4- (trifluoromethyl) cinnamaldehyde are reacted and treated to obtain the main product, which is the title object. The compound was obtained as an oil in a yield of 73%.

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-
1,2,4-triazol-5-yl) -2-butanol is reacted 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 ) δppm: 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-butadiene-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol

[0141]

[Chemical 33]

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- described in Reference Example 25.
By reacting with (trifluoromethyl) phenyl] -2,4-pentadienal and treating, the title compound as a main product was obtained 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 ) δppm: 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-butadiene-1-yl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2, Four
-Triazol-1-yl) -2-butanol

[0144]

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- described in Reference Example 32.
By reacting with (2,2,3,3-tetrafluoropropoxy) phenyl] -2,4-pentadienal and treating, the title compound, which is the main product, has a melting point of 75 to 8
It was obtained as a powder having a temperature of 5 ° C. (crystallized from a hexane-ether mixed solvent) in a yield of 60%.

Specific rotation [α] _D ²⁵ -69 ° (C = 0.56, 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 = 11.3,4.8Hz),
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-butadiene-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, The workup gave the main product, the title compound, 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.
By reacting with hexadienal and treating, the title compound as a main product was obtained as an oily substance in a yield of 31%.

Specific rotation [α] _D ²⁵ -59.4 ° (C = 0.90, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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-Butadiene-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 ) δppm: 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-Butadiene-1-yl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,4-triazol-1-yl) -2-butanol

[0156]

[Chemical 38]

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) -4-methyl-5- [4- (trifluoromethyl) phenyl] -2,4-pentadienyl, By the treatment, the title compound as a main product was obtained as an oily substance in a yield of 69%.

Specific rotation [α] _D ²⁵ -63.4 ° (C = 1.07, CHCl
₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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 = 8.2Hz), 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]

[Chemical Formula 39]

[Manufacturing Method A] Described in 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 (1.02 m) of triethylamine at 0 ° C under nitrogen atmosphere
mol) then 5 minutes later (E) -4- (trifluoromethoxy) cinnamoyl chloride 128 mg (0.510 mmol) was added. After stirring at the same temperature for 30 minutes, the solvent was distilled off, ethyl acetate was added to the obtained residue, and the mixture was washed with brine. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with ethyl acetate to give the title compound (160 mg, yield 81%).
Was obtained as a colorless foam.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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) 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 dimethylformamide 4 ml. , 129 μl of 28% sodium methoxide-methanol solution under nitrogen atmosphere (0.613 mm
ol) was added and the mixture was stirred at 50 ° C. for 3 hours. After cooling, the reaction solution was diluted with ethyl acetate and washed with water and then saturated saline. The oily substance obtained by distilling off 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 the same as the compound obtained in [Production Method A]
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]

[Chemical 40]

(E) -4-Methylcinnamoyl chloride (Can. J. Chem. 45 1001 (1967)) obtained as a colorless foam according to Example 21 [Production Method A].

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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) -4-Nitrocinnamoyl Chloride, a pale yellow foam obtained according to Example 21 [Production Method A].

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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
A colorless foam obtained from chloride according to Example 21 [Production Method A].

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

[Chemical 43]

4- (acetylthio) -1-[((E)-
A colorless foam obtained from 3- (pyridin-4-yl) -acryloyl] piperidine according to Example 21 [Production Method B].

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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,
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]

[Chemical 44]

Described in 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 as a pale yellow foam obtained according to Example 21 [Production A].

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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-butadiene-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 and (2E, 4E) -5- (2,4-difluorophenyl) -2,4-pentadienal are reacted to give the title product, which is the main product. The compound was obtained as an oil in a yield of 61%.

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-butadiene-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 Reference Example 37 (2E, 4E) -5.
[6- (2,2,3,3-tetrafluoropropoxy)
-3-Pyridyl] -2,4-pentadienal 501 mg
(1.73 mmol) was dissolved in 11 ml of methylene chloride, and 320 mg of p-toluenesulfonic acid monohydrate (1.
68 mmol) and molecular sieves 4A4g,
Stir for 1 hour at room temperature. The reaction solution was cooled with ice to a 20% aqueous solution of 3% sodium bicarbonate
The mixture was poured into ml and stirred for 5 minutes, then molecular sieves were removed by filtration and the organic layer was separated and dried, and the solvent was distilled off under reduced pressure. The obtained oily substance 908 mg was subjected to column chromatography using 19 g of silica gel and eluted with a hexane-ethyl acetate (1: 1) mixed solvent to obtain 448 mg (yield 63%) of the title target compound as an oily substance.

Specific rotation [α] _D ²⁵ −58.6 ° (c = 0.52,
CHCl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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-Butadiene-1-yl] -1,3-dioxan-5-yl] thio] -1- (1H-1,2,3-triazol-1-yl) -2-butanol

[0186]

[Chemical 47]

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,
4-triazol-5-yl) -2-butanol and (2
E, 4E) -2-Methyl-5- [4- (trifluoromethyl) phenyl] -2,4-pentadienal was reacted to give the main product, the title compound, 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) described in Reference Example 55 was used. ) Phenyl] -1- (1H-1,2,4-triazol-1-yl) -2-butanol and trans-4- (trifluoromethyl) cinnamaldehyde described in Reference Example 22 are reacted to give the title object 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-butadiene-1-yl] -1,3-dioxane-5
-Yl] thio] -2-butanol

[0196]

[Chemical 49]

(RS) -3-[(1,3-dihydroxy-2-propyl) thio] -3-methyl-2- [4- (trifluoromethyl) described in Reference Example 55 in the same manner as in Example 4. ) Phenyl] -1- (1H-1,2,4-triazol-1-yl) -2-butanol and (2E, 4E) -5- [4- (trifluoromethyl) phenyl] -described in Reference Example 25. 2,4-Pentadienal was reacted to give 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-butadiene-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 was reacted with (2E, 4E) -5- [4- (trifluoromethylthio) phenyl] -2,4-pentadienal to give the main product. Certain title compound was 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]

[Chemical 51]

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) -5- [4- (2,2,3,3-Tetrafluoropropoxy) phenyl] -2,4-pentadienal was reacted to give the main product of the title compound 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), 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-Butadiene-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-butadiene-1-yl] -1,3-dioxane was reacted to give 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 = 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-Butadiene-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol

[0216]

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- (trifluoromethylsulfinyl) phenyl] -2,4-pentadienal are reacted to produce the 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-butadiene-1-yl] cyclohexyl] thio] -2-butanol

[0221]

[Chemical 54]

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-butadiene-1-yl] cyclohexane is reacted to give a melting point of 74
The title compound having -76 ° C was obtained with a yield of 59%.

Specific rotation [α] _D ²⁵ −83 ° (c = 0.90, CH
Cl ₃ ) NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

[Chemical 55]

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 Reference Example 28 (2E, 4E ,, 6E) -7-
[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,
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-
Ill) -3-[[trans-2-[(1E, 3E) -4
-[4- (trifluoromethyl) phenyl] -1,3-
Butaden-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol

[0231]

[Chemical 56]

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 give the main product, the title compound, 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-butene-3-yne-
1-yl] -1,3-dioxan-5-yl] thio]-
2-butanol

[0235]

[Chemical 57]

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-ynal 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 ) δppm: 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]

Embedded image

(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) was dissolved in 20 ml of dimethylformamide,
After adding 2.5 ml (4.00 mmol) of 1.6 M sodium methoxide-methanol solution under a nitrogen atmosphere, 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 brine and dried, and the solvent was evaporated under reduced pressure. The obtained crude product was subjected to column chromatography using 60 g of silica gel and eluted with a mixed solvent of benzene-ethyl acetate (5: 1) to obtain 2.53 g (yield 91%) of the title compound as a solid. Recrystallization from ethyl acetate-hexane gave a pure product with a melting point of 58-60 ° C.

Specific optical 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 ) δppm: 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]

Embedded image

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

Embedded image

(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)
2-Butanol (253 mg) was dissolved in methanol (3.5 ml), 4N-HCl dioxane solution (0.35 ml) was added and the mixture was stirred at room temperature for 30
Stir 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 give 179 mg (yield 88%) 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 (1
H, s), 7.86 (1H, s). Reference Example 3 trans-5-[(4-chlorobenzyl) thio] -2-
Phenyl-1,3-dioxane

[0250]

[Chemical formula 61]

55% sodium hydride 240 mg (5.50 mmo
l) was washed with hexane, suspended in 15 ml of dimethylformamide, and 903 mg (5.70 mmol) of 4-chlorobenzylmercaptan was added with stirring under a nitrogen atmosphere. After 15 minutes, cis-5- (p-toluenesulfonyloxy) -2
-Phenyl-1,3-dioxane (1.66 g, 4.96 mmol) 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 brine. After distilling off the solvent, the crystalline residue obtained is recrystallized from a benzene-hexane mixed solvent to give the title compound 670 having a melting point of 95-99 ° C.
mg (yield 42%) was obtained as flaky crystals.

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

[0253]

Embedded image

Trans-5-[(4-chlorobenzyl)
Thio] -2-phenyl-1,3-dioxane 750 mg
Was dissolved in 10 ml of methanol, 1 ml of 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 filtered off and the solvent was distilled off. Ethyl acetate was added to the residue and the insoluble material was filtered off. The crystal obtained by distilling off the solvent is recrystallized from a benzene-hexane mixed solvent to give the title compound 46 having a melting point of 70-75 ° C.
8 mg (yield 86%) was obtained.

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

[0256]

[Chemical formula 63]

2-[(4-chlorobenzyl) thio]-
341 mg (1.46 mmol) of 1,3-propanediol and (E)
-4- (Trifluoromethyl) -α-methylcinnamaldehyde (375 mg, 1.75 mmol) was dissolved in benzene (12 ml), p-toluenesulfonic acid (3 mg) was added, and the mixture was placed under a nitrogen atmosphere.
Heated to reflux for hours. After cooling, the mixture was washed with aqueous sodium hydrogen carbonate, the solvent was evaporated, and the obtained residue was subjected to column chromatography using 15 g of silica gel. Fractions eluted with a hexane-ethyl acetate (9: 1) mixed solvent were 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 ) δppm: 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]

[Chemical 64]

Trans-5-[(4-chlorobenzyl)
Thio] -2-[(E) -1-methyl-2- [4- (trifluoromethyl) phenyl] vinyl] -1,3-dioxane (382 mg, 0.89 mmol) was dissolved in methylene chloride (10 ml), and m was added at 0 ° C. -Chloroperbenzoic acid (purity 85%) 188
mg (0.92 mmol) was added and stirred for 15 minutes. The reaction mixture was washed with aqueous sodium hydrogen carbonate and the solvent was evaporated to give a solid, which was washed with ethyl acetate-
It was washed with a hexane mixed solvent to obtain 328 mg (yield: 83%) of the title compound having a melting point of 192-194 ° C.

NMR spectrum (60 MHz, CDCl ₃ ) δppm:
1.88 (3H, d, J = 1.5Hz), 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, brs), 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]

Embedded image

Trans-5-[(4-chlorobenzyl)
Sulfinyl] -2-[(E) -1-methyl-2- [4
-(Trifluoromethyl) phenyl] vinyl] -1,3
Dioxane 309 mg (0.696 mmol) was dissolved in tetrahydrofuran-acetonitrile (1: 1) mixed solvent 8 ml, and 2,6-lutidine 500 mg (4.67 mmol) was added. Trifluoroacetic anhydride 5 with 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 hydrogen carbonate was added, the mixture was stirred for 5 minutes, and extracted with ethyl acetate. The oily residue obtained after distilling off the solvent (approx. 350 m
g) was dissolved in 5 ml of methylene chloride, 210 mg of triethylamine was added at 0 ° C., and then 109 mg of acetyl chloride was added. After 5 minutes, the reaction solution was washed with water, the solvent was distilled off, and the residue was subjected to column chromatography using 10 g of silica gel. Elution with a hexane-benzene (1: 1 to 1: 2) mixed solvent 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 128-129 ° C.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

[Chemical formula 66]

45 mg of 55% sodium hydride (1.03 mmol)
Was washed with hexane, suspended in 3 ml of 1,2-dimethoxyethane and stirred under nitrogen atmosphere at 0 ° C. while stirring with triethyl.
273 mg (1.03 m) of 3-methyl-4-phosphonocrotonate
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, and the mixture was extracted with ethyl acetate. The crude product obtained by distilling off the solvent was used as silica gel 5
column chromatography using g and eluting with ethyl acetate-hexane (4:96) mixed solvent to give the (2E, 4E) isomer of the title compound and its (2Z, 4E).
159 mg (97% yield) of a 5: 1 mixture with isomers were obtained as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: (2
E, 4E) -isomer, 1.31 (3H, t, J = 6.6Hz), 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]

Embedded image

Ethyl (4E) -3-methyl-5- [4- (trifluoromethyl) phenyl]-as described in Reference Example 8.
2,4-pentadienoate ((2E) / (2Z) = 5
1/1) A solution of 150 mg (0.53 mmol) dissolved in 2 ml of toluene was stirred at 0 ° C. and 0.7 ml (1.06 mmol) of 1.5M 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. It was extracted with ethyl acetate, dried and the solvent was distilled off to obtain an oily substance. Silica gel 5
column chromatography using g, 30-4
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 ) δppm: 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 = 8.5Hz), 7.57 (2H, d, J = 8.5Hz). Reference Example 10 (2E, 4E) -3-Methyl-5- [4- (trifluoromethyl) phenyl] -2,4-pentadienal

[0271]

[Chemical 68]

(2E, 4E) -3-Methyl-5- [4-
(Trifluoromethyl) phenyl] -2,4-pentadiene-1-ol (460 mg, 1.90 mmol) was added to methylene chloride 1
It was dissolved in 0 ml, 5 g of active manganese dioxide was added, and the mixture was stirred at room temperature for 30 minutes. Solids are filtered off and the filtrate is concentrated and purified by silica gel chromatography (eluting solvent: 4%
Ethyl acetate-hexane) to obtain 460 mg of the title compound as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

[Chemical 69]

1- (tert-butoxycarbonyl) -4-
(Methanesulfonyloxy) piperidine 4.12g (14.7mmo
l) is dissolved in 40 ml of dimethylformamide, 2.53 g (2.21 mmol) of potassium thioacetate is added, and 105
Stirred at C for 4 hours. After cooling, it was diluted with ethyl acetate, washed with water and then with saturated brine, and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography, and the fractions eluted with a hexane-ethyl acetate (5: 1) mixed solvent were collected to give 5.19 g of the title compound as an oil (yield 81%).
I got

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

Embedded image

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 mmo) under ice cooling and a nitrogen atmosphere.
l) was added and stirred for 40 minutes. Then acetic acid 173 μl
After the solvent was distilled off at room temperature, the residue was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine in that order and the solvent was distilled off to obtain 430 mg of a red-orange oil. This product was used in the next reaction without purification.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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-diololophenyl)
-3- (1H-1,2,4-triazol-1-yl)
-3-[[1- (tert-butoxycarbonyl) piperidin-4-yl] thio] -2-butanol

[0280]

Embedded image

1- (tert-Butoxycarbonyl) -4-mercaptopiperidine (in charge of 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 for 20 minutes at the same temperature. 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 with ethyl acetate and washed with water and saturated brine in this order. The oil obtained by distilling off the solvent was subjected to silica gel column chromatography and eluted with ethyl acetate to obtain 557 mg (yield 53%) of the target compound as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

Embedded image

(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
Dissolve 57 mg (1.05 mmol) in 20 ml of ethyl acetate and add 4N.
After adding 2.63 ml (10.5 mmol) of 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]

Embedded image

4- (Acetylthio) described in Reference Example 11
-1- (tert-butoxycarbonyl) piperidine 1.25g
(4.82 mmol) was dissolved in 45 ml of ethyl acetate, 12.0 ml (48.2 mmol) of 4N hydrogen chloride-ethyl acetate solution was added, and then 50
Stirred at C for 4 hours. After cooling, the precipitated solid was collected by filtration and washed with hexane to obtain 885 mg (yield 94%) of the target compound as a pale 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), 3.3-3.5 (2H, m), 3.6-3.8 (1H, m). Reference Example 16 4- (acetylthio) -1-[(E) -4- (trifluoromethoxy) cinnamoyl] -piperidine

[0289]

[Chemical 74]

4- (Acetylthio) piperidine Hydrochloride 1.
28 g (6.53 mmol) was suspended in 17 ml of dichloromethane, and 2.27 ml (16.3 mmol) of triethylamine was added dropwise while stirring with ice cooling. Then, a solution prepared by dissolving 1.80 g (7.18 mmol) of (E) -4- (trifluoromethoxy) cinnamoyl chloride 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 target compound as a slightly yellow solid.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

[Chemical 75]

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

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

[Chemical 76]

From 3- (acetylthio) -1- (tert-butoxycarbonyl) azetidine to Reference Examples 12 and 13
A pale yellow foam obtained according to.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

Embedded image

(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 ) δppm: 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

55% sodium hydride 903 mg (2
(0.7 mmol) was washed with hexane, suspended in 60 ml of 1,2-dimethoxyethane, and stirred with triethyl phosphonoacetate 4.63 under nitrogen atmosphere at 0 ° C.
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 and washed with water. After drying, the solvent was distilled off and the oily residue obtained was subjected to column chromatography using 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. Earned in%.

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]

Embedded image

Ethyl trans-4- (trifluoromethyl) cinnamate (3.00 g, 12.3 mmol) was dissolved in toluene (15 ml) and stirred at 0 ° C. to give 1.5.
M diisobutylaluminum hydride-toluene solution 1
6.4 ml (24.6 mmol) was added. 20 minutes later,
Ice-water was added and the mixture was stirred for 10 minutes, and insoluble materials were removed by filtration using Celite. It was extracted with ethyl acetate, dried and the solvent was distilled off to give a crystalline residue. Recrystallization from a benzene-hexane mixed solvent gave 2.36 g (yield 96%) 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]

Embedded image

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

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]

[Chemical 81]

4.51 g of 55% sodium hydride (10
(3 mmol) was washed with hexane, suspended in 70 ml of 1,2-dimethoxyethane, and stirred at 0 ° C. under a nitrogen atmosphere with stirring to obtain 25.9 g of triethylphosphonocrotonate (1
(03 mmol) was added dropwise. After 15 minutes, at the same temperature 4-
(Trifluoromethyl) benzaldehyde 10.0 g
(57.4 mmol) was added and stirred for 10 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The oily residue obtained by distilling the solvent off 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 oily substance.

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]

[Chemical formula 82]

In the same manner as in Reference Example 21, ethyl (2
E, 4E) -5- [4- (Trifluoromethyl) phenyl] -2,4-pentadienoate was treated with diisobutylaluminium 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]

[Chemical 83]

In the same manner as in Reference Example 22, (2E, 4E)
-5- [4- (trifluoromethyl) phenyl] -2,
4-Pentadien-1-ol was treated with activated manganese dioxide to give the title compound in 92% yield.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

[Chemical 84]

In the same manner as in Reference Example 20, (2E, 4E)
-5- [4- (trifluoromethyl) phenyl] -2,
Reaction of 4-pentadienal with triethylphosphonoacetate gave 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]

Embedded image

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 diisobutylaluminium 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]

[Chemical 86]

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 active 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]

[Chemical 87]

55% sodium hydride 1.90 g (4
(3.5 mmol) was washed with hexane, and then suspended in 25 ml of N, N-dimethylacetamide, and 0 ° C under a nitrogen atmosphere.
4-hydroxybenzaldehyde 5.3 g (43 mm
ol) was gradually added. When the 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 benzene-hexane (1: 1) mixed solvent was added and the mixture was washed with water. After drying, the solvent was distilled off to give 8.85 g of the title compound.
(Yield 96%) was obtained as an oil.

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

Embedded image

In the same manner as in Reference Example 23, 4- (2,2,
3,3-tetrafluoropropoxybenzaldehyde and triethylphosphonocrotonate were reacted to give a melting point of 6
The title compound having 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]

[Chemical 89]

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 diisobutylaluminium hydride to have 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]

[Chemical 90]

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

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 4.
38 (2H, br t, 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]

Embedded image

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 1
The mixture was heated under reflux for 45 minutes. 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)
Fractions eluted with a mixed solvent were collected and the title compound (387 mg)
(60% yield) was obtained 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]

Embedded image

55% sodium hydride 840 mg (1
9.3 mmol) was washed with hexane and then suspended in 40 ml of dimethylformamide, and the suspension was kept at 0 ° C. under a nitrogen atmosphere for 2,2,2.
3.00 g of 3,3-tetrafluoropropanol (2
(2.7 mmol) was gradually added. When generation of hydrogen gas ceased, 6-chloronicotinic acid ethyl ester 3.40
g (18.3 mmol) of dimethylformamide 15m
The solution dissolved in 1 was added dropwise at the same temperature over about 30 minutes. After dropping, the mixture was stirred for 30 minutes, poured into ice water, and extracted with benzene. After drying, the solvent was distilled off, and the resulting oily substance was purified by column chromatography using silica gel [eluting with a benzene-hexane (1: 1) mixed solvent].
4.42 g (yield 86%) of the title compound was 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]

Embedded image

In the same manner as in Reference Example 21, 6- (2,2,
3,3-Tetrafluoropropoxy) nicotinic acid ethyl ester 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]

Embedded image

In the same manner as in Reference Example 22, 2- (2,2,
Treatment of 3,3-tetrafluoropropoxy) -5- (hydroxymethyl) pyridine with active manganese dioxide gave 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-pyridyl] -2,4-pentadienyl

[0377]

Embedded image

According to Reference Examples 23, 24 and 25, 6-
The title compound having a melting point of 88-89 ° C. was obtained from (2,2,3,3-tetrafluoropropoxy) nicotinaldehyde in 3 steps.

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 =
7.9 Hz) .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-pentagenal

[0382]

[Chemical 96]

According to Reference Examples 23, 24, and 25, the title compound was obtained as an oil from 6-chloronicotinaldehyde in 3 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]

Embedded image

55% sodium hydride 146 mg (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 in which 426 mg (1.67 mmol) of 4-[(4-chlorobenzyl) thio] cyclohexanone was 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 obtained crude product was subjected to column chromatography using 20 g of silica gel, and methylene chloride-hexane (1:
4) Elution with a mixed solvent gave the title compound (370 mg, yield 78%) 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]

Embedded image

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

This product was stirred in 15 ml of 0.07N sodium methoxide-methanol solution at room temperature for 2.3 hours. Add 0.2 ml of acetic acid and dilute with ethyl acetate,
Washed with brine. After drying, the solvent was distilled off to obtain 865 mg of a 4: 1 mixture of the title trans isomer and the cis isomer as a solid. Recrystallized from ether-hexane mixed solvent,
220 mg of the title trans form having a melting point of 44-46 ° C was 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) cis isomers are δ3.67 (2H, s) and δ9.64 (1H, s) Gave a 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]

Embedded image

55% sodium hydride 50 mg (1.1
(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. Furthermore, 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 obtained crude product was subjected to column chromatography using 5 g of silica gel, and methylene chloride-hexane (1:
2) Elution 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 = 8Hz), 7.55 (2H, d, J = 8Hz).

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]

[Chemical 100]

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. Aqueous sodium sulfite solution and ethyl acetate were added, and the organic layer was washed with aqueous sodium hydrogen carbonate and brine. The crude product obtained by distilling the solvent off after drying 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).

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-Butadiene-1-yl] cyclohexane

[0410]

[Chemical 101]

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
Dissolve it in ml and 168 mg of 2,6-lutidine (1.57
mmol) was added. 165 mg (0.79 mmol) of trifluoroacetic anhydride was added with stirring at 0 ° C.
After 3 minutes, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. After distilling off the solvent, the oily residue obtained was diluted with 10 ml of methylene chloride.
Dissolved in triethylamine 119 mg (1.1
7 mmol) and then 62 mg of acetyl chloride
(0.79 mmol) was added. After 1 hour, the reaction solution was diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate and brine. After drying, the solvent was distilled off, and the obtained crude product was subjected to column chromatography using 5 g of silica gel and eluted with a mixed solvent of methylene chloride-hexane (1: 1), and further a row bar 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]

Embedded image

4-Bromo-α, α, α-trifluorotoluene (5.0 g, 22 mmol) and propargyl alcohol (1.25 g, 22 mmol) were added to diethylamine 50.
Dissolve it in ml, add bis (triphenylphosphine) palladium (II) chloride 80 mg (0.11 mmol) and copper (I) iodide 40 mg (0.22 mmol), and then add 5
Stir for 35 minutes at 0 ° C. Bis (triphenylphosphine) palladium (II) chloride 40 mg (0.06 mmo
l) was added and stirred for a further 35 minutes. After cooling to room temperature, the mixture was diluted with benzene, filtered, and the filtrate was washed with water. The crude product obtained by distilling off the solvent after drying 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).

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-propinal

[0421]

Embedded image

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

NMR spectrum (270 MHz, CDCl ₃ ) δppm: 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]

[Chemical 104]

181 mg of 55% sodium hydride (4.
(54 mmol) was washed with hexane, suspended in 10 ml of 1,2-dimethoxyethane, and stirred at 0 ° C. under a nitrogen atmosphere while stirring 1.02 g of triethyl 4-phosphonoacetate.
(4.54 mmol) was added. 20 minutes later, 3- [4-
Trifluoromethyl) phenyl] -2-propinal 5
00 mg (2.52 mmol) was added and 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 distilling off the solvent was subjected to column chromatography using 15 g of silica gel,
Elute with benzene to give 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 = 16Hz), 7.5-7.7 (4H, m).

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-Pentene-4-in-1-ol

[0433]

Embedded image

480 mg (1.79 mmol) of ethyl (E) -5- [4- (trifluoromethyl) phenyl] -2-pentene-4-inoate was dissolved in 4 ml of toluene and stirred at 0 ° C. to obtain 1.5M. 2.38 ml of diisobutylaluminum hydride-toluene solution (3.5
8 mmol) was added. After 10 minutes, ice was added, and insoluble materials were removed by filtration using Celite. The crude product obtained by drying the organic layer and distilling off the solvent 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-Inal

[0437]

[Chemical formula 106]

350 mg (1.56 mmol) of (E) -5- [4- (trifluoromethyl) phenyl] -2-penten-4-yn-1-ol was added to 4 ml of methylene chloride.
The reaction mixture was dissolved in water, 3.5 g of active manganese dioxide was added, and the mixture was stirred at room temperature for 30 minutes. The solid was filtered off, 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 of the title compound (yield 70%) 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]

[Chemical formula 107]

Bis (2,2,2-trifluoroethyl)
(Methoxycarbonylmethyl) phosphonate 150mg
(0.47 mmol) was dissolved in 10 ml of tetrahydrofuran, and 0.5M potassium hexamethyldisilazide-toluene solution 0.94 was stirred under 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 in 1 ml of tetrahydrofuran was added. The reaction solution was slowly warmed to room temperature, saturated aqueous 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 using silica gel (eluted with 4% ethyl acetate-hexane) to give 89 mg of the title compound (yield 70%, about 1% of (E) -isomer). / 10) was obtained 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]

[Chemical 108]

Methyl according to Reference Examples 21 and 22
Yield 8 from (Z) -4-chloro-β- (trifluoromethyl) cinnamate in 2 steps as an oil.
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]

[Chemical 109]

By a reaction of (Z) -4-chloro-β- (trifluoromethyl) cinnamaldehyde and trimethylphosphonocrotonate in the same manner as in Reference Example 23,
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 (1
H, ddq, J = 15.2,11.9,2.0Hz).

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

[0454]

[Chemical 110]

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

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]

[Chemical 111]

2-Bromo-2-methyl-4 '-(trifluoromethyl) propiophenone 619 mg (2.10)
mmol) in dimethylformamide (3.8 ml) and stirred at room temperature under a nitrogen atmosphere while stirring 28% sodium methoxide-methanol solution (0.44 ml, 2.10).
mmol) was added. After 30 minutes, water was added and the mixture was extracted with ethyl acetate. The solvent was distilled off to obtain 860 mg of the title compound (yield-
100%) was obtained 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]

[Chemical 112]

2-Methyl-2-[(trans-2-phenyl-1,3-dioxan-5-yl) thio] -4'-
(Trifluoromethyl) propiophenone 680mg
(1.66 mmol), trimethylsulfoxonium iodide 547 mg (2.49 mmol), potassium hydroxide 381 mg (6.79 mmol), 1,2,4-triazole 264 mg (3.82 mmol) in t-butanol 5.7 ml. The mixture was heated and stirred at 80 ° C. for 6 hours. After cooling, the mixture was partitioned between chloroform and water, the chloroform layer was separated, dried and the solvent was distilled off. 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 605m.
g (74% yield) was obtained 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]

[Chemical 113]

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 gave 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]

[Chemical 114]

Cis-2-Phenyl-4- (p-toluenesulfonyloxy) -1,3-dioxane (5.00 g) was dissolved in methanol (50 ml), 4N-HCl dioxane solution (5 ml) was added, and the mixture was stirred at room temperature for 2 hours. NaHCO ₃
After 3.5 g of powder was added and stirred 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 ) δppm: 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-butadiene-1-yl] -1,3
-Dioxane

[0474]

[Chemical 115]

2- (p-toluenesulfonyloxy)-
200 mg of 1,3-propanediol (0.81 mmo
1) 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. Aqueous sodium hydrogen carbonate was added to the reaction solution and the mixture was stirred for 10 minutes, then molecular sieves were removed by filtration, and the mixture was 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) to give the less polar trans isomer 107.
mg (29% yield) and the more polar cis isomer 153
mg (yield 42%) was obtained as an oil.

NMR spectrum of 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
Mice inoculated with 0 ⁶ (10 per group) were given 1, 4, 2
4 hours later, 21 mg after infection by oral administration of 20 mg / kg of drug
The survival rate up to the day was examined. The results of comparison between the compound (1) of the present invention and commercially available fluconazole are shown in Table 2. From this result, it is clear that the compound (1) exhibits excellent antifungal activity.

Table 2 Compounds% Survival% 14 days 21 days Example 2 100 100 11 100 100 15 15 100 100 100 16 100 100 18 18 100 100 100 21 100 60 30 30 100 100 32 32 100 100 35 100 100 100 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 The powder of the above formulation was mixed and passed through a 60 mesh sieve, and this powder was then 250 mg of No. 3 gelatin capsule. And make capsules.

Formulation Example 2 Tablet 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 with corn starch paste and dried, and then a tableting machine. Tablet by 1
Tablets 200 mg tablets. This tablet can be sugar-coated if necessary.

[0479]

INDUSTRIAL APPLICABILITY The compound having the general formula (1) of the present invention or a pharmacologically acceptable salt thereof has excellent antifungal activity and is useful as an antifungal agent.

[Procedure amendment]

[Submission date] July 15, 1996

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0001

[Correction method] Change

[Correction content]

[0001]

FIELD OF THE INVENTION The present invention is particularly effective against human and animal fungal diseases represented by formula (I) 1,2,
It relates to 4-triazole compounds.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0002

[Correction method] Change

[Correction content]

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 61-85369 discloses a formula (I)

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0006

[Correction method] Change

[Correction content]

[0006]

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

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0007

[Correction method] Change

[Correction content]

[0007]

Embedded image

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0017

[Correction method] Change

[Correction content]

Preferred compounds of formula (I) are those wherein 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 group, particularly preferably 2, 4-dichlorophenyl, 2,
A compound which is a 4-difluorophenyl or 4- (trifluoromethyl) phenyl group.

[Procedure correction 6]

[Document name to be amended] Statement

[Name of item to be corrected] 0025

[Correction method] Change

[Correction content]

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

[Procedure Amendment 7]

[Document name to be amended] Statement

[Correction target item name] 0052

[Correction method] Change

[Correction content]

The triazole compound (I) of the present invention has at least two asymmetric carbon atoms, and optical isomers and diastereomers exist. Optical enantiomers can be obtained as both antipodes by a general optical resolution method or an asymmetric synthesis method. The diastereomers can be separated by using a usual separation method such as fractional recrystallization or chromatography. The compound (I) of the present invention includes one or a mixture of these isomers.

[Procedure Amendment 8]

[Document name to be amended] Statement

[Correction target item name] 0053

[Correction method] Change

[Correction content]

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. The pharmacologically acceptable salt of compound (I) is, for example, a salt of an inorganic acid 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, and toluenesulfonic acid, or a salt of an amino acid such as glutamic acid and aspartic acid, preferably a carboxylic acid. It is salt.

[Procedure Amendment 9]

[Document name to be amended] Statement

[Correction target item name] 0054

[Correction method] Change

[Correction content]

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

[Procedure Amendment 10]

[Document name to be amended] Statement

[Correction target item name] 0055

[Correction method] Change

[Correction content]

The compound (I) and its pharmacologically acceptable salt of the present invention show excellent antifungal activity, and when the compound (I) and its pharmacologically acceptable salt are used as an antifungal agent, As such or in admixture with an appropriate pharmacologically acceptable excipient, diluent, etc., and administered orally by tablets, capsules, granules, powders or syrups, or parenterally by injection, etc. can do.

[Procedure Amendment 11]

[Document name to be amended] Statement

[Name of item to be corrected] 0057

[Correction method] Change

[Correction content]

[0057]

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

[Procedure Amendment 12]

[Document name to be amended] Statement

[Name of item to be corrected] 0058

[Correction method] Change

[Correction content]

[0058]

Embedded image

[Procedure Amendment 13]

[Document name to be amended] Statement

[Correction target item name] 0061

[Correction method] Change

[Correction content]

Represents ) That is, JP-A-2-191
262 (Head 2.7.27), the epoxide compound (2) is reacted with a mercaptan (3) or an acetic acid ester derivative (4) thereof under a basic condition to produce a target compound (Ia). Is. As the solvent used in the reaction, alcohols such as methanol, ethanol and propanol, and aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran are preferable, but the 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 acetic acid ester derivative (4) is used at 1 to 3 molar equivalents. The reaction temperature is room temperature to 100 ° C., and the reaction time is 2 to 10 hours. The compound (Ia) is obtained by treating the reaction solution according to a conventional method (extracting with an organic solvent, distilling off the solvent and purifying the resulting oil by column chromatography or recrystallization).

[Procedure Amendment 14]

[Document name to be amended] Statement

[Correction target item name] 0067

[Correction method] Change

[Correction content]

[0067]

[Chemical 9]

[Procedure Amendment 15]

[Document name to be amended] Statement

[Correction target item name] 0071

[Correction method] Change

[Correction content]

Of the compounds of formula (I) according to the invention,
Compound (Ia) in which R ⁰ is a hydrogen atom and n = 0 can also be produced by the method shown below.

[Procedure Amendment 16]

[Document name to be amended] Statement

[Name of item to be corrected] 0072

[Correction method] Change

[Correction content]

[0072]

[Chemical 11]

[Procedure Amendment 17]

[Document name to be amended] Statement

[Correction target item name] 0073

[Correction method] Change

[Correction content]

(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 Patent Application Laid-Open No. 3-240778 (Hair 3.10.2)
This is a method for producing the target compound (Ia) by reacting the triazolyl mercapto alcohol derivative (11) described in 8) with an alkylating reagent (12) under basic conditions. As the solvent used in the reaction, methanol, ethanol, propanol, butanol, dimethylformamide, dimethylacetamide, dimethylsulfoxide,
Examples thereof include acetonitrile, tetrahydrofuran, dioxane, diethyl ether, acetone, benzene, toluene, xylene and the like. The base used in the reaction is triethylamine, diisopropylethylamine, sodium hydride, sodium methoxide, sodium ethoxide, lithium methoxide, potassium tert-butoxide,
Sodium hydroxide, potassium hydroxide and the like are used, and the amount used is 1 to 3 molar equivalents relative to compound (11).
The alkylating reagent (12) is used at 1 to 3 molar equivalents.
The reaction temperature is −50 to 100 ° C., and the reaction time is 2 to 10 hours. The compound (Ia) is obtained by treating the reaction solution according to a conventional method (extracting with an organic solvent, purifying an oil obtained by distilling off the solvent by chromatography or recrystallization).

[Procedure 18]

[Document name to be amended] Statement

[Correction target item name] 0078

[Correction method] Change

[Correction content]

(In the above formula, R ² , R ³ , R ⁴ , R ⁵ , A
r ² , q, r, s, and t have the same meaning as described above. ) Among the compounds having the formula (I) of the present invention, R ⁰ is a hydrogen atom, n = 0, p = 0, and A is 1,3-
The compound (Ib) having a dioxane ring can also be produced by the following method.

[Procedure Amendment 19]

[Document name to be amended] Statement

[Correction target item name] 0079

[Correction method] Change

[Correction content]

[0079]

Embedded image

[Procedure amendment 20]

[Document name to be amended] Statement

[Correction target item name] 0080

[Correction method] Change

[Correction content]

(In the above formula, 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 above-mentioned epoxide compound (2)
And the thioacetic acid derivative (15) obtained by the reaction of the above-mentioned known compound (5) with sodium thioacetate, (2)
And (4) are reacted under the same conditions as described above to obtain compound (16), which is deprotected according to a conventional method such as acid treatment to give (17), By reacting the aldehyde compound (6), the target compound (I
b) is a method of manufacturing. The reaction of (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 acid used is 1-2 molar equivalents with respect to (17). Aldehyde (6) is used at 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 performed in the range of 0 ° C to the boiling point of the solvent, and the reaction time is 2 to 10 hours. Water generated in the reaction can be removed by azeotropic distillation, but molecular sieves may be used as a dehydrating agent. The reaction solution is neutralized with aqueous sodium hydrogen carbonate and the like, and then treated by a conventional method (extraction with an organic solvent, purification of an oil obtained by distilling off the solvent by chromatography or crystallization) to obtain the compound (Ib).

[Procedure correction 21]

[Document name to be amended] Statement

[Correction target item name] 0081

[Correction method] Change

[Correction content]

Among 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 heterocycle (azetidine, pyrrolidine, piperidine, homopiperidine). The compound (Ic) which is) can also be manufactured by the following method.

[Procedure correction 22]

[Document name to be amended] Statement

[Correction target item name] 0082

[Correction method] Change

[Correction content]

[0082]

[Chemical 15]

[Procedure amendment 23]

[Document name to be amended] Statement

[Name of item to be corrected] 0083

[Correction method] Change

[Correction content]

(In the above formula, 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 subjecting the thioacetic acid derivative (9) to alkali treatment are treated under the same conditions as in the reaction of (2) and (3). To react with compound (1
9) is obtained, and (19) is treated with an acid according to a conventional method for deprotection to give a compound (20), and the target compound (Ic) is obtained by reacting (20) with the above acid chloride (10). It is a manufacturing method. The reaction of (20) and (10) is carried out in the presence of a suitable base according to a conventional method in an inert solvent such as benzene, toluene, methylene chloride, chloroform or tetrahydrofuran. (Reference Example Nos. 13, 14, 18, 19) Of the compounds (I) of the present invention, the compounds with n = 1 or n = 2 can be produced by the method described below. That is, the compound (I) of n = 1 can be produced by oxidizing the compound (I) of the present invention having n = 0 obtained by the above-mentioned method with 1 equivalent of an oxidizing agent in a solvent. Further, the compound (I) with n = 2 can be produced by oxidizing with 2 equivalents or more of an oxidizing agent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but halogenated hydrocarbons such as methylene chloride and chloroform are preferred. Examples of the oxidizing agent used include peracetic acid and 3-chloroperbenzoic acid. The reaction temperature is 0 to 50 ° C, preferably room temperature, and the reaction time is usually 3
0 minutes to 2 hours. The reaction solution is treated according to a conventional method (after washing with a sodium bicarbonate solution, the solvent is distilled off to obtain a crude product, which is purified by chromatography or recrystallization).
And compound (I) (n = 1 or 2) is obtained.

[Procedure correction 24]

[Document name to be amended] Statement

[Correction target item name] 0084

[Correction method] Change

[Correction content]

Of the compounds of formula (I) of the present invention,
Compounds (I) wherein R ⁰ is lower alkyl and n = 0
The production of d) can be carried out by the method shown below.

[Procedure correction 25]

[Document name to be amended] Statement

[Correction target item name] 0085

[Correction method] Change

[Correction content]

[0085]

Embedded image

[Procedure Amendment 26]

[Document name to be amended] Statement

[Correction target item name] 0086

[Correction method] Change

[Correction content]

(In the above formula, Ar ¹ , R ⁰ , R ¹ and R
⁸ has the same meaning as described above. That is, Japanese Patent Laid-Open No. 7-2802 (7.1.6)
The bromketone (21) obtained according to the method described in 1) is reacted with the above-mentioned mercaptan (3) or its acetic acid ester derivative (4) under alkaline conditions to obtain a thioether derivative (22), and then (22) ) In the presence of a base, trimethylsulfoxonium iodide and 1,
The target compound (Id) is obtained by reacting 2,4-triazole.
Is a method of manufacturing. As the solvent used in the reaction of (21) and (3) or (4), alcohols such as methanol, ethanol and propanol are suitable, and the alkali used is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium. Such as ethoxide. The solvent used in the reaction for converting the thioether derivative (22) to (Id) is an alcohol such as methanol, ethanol, propanol, butanol or t-butanol, an aproton such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or tetrahydrofuran. Protic solvents are preferred.
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 (22 ) To 2-5 molar equivalents.
Trimethylsulfoxonium iodide and 1,2,4-
Triazole is used in an amount of 1 to 2 mol equivalent based on compound (22). The reaction temperature is room temperature to 100 ° C,
The reaction time is 2 to 10 hours. The reaction solution is treated according to a conventional method (the crude product obtained by extracting the organic solvent and then distilling the solvent away is purified by column chromatography or recrystallization) to obtain the compound (Id) (n = 0). In the compound (Id) obtained by the above method, R ⁸
But

[Procedure Amendment 27]

[Document name to be amended] Statement

[Correction target item name] 0088

[Correction method] Change

[Correction content]

From the compound (23) which is a compound (I) via the triol (24) by the method shown below, n = 0, p = 0 and A = 1,
It can be led to the compound (Ie) which is a 3-dioxane ring.

[Procedure correction 28]

[Document name to be amended] Statement

[Correction target item name] 0089

[Correction method] Change

[Correction content]

[0089]

Embedded image

[Procedure correction 29]

[Document name to be amended] Statement

[Correction target item name] 0090

[Correction method] Change

[Correction content]

(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 meanings as described above. ) The reaction conditions for the above steps are as follows: (16) → (17) → (I
It is the same as that described in the reaction of b).

[Procedure amendment 30]

[Document name to be amended] Statement

[Name of item to be corrected] 0476

[Correction method] Change

[Correction content]

NMR spectrum of 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
Mice inoculated with 0 ⁶ (10 per group) were given 1, 4, 2
4 hours later, 21 mg after infection by oral administration of 20 mg / kg of drug
The survival rate up to the day was examined. The results of comparison between the compound (I) of the present invention and commercially available fluconazole are shown in Table 2. From this result, it is clear that the compound (I) exhibits excellent antifungal activity.

[Procedure correction 31]

[Document name to be amended] Statement

[Name of item to be corrected] 0479

[Correction method] Change

[Correction content]

[0479]

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

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/535 A61K 31/535 C07D 401/12 249 C07D 401/12 249 401/14 205 401/14 205 207 207 239 239 403/12 205 403/12 205 205 207 207 239 239 405/12 249 405/12 249 405/14 205 405/14 205 207 207 211 211 211 213 213 239 239 249 249 409/12 249 409/12 249 409/14 205 205 409/14 205 207 207 207 211 211 239 239 249 249 411/12 411/12 411/14 411/14 413/12 249 413/12 249 413/14 213 413/14 213 249 249 (72) Inventor Toshiyuki Konosu 1 Hiromachi, Shinagawa-ku, Tokyo No. 2-58 Sankyo stock company (72) Inventor Atsushi Maeda 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company (72) Inventor Takeo Miyaoka 1-2-chome Hiromachi, Shinagawa-ku, Tokyo No. 58 Sankyo stock company (72) Inventor Hiro Yasuda 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company

Claims (26)

[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 substituent represents a halogen atom or a trifluoromethyl group), Ar ² represents phenyl, a 5- or 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 (wherein the substituent is a lower alkyl group, Lower alkoxy group, halogen atom, lower alkyl group substituted with halogen atom, lower alkoxy group substituted with halogen atom, nitro group, cyano group, -S (O) _m R ⁶ group (R ⁶ : substituted with halogen atom Optionally lower alkyl group; m: 0, 1 or 2) or —NHCOR ⁷ group (R ⁷ represents a lower alkyl group), wherein the aromatic heterocyclic group is nitrogen, oxygen or sulfur atom. Have at least one
R ⁰ represents a hydrogen atom or a lower alkyl group, R ¹ represents a lower alkyl group, and R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a lower alkyl group or a halogen atom. A substituted lower alkyl group, and when q and s each represent ² , R ² , R ³ , R ⁴ and R ⁵ independently represent the same or different group, n represents 0, 1 or 2, p represents 0 or 1, q, r and s represent 0, 1 or 2, and A is a 4- to 7-membered aliphatic carbocyclic group having 4 to 7 carbon atoms or at least a nitrogen, oxygen or sulfur atom. 4 to have one
A 7-membered aliphatic heterocyclic group is shown. 2. A triazole compound or a pharmacologically acceptable compound thereof 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). Ru salt. 3. The triazole compound or its pharmacology 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). Top acceptable salt. 4. Ar ² has a phenyl group, a 5- or 6-membered aromatic heterocyclic group (wherein the aromatic heterocyclic group has at least one nitrogen, oxygen, or sulfur atom) or 1 to 3 substituents. Phenyl group or 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 which may be substituted with a halogen atom; m: 0, 1 or 2 showing a) shows the, aromatic heterocyclic group nitrogen, oxygen, A triazole compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which has at least one sulfur atom). 5. Ar ² is a phenyl group, a 5- or 6-membered aromatic heterocyclic group (wherein the aromatic heterocyclic group has one of nitrogen, oxygen and sulfur atoms) or phenyl having 1 to 3 substituents. A group 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 with a halogen atom;
m: 0, 1 or 2), wherein the aromatic heterocyclic group has one nitrogen, oxygen or sulfur atom).
To 3 triazol compound or a pharmaceutically acceptable salt thereof. 6. Ar ² is a phenyl group, a 5- or 6-membered aromatic heterocyclic group (wherein the aromatic heterocyclic group has one nitrogen or sulfur atom), or a phenyl group having 1 or 2 substituents. 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,
Nitro group, 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), wherein the aromatic heterocyclic group has one of nitrogen and sulfur atoms.) The triazole compound or a pharmaceutically acceptable salt thereof according to claim 1. 7. Ar ² is a phenyl group or a pyridyl group, or a phenyl group having 1 to 2 substituents, a pyridyl group or a thienyl group (wherein the substituent is a lower alkyl group, a halogen atom or a lower group substituted with a halogen atom). An alkyl group,
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 with a halogen atom; m: 0, 1 or 2 The triazol compound or a pharmacologically acceptable salt thereof according to claim 1, wherein 8. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁰ is a hydrogen atom, a methyl group, an ethyl group or a propyl group. 9. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁰ is a hydrogen atom, a methyl group or an ethyl group. 10. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁰ is a hydrogen atom or a methyl group. 11. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is a methyl group, an ethyl group or a propyl group. 12. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is a methyl group or an ethyl group. 13. R ¹ is a methyl group.
Or a pharmacologically acceptable salt thereof. 14. R ¹ , R ³ , R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, a lower alkyl group or a lower alkyl group substituted with a fluorine or chlorine atom.
To 13 triazole compounds or pharmaceutically acceptable salts thereof. 15. R ² , R ³ , R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, a methyl group, an ethyl group or a propyl group or a methyl group, an ethyl group or a propyl group substituted with a fluorine or chlorine atom. Claims 1 to 1
The triazole compound of 3 or a pharmaceutically acceptable salt thereof. 16. R ¹ , R ³ , R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, a methyl group or an ethyl group or a methyl group or an ethyl group substituted with a fluorine or chlorine atom. Or a pharmacologically acceptable salt thereof. 17. A triazole compound or a pharmacological agent thereof 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. Top acceptable salt. 18. The triazole compound according to claim 2, wherein n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. 19. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is 0. 20. The method according to claim 2, wherein p is 0 or 1.
Or a pharmacologically acceptable salt thereof. 21. The triazole compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein q, r and s are 0, 1 or 2. 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 or sulfur atom. To 21 triazole compounds or pharmaceutically acceptable salts 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 compound or a pharmacologically acceptable salt thereof. 24. A is cyclohexane, piperidine, 1,
The triazole compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a 3-dioxane or a 1,3-dithiane ring. 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-butadiene-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-butadiene-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-pentadiene-1-yl] -1,3-dioxan-1-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-butadiene-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- (trifluoromethylthio) phenyl] -1,3
-Butadin-1-yl] -1,3-dioxan-5-
Ill] 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-butadiene-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-butadiene-1-yl] -1,3-dioxan-5-yl] thio] -2-butanol, 2- (2,2 4-difluorophenyl) -1- (1H-
1,2,4-triazol-1-yl) -3-[[4-
[4- (trifluoromethyl) phenyl] -1,3-butadiene-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-butadiene-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-dioxan-5-
Il] thio] -2-butanol or a pharmacologically acceptable salt thereof. 26. An antifungal agent comprising the triazole compound according to any one of claims 1 to 25 or a pharmacologically acceptable salt thereof as an active ingredient.