JP3040811B2 - Oxetane derivative - Google Patents

Description

The present invention relates to a novel oxetane derivative having excellent agricultural bactericidal and antifungal activities and a method for producing the same.

(Prior Art) Various triazole compounds having an agricultural fungicidal activity and an antifungal activity are known, but compounds having an oxetane skeleton are only described in EP 318214.

(Problems to be Solved by the Invention) The inventors of the present invention have conducted intensive studies on the synthesis of a derivative having a triazole skeleton and its physiological activity for many years, and as a result, the structure is completely different from that of a conventional triazole compound. The present inventors have found that a novel triazole compound having an oxetane skeleton has excellent agricultural bactericidal activity and antifungal activity, and completed the present invention.

(Constitution) The present invention provides a novel oxetane derivative or a salt thereof,
It comprises a method for producing them, an agricultural fungicide containing them as an active ingredient, and an antifungal agent containing them as an active ingredient.

The novel oxetane derivative of the present invention has the general formula [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group.

R ² represents a hydrogen atom or a lower alkyl group.

R ³ represents a hydrogen atom, a lower alkyl group or a phenyl group.

R ⁴ represents a hydrogen atom or a lower alkyl group.

At this time, R ¹ and R ⁴ together form
May form a saturated ring having 5 to 6 carbon atoms together with the carbon atoms. Alternatively, R ³ and R ⁴ may together form a saturated ring having 3 to 6 carbon atoms together with one carbon atom to which they are bonded.

R ⁵ , R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a lower alkyl group, a halogen atom, a halogeno lower alkyl group,
It represents a lower alkoxy group or a halogeno lower alkoxy group.

R ⁸ represents a hydrogen atom or a lower alkyl group. The agricultural bactericide and antifungal agent of the present invention contain the above compound or a salt thereof as an active ingredient.

In addition, the production method is represented by the general formula [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group.

R ² represents a hydrogen atom or a lower alkyl group.

R ³ represents a hydrogen atom, a lower alkyl group or a phenyl group.

R ⁴ represents a hydrogen atom or a lower alkyl group.

At this time, R ¹ and R ⁴ together form
May form a saturated ring having 5 to 6 carbon atoms together with the carbon atoms. Alternatively, R ³ and R ⁴ may together form a saturated ring having 3 to 6 carbon atoms together with one carbon atom to which they are bonded.

R ⁵ , R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a lower alkyl group, a halogen atom, a halogeno lower alkyl group,
It represents a lower alkoxy group or a halogeno lower alkoxy group.

R ⁸ represents a hydrogen atom or a lower alkyl group.

R ⁹ represents a hydrogen atom or a protecting group for a hydroxyl group.

Y represents a nucleophilic leaving group. ] Is treated with a base.

In the above general formulas (I) and (II), the “lower alkyl group” in the definition of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ includes, for example, methyl, ethyl , N-
Propyl, isopropyl, n-butyl, isobutyl, s
-Butyl, t-butyl, n-pentyl, isopentyl,
2-methylbutyl, neopentyl, n-hexyl, 4-
Methylpentyl, 3-methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,
A linear or branched alkyl group having 1 to 6 carbon atoms, such as 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, or 2,3-dimethylbutyl; Numerical 1 to 4 alkyl groups.

Examples of the saturated ring having 5 to 6 carbon atoms formed by R ¹ and R ⁴ together include cyclopentane and cyclohexane.

Examples of the saturated ring having 3 to 6 carbon atoms formed by R ³ and R ⁴ together include cyclopropane, cyclobutane, cyclopentane and cyclohexane.

The "halogen atom" in the definitions of R ^5, R ⁶ and R ^7,
Indicate fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

The `` halogeno lower alkyl group '' in the definition of R ⁵ , R ⁶ and R ⁷ includes, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,
Examples include groups such as 2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, and 2,2-dibromoethyl, and preferably trifluoromethyl, trichloromethyl, and difluoromethyl. , 2
-Bromoethyl, 2-chloroethyl and 2-fluoroethyl.

The `` lower alkoxy group '' in the definition of R <sup>5</sup> , R <sup>6</sup> and R <sup>7 represents</sup> a group in which the above-mentioned `` lower alkyl group '' is bonded to an oxygen atom, for example, methoxy, ethoxy, n-propoxy,
Isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methyl Pentoxy, 3,3-dimethylbutoxy,
2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2
-Represents a linear or branched alkoxy group having 1 to 6 carbon atoms such as dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, and preferably an alkoxy group having 1 to 4 carbon atoms. is there.

The term `` halogeno lower alkoxy group '' in the definition of R <sup>5</sup> , R <sup>6</sup> and R <sup>7</sup> refers to a group in which the aforementioned `` halogeno lower alkyl group '' is bonded to an oxygen atom, for example, trifluoromethoxy, trichloromethoxy, difluoromethoxy, bromo Difluoromethoxy, chlorodifluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy,
2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy, 2-bromoethoxy, 2-chloroethoxy, 2-
Examples include groups such as fluoroethoxy and 2,2-dibromoethoxy, and preferably trifluoromethoxy.

The `` hydroxyl protecting group '' in the definition of R ⁹ represents a protecting group in the reaction, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl , Alkylcarbonyl groups such as stearoyl, chloroacetyl, dichloroacetyl, trichloroacetyl,
Aliphatic acyl groups such as halogenated alkylcarbonyl groups such as trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; benzoyl Arylcarbonyl groups such as α-naphthoyl and β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl and 4-toluoyl. A lower alkylated arylcarbonyl group such as 4-anisoyl, a lower alkoxylated arylcarbonyl group such as 4-anisoyl, a nitrated arylcarbonyl group such as 4-nitrobenzoyl and 2-nitrobenzoyl,
Aromatic acyl groups such as lower alkoxycarbonylated arylcarbonyl groups such as (methoxycarbonyl) benzoyl and arylated arylcarbonyl groups such as 4-phenylbenzoyl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-
Tri-lower alkylsilyl groups such as butylsilyl and triisopropylsilyl, and tri-lower alkylsilyl groups substituted with one or two aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl Silyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, lower alkoxymethyl groups such as t-butoxymethyl, 2-methoxyethoxymethyl Lower alkoxylated lower alkoxymethyl group, an alkoxymethyl group such as halogenated lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; 1-ethoxyethyl,
A lower alkoxylated ethyl group such as 1- (isopropoxy) ethyl, an ethyl halide group such as 2,2,2-trichloroethyl, an arylenylenyl ethyl group such as 2- (phenylzerenyl) ethyl A substituted ethyl group such as
Benzyl, α-naphthylmethyl, β-naphthylmethyl,
A lower alkyl group substituted with one to three aryl groups such as diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl,
Methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-
Trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl,
4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl,
1 wherein the aryl ring is substituted with a lower alkyl, lower alkoxy, nitro, halogen, cyano group such as piperonyl;
Aralkyl groups such as lower alkyl groups substituted with 3 to 3 aryl groups; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl, 2,2,2-trichloroethoxy Carbonyl, an alkoxycarbonyl group such as a lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group such as 2-trimethylsilylethoxycarbonyl; an alkenyloxycarbonyl group such as vinyloxycarbonyl and allyloxycarbonyl; benzyloxycarbonyl; 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
1-2, such as nitrobenzyloxycarbonyl
Protective groups in a reaction such as an aralkyloxycarbonyl group in which the aryl ring may be substituted with a lower alkoxy or nitro group, preferably an aralkyl group or a tri-lower alkylsilyl group, Most preferably, it is a benzyl group or a trimethylsilyl group.

The term "nucleophilic leaving group" in the definition of Y includes, for example, halogen atoms such as chlorine, bromine and iodine; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; trifluoromethanesulfonyloxy, pentane A leaving group such as a halogeno lower alkanesulfonyloxy group such as fluoroethanesulfonyloxy; an arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy;
It is preferably a lower alkanesulfonyloxy group, more preferably methanesulfonyloxy.

The base used in the production of the present invention is not particularly limited as long as it is used as a base in a usual reaction. Preferably, alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate, carbonate Alkali metal bicarbonates such as potassium hydrogen; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, potassium hydroxide;
Inorganic bases such as alkali metal hydroxides such as barium hydroxide; alkali metal cyanides such as sodium cyanide and potassium cyanide; alkali metal azides such as lithium azide and sodium azide: sodium methoxide, sodium ethoxide, and potassium alkali metal alkoxides such as t-butoxide; mercaptan alkali metals such as sodium methyl mercaptan and sodium ethyl mercaptan; triethylamine;
Tributylamine, diisopropylethylamine, N-
Methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-
Ene, 1,4-diazabicyclo [2.2.2] octane (DABC
O) Organic bases such as 1,1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or organometallic bases such as butyllithium and lithium diisopropylamide.

In order to carry out the reaction effectively, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, and dibenzo-
Crown ethers such as 18-crown-6 can also be added.

The compound (I) of the present invention can be converted into a salt,
Such salts preferably include hydrofluorides, hydrochlorides, hydrobromides, hydrohalides such as hydroiodide, nitrates, perchlorates, sulfates, and the like. Inorganic salts such as phosphates; lower alkylsulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate , Succinate, and organic acid salts such as succinate.

Compound (I) of the present invention has an asymmetric carbon in the molecule,
There are stereoisomers each of which is R-coordinate or S-coordination, and each of them or a mixture thereof is included in the present invention.

In the compound (I) of the present application, preferred compounds include: (1) a compound wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom or an alkyl group having 1 to 4 carbon atoms (2) A compound in which R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom or a methyl group. (3) One of R ¹ and R ² is a hydrogen atom, and the other is a carbon atom having 1 to 4 carbon atoms. Alkyl groups, one of R ³ and R ⁴ is a hydrogen atom,
A compound in which the other is an alkyl group having 1 to 4 carbon atoms (4) ^one of R ¹ and R ² is a hydrogen atom, the other is a methyl group, one of R ³ and R ⁴ is a hydrogen atom, and the other is a methyl group (5) A compound in which R ¹ and R ² are both hydrogen atoms, and R ³ and R ⁴ are both alkyl groups having 1 to 4 carbon atoms. (6) R ¹ and R ² are both hydrogen atoms. A compound wherein R ³ and R ⁴ are both methyl groups (7) a compound wherein R ¹ , R ³ and R ⁴ are the same or different and are a lower alkyl group and R ² is a hydrogen atom (8) A compound in which R ¹ , R ³ and R ⁴ are the same or different and are a methyl group, and R ² is a hydrogen atom; (9) R ⁵ , R ⁶ and R ⁷ are the same or different and are a hydrogen atom,
A compound that is a halogen atom or a halogeno lower alkyl group (10) R ⁵ , R ^6, and R ⁷ are the same or different, and a compound that is a hydrogen atom or a halogen atom (11) R ⁵ , R ^6, and R ⁷ are the same Or differently, a hydrogen atom,
A compound which is a chlorine atom, a fluorine atom or a bromine atom (12) one of R ⁵ , R ⁶ and R ⁷ is a hydrogen atom and the other two are the same or different and are a halogen atom or a halogeno lower alkyl group; Certain compounds (13) Compounds in which one of R ⁵ , R ⁶ and R ⁷ is a hydrogen atom and the other two are the same or different and are halogen atoms (14) R ⁵ , R ⁶ and R ⁷ A compound in which one of them is a hydrogen atom and the other two are the same or different and are a chlorine atom, a fluorine atom or a bromine atom. (15) Two of R ⁵ , R ⁶ and R ⁷ are hydrogen atoms the other one is a compound which is a halogen atom or a halogeno-lower alkyl group (16) R ^5, two of R ⁶ and R ⁷ are hydrogen atom, the other one is a halogen atom compound (17) R ⁵ , two of R ⁶ and R ⁷ are hydrogen atom, the other one is a chlorine atom, a fluorine atom or Atom, Compound (18) (2R ^*, 3S ^*), compound (wherein "*" mark indicates a racemate. The display of (2R ^*, 3S ^*), the
It means a 1: 1 mixture of isomers of (2R, 3S) and (2S, 3R), which is equivalent to (2S ^* , 3R ^* ). On the other hand, (2
The notation R ^* , 3R ^* ) means a 1: 1 mixture of (2R, 3R) and (2S, 3S) isomers, which is equivalent to (2S ^* , 3S ^* ). ).

Representative compounds of the present invention include, for example, the compounds described in Tables 1, 2, and 3 below, but the present invention is not limited to these compounds.

In the following table, Me is a methyl group, Et is an ethyl group, Pr is a propyl group, iPr is an isopropyl group, Bu is a butyl group, Ph is a phenyl group, Cl is a chlorine atom, F is a chlorine atom, F is a fluorine atom, and Br is a bromine atom. , CF ₃ is a trifluoromethyl group, 2,4-F2 is a 2,4-difluoro group, 2,4-Cl2 is a 2,4-dichloro group, and other substituents are numbers on the benzene ring. Indicates the position, followed by the substituent. For example, 4-OCF ₃ is 4
-Represents a trifluoromethoxy group.

The following formulas (I-1), (I-2) and (I-3) correspond to Tables 1, 2 and 3, respectively.

Among the above exemplified compounds, preferred compounds include 1-
7, 1-21, 1-114, 1-118, 1-145, 1-146, 1
-246, 1-277, 1-317, 1-355, 1-383, 1-39
3, 1-409, 1-447, 1-470, 1-483, 1-486, 1
-487, 1-493, 1-497 and 1-508.

Further, preferred compounds include 1-7, 1-114, 1
-145, 1-146, 1-246, 1-277, 1-317, 1-38
3, 1-447, 1-483 and 1-486.

Most preferred compounds include 1-7, 1-383, 1-4
83 and 1-486.

The oxetane derivative of the present invention can be produced by the method described below.

(Method A) In the above formula, R ³ , R ⁴ and R ⁸ are as defined above,
¹⁰ represents hydrogen or a lower alkyl group, and Ar is a general formula (Wherein, R ⁵ , R ⁶ and R ⁷ have the same meanings as described above).

Step A is a step of producing an alcohol compound (AII) by reducing the ester compound (AI).

This step and the production of (AI) as a raw material thereof can be carried out according to the methods described in JP-A-2-9864 and JP-A-58-82376.

(Method B) In the above formula, R ¹ , R ³ , R ⁴ , R ⁸ , R ⁹ and Ar have the same meaning as described above.

X represents a halogen atom such as chlorine, bromine or iodine.

R ¹¹ , R ¹² and R ¹³ have the same meaning as R ² as a group having —C (R ¹¹ ) (R ¹² ) (R ¹³ ).

In step B-1, the starting compound (BI) is reacted with a Grignard reagent (BII) in a solvent according to a conventional method, and, if desired, the generated hydroxyl group is subjected to a conventional method, for example, a review of green etc. Protective Groups in Organic Synthesis "
This is a step of producing a compound (BIII) by protecting with various protecting groups according to Chapter 2, Wiley-Interscience.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether can be mentioned.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of the solvent used, but is usually from 30 minutes to 3 hours.

When the reaction is performed in the presence of a Lewis acid such as zinc chloride, tin chloride, titanium chloride, a trifluoroboron-ether complex, and diethyl aluminum chloride, the reaction may be more preferably performed.

The starting compound (BI) of the above-mentioned Method B-1 can be produced by a conventional method, for example, the method described in JP-B-63-46075 or JP-B-63-5.
It can be easily produced according to the method described in Japanese Patent Publication No. 390.

Step B-2 is a step of preparing a vinyl compound (B III) in a solvent,
This is a step for producing an alcohol compound (BIV) by subjecting it to a hydroboration reaction.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably ether, tetrahydrofuran, dioxane,
Ethers such as dimethoxyethane can be mentioned.

The hydroboration reaction is preferably carried out using diborane (B ₂ H ₆ ), borane-dimethyl sulfide complex (BH ₃ .S
After reacting a borane reagent such as (CH ₃ ) ₂ ) and 9-borabicyclononane (9-BBN), a hydrogen peroxide solution is allowed to act under alkaline conditions to oxidatively desorb boron. Is achieved by

The reaction is carried out at a temperature of -20 ° C to 80 ° C, preferably room temperature to 50 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of solvent used, but is usually from 15 minutes to 5 hours.

(Method C) In the above formula, R ¹ , R ³ , R ⁴ , R ⁸ , R ¹¹ , R ¹² , R ¹³ and Ar
Has the same significance as described above.

Step C-1 is a step of epoxidizing a vinyl compound (CI) in a solvent to produce a compound (CII).

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 preferably includes halogenated hydrocarbons such as methylene chloride and chloroform. .

The epoxidation reagent is not particularly limited as long as it is a reagent capable of oxidizing a double bond into an epoxy, but preferably, such as peracetic acid, 3-chloroperbenzoic acid, and magnesium perphthalate. Organic peracid, and it is used in an amount of 1 to 2 equivalents to the starting compound. The reaction is carried out at a temperature of 0 ° C. to 50 ° C., preferably at room temperature.

The reaction time varies depending mainly on the reaction temperature, the starting compound, the oxidizing agent or the type of the solvent used, but is usually from 30 minutes to 3 days.

Step C-2 is a step of producing an alcohol compound (C III) by reducing the epoxy compound (C II) or performing a ring opening reaction using a Grignard reagent.

The solvent used for the reduction reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably ether, tetrahydrofuran,
Ethers such as dioxane and dimethoxyethane can be mentioned.

The reduction is carried out according to a conventional method, and preferably, a reducing agent such as a metal hydride such as lithium aluminum hydride is used.

The reaction temperature is from -30 ° C to 50 ° C, and the reaction time is
Although it depends mainly on the reaction temperature, the type of the starting compound and the type of the solvent used, it is usually from 30 minutes to 3 hours.

The ring opening reaction using a Grignard reagent is carried out, for example, by a Grignard reagent having the general formula R ¹³ -X [wherein, R ¹³ has the same meaning as described above, X represents MgZ (where Z represents a halogen atom) Is carried out according to a conventional method in a solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether can be mentioned.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of the solvent used, but is usually from 30 minutes to 3 hours.

(Method D) In the above formula, R ¹ , R ³ , R ⁴ , R ⁸ and Ar have the same meaning as described above.

Step D-1 is a step in which compound (DI) and a carbonyl compound (D
In this step, compound (D III) is produced by subjecting II) to aldol condensation.

Step D-2 is a step of reducing the carbonyl compound (D III) to produce an alcohol compound (D IV).

These two steps are based on ACS Symposium Series No.355
(1987), Chapter 27, p316, PA Worthington.

(Method E) In the above formula, R ¹ , R ³ , R ⁴ , R ⁸ , R ⁹ , R ¹¹ , R ¹² and Ar are
The meaning is as defined above.

Step E-1 is a step of oxidatively decomposing the vinyl compound (EI) in a solvent to produce a carbonyl compound (E II).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Preferably, halogenated hydrocarbons such as methylene chloride and chloroform; ethyl acetate, acetic acid Esters such as propyl; ketones or ethers such as acetone,
Ethers such as tetrahydrofuran, dioxane and dimethoxyethane can be mentioned.

The reagent used for the oxidation reaction is not particularly limited as long as it can convert the double bond into a carbonyl group by oxidative decomposition, and is preferably in a solvent of a halogenated hydrocarbon or ester. Ozone at -78 ° C to room temperature followed by treatment with a sulfide such as dimethyl sulfide, or in a mixed solvent of ethers or ketones and water at 0 to 50 ° C at 2 to 4 ° C. An equivalent amount of an alkali metal metaperiodate such as sodium metaperiodate and a catalytic amount of osmium oxide such as osmium tetroxide are added and reacted.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the kind of the solvent used, but is usually from 3 hours to 10 hours.

Step E-2 is a step for producing an alcohol compound (EIII) by reducing the carbonyl group of the carbonyl compound (EII).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an ether such as tetrahydrofuran, dioxane, dimethoxyethane or methanol. , Etano-
And n-propanol.

The reduction is carried out according to a conventional method, but preferably a reducing agent such as a metal hydride such as sodium borohydride is used.

The reaction temperature is from -30 ° C to room temperature, and the reaction time is
Although it depends mainly on the reaction temperature, the starting compound and the kind of the solvent used, it is usually 5 to 30 minutes.

Step E-3 is a step of producing compound (E IV) by removing hydroxyl-protecting group R ⁹ .

The removal of the protecting group for the hydroxyl group depends on the type of the protecting group, but is generally carried out as follows by a method well known in the art.

When a silyl group is used as a protecting group for a hydroxyl group, the silyl group is usually removed by treating with a compound that generates a fluorine anion such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferred. The reaction temperature and reaction time are not particularly limited, but the reaction is usually performed at room temperature for 10 to 18 hours.

When the protecting group for the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group, it can be usually removed by contact with a reducing agent. For example, using a catalyst such as palladium carbon, platinum, Raney-nickel,
This is achieved by performing catalytic reduction at room temperature. The reaction is performed in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in the reaction.
Alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, fatty acids such as acetic acid, or mixed solvents of these organic solvents and water are preferred. The reaction temperature and reaction time vary depending on the starting material, the reducing agent used, and the like, but are usually 0 ° C. to room temperature and 5 minutes to 12 hours.

In addition, in liquid ammonia or methanol, ethanol
At -78 ° C to -20 ° C in an alcohol such as
It can also be removed by the action of metallic lithium or sodium.

Furthermore, it can be removed by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilyl iodide.

The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in the reaction.Preferably, nitriles such as acetonitrile,
Halogenated hydrocarbons such as methylene chloride and chloroform or mixed solvents thereof are used. The reaction temperature varies depending on the starting materials and the like, but is usually 0 ° C to 50 ° C.

When the reactant has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

When the hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with a base in the presence of a solvent. The base is not particularly limited as long as it does not affect the other parts of the compound, but preferably, metal alcoholates such as sodium methoxide, aqueous ammonia,
It is carried out using an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or concentrated ammonia-methanol. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and water, alcohols such as methanol, ethanol and n-propanol or tetrahydrofuran, dioxane Organic solvents, such as ethers, or mixed solvents of water and an organic solvent are preferred. The reaction temperature and reaction time vary depending on the starting material, the base used, and the like, and are not particularly limited.
In order to suppress side reactions, the temperature is usually 1 to 0 ° C to 150 ° C.
Up to 10 hours.

When the protecting group for the hydroxyl group is an alkoxymethyl group or a substituted ethyl group, it can be removed usually by treating with an acid in a solvent. The acid used is preferably hydrochloric acid, acetic acid-sulfuric acid, p-toluenesulfonic acid, acetic acid or the like, but a strongly acidic cation exchange resin such as Dowex 50W can also be used. The solvent to be used is not particularly limited as long as it does not participate in the reaction, but may be an alcohol such as methanol or ethanol or an ether such as tetrahydrofuran or dioxane and water. Mixed solvents are preferred. The reaction temperature and the reaction time vary depending on the starting material and the kind of the acid used, but are usually from 0 ° C. to 50 ° C. for 10 minutes to 18 hours.

When the protecting group for the hydroxyl group is an alkenyloxycarbonyl group, it is usually treated with a base in the same manner as in the removal reaction when the protecting group for the hydroxyl group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group. Can be desorbed.

In the case of allyloxycarbonyl, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions.

(Method 1 of F) In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁸ and Ar have the same meaning as described above.

Step F-1 is a step of subjecting a carbonyl compound (FI) and an olefin compound (F II) to a photoreaction to produce an oxetane compound (F III).

The optimal wavelength of light to be irradiated depends on the carbonyl compound and olefin compound as raw materials, but it is generally 280
The light source is not limited as long as it includes light of −350 nm, but is preferably removed using a filter or the like when a wavelength of 280 nm or less is included.

This step is performed in the presence of a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction.
For example, aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile and benzonitrile; alcohols such as methanol, ethanol and i-propanol; ethers such as ether and tetrahydrofuran; hexane, pentane and cyclohexane. Lower aliphatic hydrocarbons or a mixed solvent thereof is used.
Preferably, benzene, toluene, or a mixed solvent thereof, which serves as a filter, is used to prevent transmission of light having a wavelength of 285 nm or less.

The reaction temperature is not particularly limited, and the reaction is carried out at -20 ° C to 80 ° C, preferably at 10 ° C to 40 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound, the light to be irradiated, or the type of the solvent used.
Hours to 4 days.

(2 methods of F) In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁸ and Ar have the same meaning as described above.

Step F-2 is a step of producing an oxetane compound (F III) by reacting a carbonyl compound (FI) with 2 equivalents or more of dimethyloxosulfonium methylide, which is a so-called Corey reagent. Or, Journal of American Chemical Society (1973), 4
287 (Johnson. CR et al.) By a nucleophilic methylene transfer reaction in the presence of two or more equivalents of sodium dimethyl N- (p-toluenesulfonium) sulfoximine.

As a reaction reagent, trimethyloxosulfonium iodide, trimethyloxosulfonium chloride, sodium dimethyl N- (P-toluenesulfonyl)
A methyleneation reagent such as sulfoximine is used.
The amount used is not particularly limited as long as it is at least 2 equivalents to the carbonyl compound, and usually 2 to 3 equivalents are used.

In the reaction, a base is usually used, and examples of the base include inorganic bases such as sodium hydride and sodium hydroxide, and organic bases such as potassium t-butoxide.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include ethers such as ether and tetrahydrofuran, and sulfoxides such as dimethyl sulfoxide.

The reaction is carried out at a temperature of -20 ° C to 130 ° C, preferably 0 ° C to room temperature.

The reaction time differs mainly depending on the reaction temperature, the solvent and the type of the base, but is usually 2 to 6 hours (Method G). In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁸ and Ar have the same meaning as described above.

Step G-1 is a step of producing an oxetane compound (G III) from a carbonyl compound (GI).

The reaction was performed according to T. Sato, K. Tamura Tetrahedron Letters, Vol.
25, 1821-1824 (1984).

Step G-2 is a step of producing a triazole compound (G IV) from a chloro compound (G III).

The reaction is performed by reacting one equivalent or more of 1H-1,2,4-triazole in a solvent in the presence of one or more equivalents of a base, or
This is a method for producing the compound of the present invention by reacting a base salt of 1H-1,2,4-triazole.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol , N-propanol, isopropanol, n-butanol, isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile ;
Examples include amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, and 1,3-dimethyl-2-imidazolidinone; and sulfoxides such as dimethyl sulfoxide and sulfolane.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but is preferably an alkali metal carbonate such as sodium carbonate or potassium carbonate; Alkali metal hydrogencarbonates such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and barium hydroxide; sodium methoxide And alkali metal alkoxides such as sodium ethoxide, potassium-t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethyl Aniline, N, N
-Diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-
Organic bases such as 7-ene (DBU) or organometallic bases such as butyllithium and lithium diisopropylamide can be mentioned.

In order to carry out the reaction effectively, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, and alkaline earth metal halides such as sodium iodide, sodium bromide and lithium bromide. And crown ethers such as dibenzo-18-crown-6.

The reaction temperature is from -78 ° C to the boiling point of the solvent, preferably from -20 ° C to 150 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of the solvent used, but is usually from 1 hour to 24 hours.

(H method) In the above formula, R ⁸ and Ar have the same meaning as described above.

Step H-1 is a step of producing an epoxy compound (H II) from a carbonyl compound (HI).

The reaction can be easily carried out according to the method described in JP-A-59-176266.

Step H-2 is a step of producing an oxetane compound (H III) from the epoxy compound (H II).

The reaction is performed when the amount of the reagent used is not more than 2 equivalents and 1
Except that the amount is equal to or more than the equivalent, the reaction can be performed according to the F-2 step.

(J method) In the above formula, R ¹ , R ³ , R ⁴ , R ⁸ , R ⁹ , Ar and Y have the same meaning as described above.

Step J-1 is to convert the unprotected terminal hydroxyl group of the alcohol compound (JI) to a nucleophilic leaving group Y in a solvent in the presence or absence of a base, and if necessary, to protect the hydroxyl group. it is a step for preparing compound by removing the R ⁹ a (J II).

For example, in the case of halogenation, the reaction is usually performed using a halogenating reagent.
Thionyl chloride, thionyl bromide, thionyl halides such as thionyl iodide, sulfonyl chloride, sulfonyl halides such as sulfotyl bromide, phosphorus trichloride, phosphorus trichloride such as phosphorus tribromide, phosphorus pentachloride, The reaction is carried out using phosphorus pentahalides such as phosphorus pentabromide and phosphorus pentaiodide or phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide. Alternatively, thionyl halides are used.

In the case of sulfonylation, for example, the general formula R ¹⁴ SO ₂
A compound having —O—SO ₂ R ¹⁴ (where R ¹⁴ is methyl,
Lower alkyl groups such as ethyl; trifluoromethyl,
A halogeno lower alkyl group such as pentafluoroethyl; an aryl group such as benzene and p-toluene; ) Or a compound having the formula R ¹⁴ SO ₂ —Y (wherein R ¹⁴ and Y have the same meanings as described above).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but is preferably aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, Halogenated hydrocarbons such as chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide And amides such as

The base to be used is not particularly limited as long as it is used as a base in a normal reaction, but preferably, lithium hydride, sodium hydride, alkali metal hydride such as potassium hydride, or the like is used. Inorganic bases: triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene Organic bases such as 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or organic metal bases such as butyllithium and lithium diisopropylamide And the like.

The reaction temperature is from -20 ° C to 50 ° C, preferably from -15 ° C to room temperature.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of the solvent used, but is usually from 5 minutes to 10 hours.

The step of removing the hydroxyl-protecting group, which is a desired step,
Although the conditions vary depending on the type of the protecting group, the reaction is generally carried out as follows by a method well known in the art.

When a silyl group is used as a protecting group for a hydroxyl group, the silyl group is usually removed by treating with a compound that generates a fluorine anion such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferred. The reaction temperature and reaction time are not particularly limited, but the reaction is usually performed at room temperature for 10 to 18 hours.

When the protecting group for the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group, it can be usually removed by contact with a reducing agent. For example, using a catalyst such as palladium carbon, platinum, Raney-nickel,
This is achieved by performing catalytic reduction at room temperature. The reaction is performed in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in the reaction.
Alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, fatty acids such as acetic acid, or mixed solvents of these organic solvents and water are preferred. The reaction temperature and reaction time vary depending on the starting material, the reducing agent used, and the like, but are usually 0 ° C. to room temperature and 5 minutes to 12 hours.

In addition, in liquid ammonia or methanol, ethanol
At -78 ° C to -20 ° C in an alcohol such as
It can also be removed by the action of metallic lithium or sodium.

Furthermore, it can be removed by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilyl iodide. The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in the reaction, but preferably, nitriles such as acetonitrile, methylene chloride,
Halogenated hydrocarbons such as chloroform or mixed solvents thereof are used. The reaction temperature varies depending on the starting materials and the like, but is usually 0 ° C to 50 ° C.

When the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

When the hydroxyl-protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with a base in the presence of a solvent. The base is not particularly limited as long as it does not affect the other parts of the compound, but preferably, metal alcoholates such as sodium methoxide, aqueous ammonia,
It is carried out using an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or concentrated ammonia-methanol. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and water, alcohols such as methanol, ethanol and n-propanol or tetrahydrofuran, dioxane Organic solvents, such as ethers, or mixed solvents of water and an organic solvent are preferred. The reaction temperature and reaction time vary depending on the starting material, the base used, and the like, and are not particularly limited.
In order to suppress side reactions, the temperature is usually 1 to 0 ° C to 150 ° C.
Up to 10 hours.

When the protecting group for the hydroxyl group is an alkoxymethyl group or a substituted ethyl group, it can be removed usually by treating with an acid in a solvent. The acid used is preferably hydrochloric acid, acetic acid-sulfuric acid, p-toluenesulfonic acid, acetic acid or the like, but a strongly acidic cation exchange resin such as Dowex 50W can also be used. The solvent to be used is not particularly limited as long as it does not participate in the reaction, but may be an alcohol such as methanol or ethanol or an ether such as tetrahydrofuran or dioxane and water. Mixed solvents are preferred. The reaction temperature and the reaction time vary depending on the starting material and the kind of the acid used, but are usually from 0 ° C. to 50 ° C. for 10 minutes to 18 hours.

When the protecting group for the hydroxyl group is an alkenyloxycarbonyl group, it is usually treated with a base in the same manner as in the removal reaction when the protecting group for the hydroxyl group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group. Can be desorbed.

In the case of allyloxycarbonyl, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions.

Step J-2 comprises reacting a compound having the general formula (J III)
In this step, the reaction is carried out in a solvent in the presence of one or more equivalents of a base, and the ring is closed to produce the compound (JIII) of the present invention.

When the protecting group for the hydroxyl group is to be removed under basic conditions, this reaction can be carried out using a starting compound in which the hydroxyl group is protected.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; methanol , Ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile ;
Examples include amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide; and sulfoxides such as dimethylsulfoxide and sulfolane.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but is preferably an alkali metal carbonate such as sodium carbonate or potassium carbonate; Alkali metal hydrogencarbonates such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide; sodium cyanide And inorganic bases such as alkali metal cyanide such as potassium cyanide; alkali metal azides such as lithium azide and sodium azide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; methyl mercaptan Sodium, ethyl mel Mercaptan alkali metals such as sodium butane; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline , 1,5-diazabicyclo [4.3.0] non-5-ene, 1,
4-diazabicyclo [2.2.2] octane (DABCO), 1,8-
Organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU) or organic metal bases such as butyllithium and lithium diisopropylamide can be mentioned.

In order to carry out the reaction effectively, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, and dibenzo-
Crown ethers such as 18-crown-6 can also be added.

The reaction temperature is from -78 ° C to the boiling point of the solvent, preferably from -20 ° C to 100 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of solvent used, but is usually from 10 minutes to 24 hours.

(K method) In the above formula, R ¹ , R ² , R ³ , R ⁴ , Ar and Y have the same meanings as described above, and R ¹⁵ represents a hydrogen atom or a lower alkyl group.

Step K-1 is a step of producing an oxetane compound (K III) from a carbonyl compound (KI).

This process is based on T. Oppenlnder and P. Schnholzer He
lvetica Chimica Acta, Vol. 72, 1792 (1989).

Step K-2 is a step of reducing the ester group of (K III) to produce an alcohol compound (K IV).

This step is carried out by a general ester reduction method, for example, New Experimental Chemistry Course (edited by The Chemical Society of Japan), Vol. 15, Oxidation and Reduction [II]
Can be performed using the method described in (1).

Step K-3 converts the unprotected hydroxyl group of the alcohol compound (K IV) into a nucleophilic leaving group Y, and converts the compound (K
V).

This step can be performed according to a usual method, for example, the J-1 step.

Step K-4 is a step of substituting the nucleophilic leaving group Y of the compound (KV) with a triazole to form the compound (KV) of the present invention.
VI).

This step can be easily performed according to Step G-2.

(L method) In the above formula, R ³ , R ⁴ , R ⁸ , R ¹⁰ , Ar and X have the same meaning as described above.

The L step is a step of producing a compound (L III) by subjecting the carbonyl compound (LI) and the ester compound (L II) to a reformatsky reaction.

This step can be performed without using a catalyst or using a catalyst.

When a catalyst is not used, it can be easily carried out according to the method described in JP-A-58-82376. However, in that case, the yield is not good.

On the other hand, when a catalyst is used, a surprising improvement in yield is observed as compared with the above publication.

Examples of the catalyst in this case include diethylaluminum chloride, triisopropyltitanium chloride, copper cyanide, bis [tri (o-tolyl) phosphine] palladium dichloride, tetrakis (triphenylphosphine) palladium, and CuCN · 2LiCl. Can be.

The solvent, the temperature and the reaction time can be carried out in the same manner as in a usual Reformatsky reaction.

(M method) In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁸ , Y and Ar have the same meaning as described above.

In step M, the alcohol compound (MI) is converted to the compound (MI
This is a step of manufacturing I), and can be easily performed according to the J-1 step.

(N method) In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁸ and Ar are as defined above, HM is hydrofluoric acid, hydrobromic acid, perchloric acid,
Inorganic acids such as nitric acid, hydrochloric acid, sulfuric acid and phosphoric acid; lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; arylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; Shows organic acids such as acid and succinic acid.

Step N comprises converting the compound of the present invention (NI) into a salt thereof (NI
This is a process for producing I), and can be easily carried out using a usual method for obtaining a salt.

In the above [Method A] to [N Method], the compound synthesized as a racemic compound is obtained by adding a known resolving reagent, for example, an optically active acid such as l-camphorsulfonic acid to the racemic compound, By forming a salt of the above and performing optical resolution, only one optically active substance can be taken out.

After completion of the reaction in each of the above steps, the target compound is collected from the reaction mixture according to a conventional method.

For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization,
It can be further purified by reprecipitation or chromatography.

(Effect) The compound of the present invention is used as an agricultural fungicide, and has a therapeutic and preventive effect on plant diseases without damaging host plants.

That is, by using as a spraying agent or a water application agent, rice sheath blight, which is an important disease in rice cultivation, can be particularly effectively controlled.

In addition, by using as a soil treatment or seed treatment agent, beet, cotton, cucumber, etc. caused by Rhizoctonia fungus is particularly effective for seedling blight of various crops, such as eggplant, cucumber, etc. It can effectively control soil-borne diseases such as potato black bruise.

On the other hand, crops such as rice, tomato, potato, cotton, eggplant, cucumber, and kidney bean are not harmful in practical use.

Further, it can be effectively used as a fungicide in orchards, non-agricultural lands, mountain forests and the like.

The compound of the present invention can be mixed with a carrier and, if necessary, other adjuvants, and can be used in the form of a preparation usually used as an agricultural fungicide, for example, powders, coarse powders, fine granules, granules, wettable powders, flowables. Preparations, emulsions, aqueous solutions, aqueous solvents, oil suspensions and the like. Of course, the purification can be stopped at any stage of the purification, and the crude product can be used as the active ingredient.

The carrier as used herein refers to a synthetic or synthetic compound that is mixed with an agricultural fungicide in order to help the active ingredient compound reach the site to be treated and to facilitate storage, transport or handling of the active ingredient compound. Means a natural inorganic or organic substance.

Suitable solid carriers include clays represented by kaolinite group, montmorillonite group, atabalgitite group, etc., talc, mica, phyllite, pumice, permukilite, gypsum, calcium carbonate, dolomite, diatomaceous earth, magnesium lime, apatite, Inorganic substances such as zeolite, silicic anhydride, synthetic calcium silicate, etc., vegetable organic substances such as soybean flour, tobacco flour, walnut flour, wheat flour, wood flour, starch, crystalline cellulose, coumarone resin, petroleum resin, alkyd resin, polyvinyl chloride And synthetic or natural polymer compounds such as polyalkylene glycol, ketone resin, ester gum, copal gum and dammar gum; waxes such as carnapa wax and beeswax; and urea.

Suitable liquid carriers include paraffinic or naphthenic hydrocarbons such as kerosene, mineral oil, spindle oil and white oil, aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, cumene and methylnaphthalene, carbon tetrachloride, chloroform. , Trichlorethylene,
Monochlorobenzene, chlorinated hydrocarbons such as o-chlorotoluene, dioxane, ethers such as tetrahydrofuran, acetone, methyl ethyl ketone, diisobutyl ketone, cyclohexanone, acetophenone, ketones such as isophorone, ethyl acetate, amyl acetate, ethylene glycol acetate, Esters such as diethylene glycol acetate, dibutyl maleate and diethyl succinate; alcohols such as methanol, n-hexanol, ethylene glycol, diethylene glycol, cyclohexanol and benzyl alcohol; ethylene glycol ethyl ether; ethylene glycol phenyl ether; diethylene glycol ethyl ether; Ether alcohols such as diethylene glycol butyl ether,
Examples thereof include polar solvents such as dimethylformamide and dimethylsulfoxide, and water.

Surfactants used for the purpose of emulsification, dispersion, wetting, spreading, binding, disintegration control, stabilization of active ingredients, improvement of fluidity, rust prevention, etc. are nonionic, anionic, cationic and Any zwitterionic one can be used, but usually non-ionic and / or anionic ones are used.

Suitable nonionic surfactants include, for example, lauryl alcohol, stearyl alcohol, those obtained by polymerizing ethylene oxide with higher alcohols such as oleyl alcohol, isooctylphenol, those obtained by polymerizing ethylene oxide with alkylphenols such as nonylphenol, Mono- or di-alkyl phosphoric acids such as those obtained by polymerizing ethylene oxide to alkyl naphthols such as butyl naphthol and octyl naphthol; those obtained by polymerizing ethylene oxide to higher fatty acids such as valmitic acid, stearic acid and oleic acid; stearic phosphoric acid and dilauryl phosphoric acid Polymerized ethylene oxide, amines such as dodecylamine and stearamide, ethylene oxide polymerized, polyhydric alcohols such as sorbitan Higher fatty acid ester and those it is ethylene oxide polymerized addition, such as those obtained by polymerizing addition of ethylene oxide and propylene oxide. Suitable anionic surfactants include, for example, alkyl sulfates such as sodium laurin sulfate and amine salt of oleyl alcohol sulfate, and alkyl sulfonates such as sodium dioctyl sulfosuccinate and sodium 2-ethylhexene sulfonate. And arylsulfonic acid salts such as sodium isopropylnaphthalenesulfonate, sodium methylenebisnaphthalenesulfonate, sodium ligninsulfonate and sodium dodecylbenzenesulfonate.

Furthermore, the agricultural bactericide of the present invention includes a polymer such as casein, gelatin, albumin, glue, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose and polyvinyl alcohol for the purpose of improving the properties of the preparation and enhancing the biological effect. Compounds and other auxiliaries can also be used in combination.

The above carriers and various adjuvants are appropriately used alone or in combination depending on the purpose, in consideration of the dosage form of the preparation, the application scene, and the like.

Dusts usually contain, for example, 0.1 to 25 parts by weight of an active ingredient compound, and the remainder is a solid carrier.

The wettable powder contains, for example, the active ingredient compound usually in an amount of 1 to 80 parts by weight, and the remainder is a solid carrier and a dispersing wetting agent. If necessary, a protective colloid agent, a thixotropic agent, an antifoaming agent and the like are added. .

Granules generally contain, for example, 1 to 35 parts by weight of an active ingredient compound, and the remainder is mostly a solid carrier.

When used, mix with other fungicides, insecticides, acaricides, nematicides, herbicides, plant growth regulators, fertilizers, soil conditioners, etc. to expand the application range and save labor You can also.

The treatment amount varies depending on weather conditions, formulation form, treatment time, treatment method, location, target disease, target crop, etc., but is usually 0.1 g to 100 g per are as an active ingredient, preferably 5 g. g to 40 g. Emulsions, wettable powders, suspensions and the like are usually prepared in a predetermined amount of 1 to 1 g.
Dilute with 10 to 10 liters of water (a surfactant, polyoxyethylene resin acid, a ligninsulfonate, abietic acid salt, dinaphthyl methanedisulfonate, paraffin, etc. can be added if desired). The granules and the like are usually processed without any dilution.

 Hereinafter, various effects were examined.

(1) Effect as pesticide Test example 1 Rice blast control test (therapeutic effect) A conidia spore suspension of rice blast fungus (Pyricularia oryzae) was applied to 4-5 leaf stage rice seedlings (variety: Kofu). Spray inoculated. After inoculation, the rice seedlings were placed in a room at a temperature of 20-22 ° C. and a relative humidity of 100% for 24 hours, and then a 10 ppm solution of the test compound was sprayed at a rate of 30 ml per 3 pots.

Subsequently, the rice seedlings were placed in the same room for 6 days to cause disease, and the control efficacy was examined based on the number of lesions formed on the upper two leaves.

 The results are shown in Table 4.

In addition, the controlling effect (similar in the following test examples) was indicated by the following criteria by visually observing the degree of onset of the test plant.

5: No onset is observed.

4: Disease onset is 10% or less of the untreated group (the same applies when no test compound is used).

3: Disease incidence is 10% or more and 30% or less of the untreated area.

2: Disease incidence is 30% or more and 50% or less of the untreated area.

1: The disease incidence is 50% or more and 70% or less of the untreated area.

0: The disease incidence was 70% or more of the untreated group, and no difference was observed from the untreated group.

Test Example 2 Test for controlling rice sheath blight (preventive effect) A test compound was applied to rice seedlings (variety: Nipponbare) at the 4-5 leaf stage.
A 100 ppm solution was sprayed at a rate of 30 ml per 3 pots. Twenty-four hours after the application of the chemical solution, the Rhizoctonia sola
ni) was cultured, and 4 to 5 oat grains were placed beside the rice seedlings. The disease was caused in a room at a temperature of 25 to 27 ° C. and a relative humidity of 100% for 5 days. The control efficacy was examined based on the height of the lesion formed on the leaf sheath.

 The results are shown in Table 5.

Test Example 3 Rice Blight Control Test (Therapeutic Effect) At the base of a rice seedling at the 4-5 leaf stage (variety: Nipponbare), oat grains previously cultured with Rhizoctonia solani were cultured for 4-5. Grains were placed and inoculated. After inoculation, the rice seedlings are
After 24 hours in a room at 27 ° C. and 100% relative humidity, a 10 ppm solution of the test compound was sprayed at a rate of 30 ml per 3 pots. Subsequently, the rice seedlings were placed in the same room for 5 days to cause disease, and the control efficacy was examined based on the height of the lesion formed on the leaf sheath.

 The results are shown in Table 6.

Test Example 4 Rice Blight Control Test (Water Surface Application) A 3-4 leaf stage rice seedling (variety: Nipponbare) grown in a pot was kept in a flooded state at a depth of 1 cm, and the amount of the test compound was reduced by the amount of the active ingredient. It was applied in a pot to 100 g / 10a.
After the rice seedlings were placed in a glass greenhouse for 7 days, 4-5 oat grains previously cultured with Rhizoctonia solani were inoculated at the base of the rice seedlings and inoculated. Temperature 25-27 ° C, relative humidity
After being placed in a 100% room for 5 days to cause the disease, the controlling effect was examined based on the height of the lesion formed on the leaf sheath.

 The results are shown in Table 7.

Test Example 5 Inaba sapling disease control test (seed immersion)
bberella fujikuroi), 10 g of diseased seeds obtained by spray inoculation of a conidia spore suspension were added to 20 ml of a 100 ppm solution of the test compound.
Dipped for days. Next, the seeds were densely sown on the soil in the pot, covered with soil, and raised in a glass greenhouse at a temperature of 20 to 30 ° C. for 3 weeks. The control efficacy was investigated based on the number of diseased seedlings.

 The results are shown in Table 8.

Test Example 6 Wheat Leaf Rust Control Test (Therapeutic Effect) A spore of wheat leaf rust (Puccinia recondita) was sprinkled on a 1.5-leaf stage wheat seedling (variety: Norin 61) and inoculated. After inoculation, the wheat seedlings are kept at a temperature of 20-22 ° C and a relative humidity of 100%.
After 24 hours in the room, and then transferred to a glass greenhouse at 15-20 ° C., 2 days later, a 3 ppm solution of the test compound was sprayed at a rate of 30 ml per 3 pots. Subsequently, the wheat seedlings were placed in a glass greenhouse for 10 days to cause disease, and the control efficacy was examined based on the area of the lesion formed on the first leaf.

 The results are shown in Table 9.

Test Example 7 Barley Powdery Mildew Control Test (Therapeutic Effect) A conifer of barley powdery mildew (Erysiphe graminis f.sp.hordei) was sprinkled on a single-leaf barley seedling (variety: Akagami Power) and inoculated. After the inoculation, the barley seedlings were placed in a glass greenhouse at a temperature of 15 to 20 ° C. for 24 hours, and then a 3 ppm solution of the test compound was sprayed at a rate of 30 ml per 3 pots. Subsequently, the barley seedlings were placed in a glass greenhouse for 10 days to cause disease, and the control efficacy was examined based on the area of the lesion formed on the first leaf.

 The results are shown in Table 10.

Test Example 8 Cucumber Powdery Mildew Control Test (Preventive Effect) A 300 ppm solution of a test compound was sprayed on 3 to 4 leaf stage cucumber seedlings (variety: Sagami Hanjiro) at a ratio of 30 ml per 3 pots. Cucumber powdery mildew (Spha) 24 hours after spraying the drug solution
erotheca fuliginea). After the inoculation, the cucumber seedlings were placed in a glass greenhouse at a temperature of 20 to 30 ° C. for 7 days to cause disease, and the controlling effect was examined based on the area of the lesion formed on the 3rd to 4th leaves.

 The results are shown in Table 11.

Test Example 9 Apple Scab Control Test (Preventive Effect) A 300 ppm solution of the test compound was sprayed onto apple seedlings at the 3-4 leaf stage at a ratio of 30 ml per 3 pots. Spray chemical 24
After an hour, a conidia suspension of apple scab (Venturia inaequalis) was spray-inoculated. After inoculation, the apple seedlings were placed in a room at a temperature of 20 to 22 ° C. and a relative humidity of 100% for 3 days, and then placed in a glass room at a temperature of 20 to 22 ° C. for 10 days to cause disease and formed on the 3rd to 4th leaves. The control efficacy was investigated based on the area of the lesion.

 The results are shown in Table 12.

(2) Effect as Wood Preservative Test Example 10 Antifungal Test 10 ml of an agar medium (containing 2% malt extract, 1% glucose, 0.3% peptone and 2% agar) was placed in a 9 cm diameter petri dish and solidified. Thereafter, a microflora disk (approximately 4 mm in diameter) of the test microorganism pre-cultured was inoculated into the center of the medium.

3 days after inoculation, a paper disc (diameter 8 mm, thickness 0.7 mm) sterilized by dry heat after chemical treatment was placed on the circumference about 1 cm away from the outer periphery of the growing bacteria, and the paper was cultured at 25 ° C for 5 days. Efficacy was determined by the presence or absence of bacteria in the disc.

The test bacteria were Aspergillus niger (Aspegillus niger).
rgillus niger) (hereinafter referred to as fungus A), Gliocladium virens (hereinafter referred to as fungus B)
And Fusarium monilforme
A sample prepared by adding 30 μl of an acetone solution prepared by using an iforme (hereinafter referred to as bacteria C) to a concentration of 300 ppm of the compound of the present invention on a paper disk was used as a sample.

 In addition, the display indicating the antifungal effect was as follows.

+: No growth of bacteria was observed on the sample.-: Growth of bacteria was observed on the sample. Table 13 shows the results.

Test Example 11 Wood Preservative Efficacy Test A test was conducted in the same manner as in the antifungal test. However, as the test bacteria, both bacteria of wood rot test fungi (Coriolus versicolor) (hereinafter referred to as fungus D) and Tyromyces palustris (hereinafter referred to as fungus E) specified in JIS-A-9302 are used. Was.

Table 14 shows the results. The display method conforms to Test Example 10.

(3) Effect as a pharmaceutical The novel oxetane derivative of the present invention has excellent antifungal activity even when used as an oral agent as well as a topical agent, and as a therapeutic agent for deep mycosis such as candidiasis. Useful.

Administration forms of the compound of the present invention include, for example, tablets,
Oral administration by capsule, granule, powder or syrup or injection or injection, suppository suitable for topical use, cream,
Parenteral administration with ointments and the like can be mentioned. These formulations include excipients, diluents, dispersants, binders, disintegrants,
It is manufactured by a known method using additives such as a lubricant, a stabilizer and a flavoring agent.

The dose and frequency of administration vary depending on symptoms, age, body weight, dosage form, etc., but in the case of oral administration, 50 to 2000 m / day
g, preferably 100-600 mg, usually 1 adult.
It can be administered once or several times a day.

Hereinafter, the present invention will be described more specifically with reference to Examples, Reference Examples, and Formulation Examples.

Example 1 (2R ^* , 3S ^* , 4R ^* )-2- (2,4-difluorophenyl) -3,4-dimethyl-2-[(1H-1,2,4-triazol-1-yl) methyl Oxetane (2R ^* , 3S ^* , 4S ^* )-2- (2,4-difluorophenyl) -4- (methanesulfonyloxy) -3-methyl-
1- (1H-1,2,4-triazol-1-yl) -2-pentanol (a low-polarity 4,5-epoxy compound among the stereoisomers at the C ⁴ position of the compound described in Reference Example 2) 15% in methanol (10 ml) solution of a compound derived from 389 mg)
Was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated brine, embedded with sodium sulfate, and the solvent was distilled off. The obtained oil (256 mg) was subjected to silica gel column chromatography, and hexane was added. Elution with ethyl acetate (1: 1) gave 143 mg of the desired compound as an oil.

Mask spectrum (m / z): 279 (M ⁺ ), 246,231,224,213,19
7,182,167,149,141,127,113,101,83. NMR spectrum (CDCl ₃ ) δ ppm: 0.83 (3H, dd, J = 7.2 Hz); 1.18 (3H, d, J = 7 Hz); 3.18
(1H, quint, J = 7 Hz); 4.50 (1H, d, J = 14.5 Hz); 4.58
(1H, quint, J = 7 Hz); 4.94 (1H, d, J = 14.5 Hz);
6.9 (2H, m); 7.4-7.5 (1H, m); 7.87 (1H, s); 8.24 (1
H, s). Infrared absorption spectrum ν _max (liquid film) cm ^-1 : 3100,1610,1600. Dissolve 100 mg of the synthesized oxetane in ethyl acetate, dissolve 33 mg of oxalic acid, then add hexane, and collect the precipitated crystals by filtration. did. 92 mg of oxalate crystals having a melting point of 145-150 ° C. were obtained.

NMR spectrum (d ₆ -DMSO) δ ppm: 0.74 (3H, dd, J = 7.2 Hz); 1.10 (3H, d, J = 7 Hz); 2.7−
4.5 (2H, br.s); 3.18 (1H, quint, J = 7 Hz); 4.57 (1H,
d, J = 14.5 Hz); 4.66 (1H, quint, J = 7 Hz); 4.93 (1H,
d, J = 14.5 Hz); 7.05 (1H, dt, J = 8.5, 2.5 Hz); 7.2-7.
4 (2H, m); 7.80 (1H, s); 8.40 (1H, s). Infrared absorption spectrum ν _max (nujol) cm ^-1 : 3500,3
130,2800-2300,1740,1610,1600. 100 mg of the synthesized oxetane was dissolved in dichloromethane, 1 ml of nitric acid (specific gravity 1.38) was added, ether was further added, and the precipitated crystals were collected by filtration. 115 mg of crystals of nitrate having a melting point of 160-177 ° C. were obtained.

NMR spectrum _{(d 6 -DMSO) δppm: 0.75} (3H, dd, J = 7,2 Hz); 1.1 (3H, d, J = 7 Hz); 3.19
(1H, quint, J = 7 Hz); 4.59 (1H, d, J = 14.5 Hz); 4.70
(1H, quint, J = 7 Hz); 4.93 (1H, d, J = 14.5 Hz); 7.05
(1H, dt, J = 8.5,3 Hz); 7.2-7.3 (1H, m); 7.89 (1H,
s); 8.53 (1H, s). Example 2 (2R ^* , 3S ^* , 4R ^* )-2- (2,4-difluorophenyl) -3,4-dimethyl-2-[(1H-1,2,4-triazol-1-yl) methyl Oxetane (C ⁴ stereoisomer of Example 1) (2R ^* , 3S ^* , 4S ^* )-2- (2,4-difluorophenyl) -4- (methanesulfonyloxy) -3-methyl-
1- (1H-1,2,4-triazol-1-yl) -2-pentanol (C ⁴ position isomer of the starting compound of Example 1; 221
mg) to give the same reaction as in Example 1 to obtain 43 mg of the desired compound as an oil.

Mass spectrum (m / z): 280 (M + 1 ⁺ ), 279,270,256,23
4,224,197,179,165,151,142,127,113,101,82. NMR spectrum (CDCl ₃ ) δ ppm: 0.86 (3H, dd, J = 7,2.5 H
z); 1.11 (3H, d, J = 7 Hz); 2.73 (1H, quint, J = 7 Hz);
4.23 (1H, quint, J = 7 Hz); 42 (1H, d, J = 14.5 Hz); 4.8
1 (1H, d, J = 14.5 Hz); 6.8-7.0 (2H, m); 7.5-7.7 (1
H, m); 7.93 (1H, s); 8.28 (1H, s). Infrared absorption spectrum ν _max (liquid film) cm ^-1 : 1610,1600. Furthermore, recrystallization was performed from ethyl acetate, and the melting point was 105-107 ° C.
Was obtained.

Example 3 (2R ^* , 3R ^* , 4R ^* )-2- (2,4-difluorophenyl) -3,4-dimethyl-2-[(1H-1,2,4-triazol-1-yl) methyl Oxetane (C ³ stereoisomer of Example 1) (2R ^* , 3R ^* , 4S ^* )-2- (2,4-difluorophenyl) -4- (methanesulfonyloxy) -3-methyl-
The main component of the 1-(IH-1,2,4-triazol-1-yl) -2-pentanol (stereoisomer about C ⁴ position of the compound described in Reference Example 4 was obtained by mesylation. 255 mg)
And subjected to the same reaction as in Example 1;
135 mg of crystals of the target compound having a temperature of ° C. were obtained.

Mass spectrum (m / z): 279 (M ⁺ ), 235,224,215,197,18
2,166,153,141,133,127,113,101,83. NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.0 Hz); 1.39 (3H, d, J = 7 Hz); 2.80
(1H, quint, J = 7 Hz); 4.63 (1H, quint, J = 7 Hz); 4.67
(1H, d, J = 14 Hz); 4.94 (1H, d, J = 14 Hz); 6.6−6.8
(2H, m); 7.0-7.2 (1H, m); 7.77 (1H, s); 8.02 (1H,
s). Infrared absorption spectrum ν _max (nujol) cm ^-1 : 1610,1
Example 4 (2R ^* , 3S ^* , 4R ^* )-2- (2-chlorophenyl) -3,
4-dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane (2R ^* , 3S ^* , 4S ^* )-2- (2-chlorophenyl)-
4- (methanesulfonyloxy) -3-methyl-1-
(1H-1,2,4-triazol-1-yl) -2-pentanol (synthesized according to the method described in Reference Example 2. Among the C ⁴ position stereoisomers, 4,5-epoxy of low polarity was used. Sodium hydride (about 60% oil content, 11 mg) was added to a solution of 51 mg) in 2 ml of dimethylformamide, and the mixture was stirred at 60 ° C. for 2 hours. After completion of the reaction, the mixture was poured into ice water, extracted with ethyl acetate, washed with water, dried over sodium sulfate, and the solvent was distilled off. The obtained oil was purified by silica gel preparative thin-layer chromatography [developing solvent: hexane]. -Ethyl acetate (1: 2)] to give 10 mg of the desired compound as an oil.

Mass spectrum (m / z): 280 (M ⁺⁺ 2), 278 (M ⁺ ), 259,
242,222,197,195,141,139,129,111,101,89,75. NMR spectrum (CDCl ₃ ) δ ppm: 0.95 (3H, d, J = 7 Hz); 1.18 (3H, d, J = 7 Hz); 3.20 (1
H, quint, J = 7 Hz); 4.60 (1H, quint, J = 7 Hz); 4.80 (1
H, d, J = 14.5 Hz); 5.19 (1H, d, J = 14.5 Hz); 7.2−7.6
(4H, m); 7.84 (1H, s); 8.12 (1H, s). Example 5 (2R ^* , 3S ^* , 4S ^* )-2- (2-chlorophenyl) -3,
4-dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane (C ⁴ stereoisomer of Example 4) (2R ^* , 3S ^* , 4R ^* )-2- (2-chlorophenyl)-
4- (methanesulfonyloxy) -3-methyl-1-
(1H-1,2,4-triazol-1-yl) -2-pentanol (synthesized according to the method described in Reference Example 2. Among the C ⁴ stereoisomers, 4,5-epoxy having a high polarity was used. Compound 50.7 mg) was subjected to the same reaction as in Example 4 to obtain 10 mg of the desired compound as an oil.

Mass spectrum (m / z): 280 (M ⁺⁺ 2), 278 (M ⁺ ), 266,
253,242,222,195,141,139,129,125,111,101,89. NMR spectrum (CDCl ₃ ) δ ppm: 0.99 (3H, d, J = 7 Hz); 1.12 (3H, d, J = 7 Hz); 2.80 (1
H, quint, J = 7 Hz); 4.19 (1H, quint, J = 7 Hz); 4.66 (1
H, d, J = 14.5 Hz); 5.17 (1H, d, J = 14.5 Hz); 7.2−7.7
(4H, m); 7.90 (1H, s); 8.20 (1H, s). Example 6 (2R ^* , 3S ^* , 4R ^* )-2- (2-chloro-4-fluorophenyl) -3,4-dimethyl-2-[(1H-1,2,4-triazol-1-yl ) Methyl] oxetane (2R ^* , 3S ^* , 4S ^* )-2- (2-chloro-4-fluorophenyl) -4- (methanesulfonyloxy) -3-
Methyl-1- (1H-1,2,4-triazol-1-yl)
Using -2-pentanol (synthesized according to the method described in Reference Example 2; a compound derived from a low-polarity 4,5-epoxy compound among the C ⁴ stereoisomers, 133 mg), an Example was prepared. The same reaction as in 4 was performed to obtain 86 mg of the desired compound as an oil.

Mass spectrum (m / z): 297 (M ⁺⁺ 2), 295 (M ⁺ ), 280,
278,260,251,240,216,215,214,213,182,160,159,158,15
7,147,129,123,107,94,82. NMR spectrum (CDCl ₃ ) δ ppm: 0.94 (3H, d, J = 7 Hz); 1.18 (3H, d, J = 7 Hz); 3.18 (1
H, quint, J = 7 Hz); 4.62 (1H, quint, J = 7 Hz); 4.80 (1
H, d, J = 14.5 Hz); 5.14 (1H, d, J = 14.5 Hz); 6.9-7.0
(1H, m); 7.12 (1H, dd, J = 8.5,2.5 Hz); 7.50 (1H, dd, J
= 8.5,6.0 Hz); 7.83 (1H, s); 8.17 (1H, s). Example 7 (2R ^* , 3S ^* , 4S ^* )-2- (2-chloro-4-fluorophenyl) -3,4-dimethyl-2-[(1H-1,2,4-triazol-1-yl ) Methyl] oxetane (of Example 6)
C ^4- position stereoisomer) (2R ^* , 3S ^* , 4R ^* )-2- (2-chloro-4-fluorophenyl) -4- (methanesulfonyloxy) -3-
Methyl-1- (1H-1,2,4-triazol-1-yl)
Using -2-pentanol (synthesized according to the method described in Reference Example 2; a compound derived from a highly polar 4,5-epoxy compound among the C ⁴ stereoisomers, 32 mg), an Example was prepared. The same reaction as in 4 was performed to obtain 14 mg of the desired compound as an oil.

Mass spectrum (m / z): 296 (M ⁺ ), 279,260,240,213,21
1,204,182,171,159,157,143,129,123,107,94,82. NMR spectrum (CDCl ₃ ) δ ppm: 0.98 (3H, d, J = 7 Hz); 1.15 (3H, d, J = 7 Hz); 2.79 (1
H, quint, J = 7 Hz); 4.18 (1H, quint, J = 7 Hz); 4.67 (1
H, d, J = 14.5 Hz); 5.10 (1H, d, J = 14.5 Hz); 6.9-7.1
(1H, m); 7,17 (1H, dd, J = 8.5,2.5 Hz); 7.68 (1H, dd, J
= 8.5,6.5 Hz); 7.90 (1H, s); 8.22 (1H, s) Example 8 (2R ^* , 3R ^* )-2- (2-chloro-4-fluorophenyl) -3,4-dimethyl- 2-[(1H-1,2,4-triazol-1-yl) methyl] oxetane (stereoisomer at C ³ position in Example 6) (2R ^* , 3R ^* )-2- (2-chloro-4) -Fluorophenyl) -4- (methanesulfonyloxy) -3-methyl-1- (1H-1,2,4-triazol-1-yl) -2
-Pentanol (the compound obtained by mesylation of the main component among the C ⁴ stereoisomers of the diol synthesized according to the method described in Reference Example 4; 139 mg) was used, and used in the same manner as in Example 4. The reaction was performed to give 91 mg of the desired compound as crystals.

Melting point: 145-147 ° C Mass spectrum (m / z): 297 (M ⁺ +2), 295,260,240,21
3,211,198,179,159,158,149,129,123,109,98,83. NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J = 7 Hz); 1.5 (3H, d, J = 7 Hz); 2.81 (1H,
quint, J = 7 Hz); 4.59 (1H, quint, J = 7 Hz); 4.91 (2H,
s), 6.7-6.8 (1H, m); 7.09 (1H, dd, J = 8.5,2.5 Hz);
7.20 (1H, dd, J = 8.5,6.0 Hz); 7.69 (1H, s); 7.94 (1H,
s). Example 9 (2R ^* , 3S ^* , 4S ^* )-2- (2-fluoro-4-chlorophenyl) -3,4-dimethyl-2-[(1H, 1,2,4-triazol-1-yl) Methyl] oxetane (2R ^* , 3S ^* , 4R ^* )-2- (2-fluoro-4-chlorophenyl) -4- (methanesulfonyloxy) -3-
Methyl-1- (1H-1,2,4-triazol-1-yl)
-2-pentanol (synthesized according to the method described in Reference Example 2. Among the C ⁴ stereoisomers, a compound derived from a highly polar 4,5-epoxy compound. 260 mg) was used. The same reaction as in Example 4 was performed to obtain 150 mg of the desired compound as an oil.

Mass spectrum (m / z): 297 (M ⁺⁺ 2), 295 (M ⁺ ), 280,
250,240,215,214,206,179,159,158,143,129,123,109,9
9,94,82. NMR spectrum (CDCl ₃ ) δ ppm: 0.84 (3H, dd, J = 7,2.5 Hz); 1.10 (3H, d, J = 7 Hz); 2.7
4 (1H, quint, J = 7 Hz); 4.21 (1H, quint, J = 7 Hz); 4.4
0 (1H, d, J = 14.5 Hz); 4.80 (1H, d, J = 14.5 Hz); 7.14
(1H, dd, J = 10.5,2.0 Hz); 7.20 (1H, dd, J = 8,2.0 H
z); 7.56 (1H, t, J = 8 Hz); 7.91 (1H, s); 8.22 (1H,
s). Infrared absorption spectrum ν _max (liquid film) cm ^-1 : 3120,1610,1570. Example 10 (2R ^* , 3S ^* , 4R ^* )-2- (2-fluoro-4-chlorophenyl) -3,4- Dimethyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxetane (of Example 9
C ^4- position stereoisomer) (2R ^* , 3S ^* , 4S ^* )-2- (2-fluoro-4-chlorophenyl) -4- (methanesulfonyloxy) -3-
Methyl-1- (1H-1,2,4-triazol-1-yl)
-2-Pentanol (synthesized according to the method described in Reference Example 2. Among the C ^4- position isomers, a compound derived from a low-polarity 4,5-epoxy compound; 390 mg) was used. The same reaction as in Example 4 was performed to obtain 220 mg of the desired compound as an oil.

Mass spectrum (m / z): 297 (M ⁺⁺ 2), 295 (M ⁺ ), 247,
240,215,214,182,159,158,157,147,129,122,107,94,82. NMR spectrum (CDCl ₃ ) δ ppm: 0.83 (3H, dd, J = 7,2.0 Hz); 1.17 (3H, d, J = 7 Hz); 3.1
9 (1H, quint, J = 7 Hz); 4.49 (1H, d, 14.5 Hz); 4.57 (1
H, quint, J = 7 Hz); 4.90 (1H, d, J = 14.5 Hz); 7.0-7.1
(1H, m); 7.15 (1H, dd, J = 8.5,2.0 Hz); 7.46 (1H, t, J
= 8.5 Hz); 7.86 (1H, s); 8.21 (1H, s). Infrared absorption spectrum ν _max (liquid film) cm ^-1 : 3110,1610,15
70. Example 11 (2R ^* , 3S ^* , 4R ^* )-2- (2,6-difluorophenyl) -3,4-dimethyl-2-[(1H-1,2,4-triazol-1-yl ) Methyl] oxetane (2R ^* , 3S ^* , 4S ^* )-2- (2,6-difluorophenyl) -4- (methanesulfonyloxy) -3-methyl-
1- (1H-1,2,4-triazol-1-yl) -2-pentanol (synthesized according to the method described in Reference Example 2).
A compound derived from a low-polarity 4,5-epoxy compound among C ⁴ stereoisomers. (120 mg), and subjected to the same reaction as in Example 4 to obtain 63 mg of the desired compound as an oil.

Mass spectrum (m / z): 297 (M ⁺ ), 224,197,179,166,15
1,141,127,113,101,82. NMR spectrum (CDCl ₃ ) δ ppm: 1.00 (3H, dt, J = 7.1 Hz); 1.24 (3H, d, J = 7 Hz); 3.20
(1H, quint, J = 7 Hz); 4.57 (1H, quint, J = 7 Hz); 4.60
(1H, d, J = 14.5 Hz); 4.92 (1H, d, J = 14.5 Hz); 6.86
(2H, t, J = 9 Hz); 7.2-7.3 (1H, m); 7.87 (1H, s); 8.3
1 (1H, s). Example 12 (2R ^* , 3S ^* , 4S ^* )-2- (2,6-difluorophenyl) -3,4-dimethyl-2-[(1H-1,2,4-triazol-1-yl) methyl Oxetane (C ⁴ stereoisomer of Example 11) (2R ^* , 3S ^* , 4R ^* )-2- (2,6-difluorophenyl) -4- (methanesulfonyloxy) -3-methyl-
1- (1H-1,2,4-triazol-1-yl) -2-pentanol (synthesized according to the method described in Reference Example 2).
A compound derived from a highly polar 4,5-epoxy compound among C ⁴ stereoisomers. (121 mg) and subjected to the same reaction as in Example 4 to obtain 44 mg of the desired compound as an oil.

Mass spectrum (m / z): 279 (M ⁺ ), 261,235,224,206,19
7,179,166,153,141,133,123,113,95,82. NMR spectrum (CDCl ₃ ) δ ppm: 0.99 (3H, dt, J = 7.2 Hz); 1.10 (3H, d, J = 7 Hz); 2.82
(1H, quint, J = 7 Hz); 4.38 (1H, quint, J = 7 Hz); 4.55
(1H, d, J = 14.5 Hz); 4.83 (1H, d, J = 14.5 Hz); 6.8−
7.0 (2H, m); 7.2-7.4 (1H, m); 7.92 (1H, s); 8.33 (1
H, s). Example 13 (2R ^* , 3S ^* )-2- (2,4-difluorophenyl) -3
-Methyl-2-[(1H-1,2,4-triazol-yl)
Methyl] oxetane (2R ^* , 3S ^* )-2- (2,4-difluorophenyl)-
4- (methanesulfonyloxy) -3-methyl-1-
(1H-1,2,4-triazol-1-yl) -2-butanol (Synthesized according to the method described in Reference Example 7. 100 m
g) and treated in the same manner as in Example 1 to give 54 mg of the desired compound
Was obtained as an oil.

Mass spectrum (m / z): 265 (M ⁺ ), 247,232,224,184,18
3,165,153,141,133,127,113,101,94,82. NMR spectrum (CDCl ₃ ) δ ppm: 0.93 (3H, dd, J = 7.2 Hz); 3.15 (1H, six, J = 7 Hz); 3.9
9 (1H, t, J = 7 Hz); 4.37 (1H, dd, J = 7.6 Hz); 4.48 (1
H, d, J = 14.5 Hz); 4.90 (1H, d, J = 14.5 Hz); 6.8-7.0
(2H, m); 7.2-7.4 (1H, m); 7.90 (1H, s); 8.30 (1H,
s). Example 14 2- (2,4-difluorophenyl) -4-methyl-2
[(1H-1,2,4-triazol-yl) methyl] oxetane 2- (2,4-difluorophenyl) -4- (methanesulfonyloxy) -4-methyl-1- (1H-1,2,4 -Triazol-1-yl) -2-butanol (590 mg, synthesized from allylmagnesium chloride according to the production method described in JP-A-59-517 and the methods described in Reference Examples 2, 3 and 4). The resulting product was treated in the same manner as in Example 4 to isolate the main product among the resulting stereoisomers at the C ⁴ position as the desired product.

Oil Mass spectrum (m / z): 265 (M ⁺ ), 250, 224, 202, 184, 18
3,142,141,133,127,119,113.99,83. NMR spectrum (CDCl ₃ ) δ ppm: 1.28 (3H, d, J = 6 Hz); 2.35 (1H, dq, J = 8.6 Hz); 3.10
(1H, dd, J = 8.7 Hz); 4.34 (1H, d, J = 14.5 Hz); 4.3−
4.5 (1H, m); 4.72 (1H, d, J = 14.5 Hz); 6.8-6.9 (2H,
m); 7.4-7.5 (1H, m); 7.90 (1H, s); 8.20 (1H, s). Infrared absorption spectrum ν _max (liquid film) cm ^-1 : 1610,1600,1500. Example 15 (2R ^* , 3S ^* )-2- (2,4-dichlorophenyl) -3-
Methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxetane and its nitrate (2R ^* , 3S ^* )-2- (2,4-dichlorophenyl) -4
-(Methanesulfonyloxy) -3-methyl-1- (1H
The target compound 25 was treated in the same manner as in Example 1 by using -1,2,4-triazol-1-yl) -2-butanol (synthesized according to the method described in Reference Example 7; 72 mg). mg was obtained as an oil.

NMR spectrum (CDCl ₃ ) δ ppm: 1.05 (3H, d, J = 7 Hz); 3.15 (1H, m); 3.90 (1H, dd, J =
6,5.5 Hz); 4.38 (1H, dd, J = 7.6 Hz); 4.67 (1H, d, J = 1
4.5 Hz); 5.16 (1H, d, J = 14.5 Hz); 7.1-7.6 (3H, m);
7.88 (1H, s); 8.20 (1H, s). Infrared absorption spectrum ν _max (chloroform) cm ^-1 : 159
0,1275,1137,975. Dissolve 17 mg of this oxetane compound in 0.4 ml of ether and add about 0.1 ml of a 5% nitric acid-ether solution under ice-cooling.
17 mg of nitrate crystals of the target compound having a melting point of 162-165 ° C were obtained.

Example 16 (2R ^* , 3S ^* )-2- (2,4-dichlorophenyl) -3,4
-Dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane and its nitrate (2R ^* , 3S ^* )-2- (2,4-dichlorophenyl) -3
-Methyl-1- (1H-1,2,4-triazol-1-yl) -2,4-pentanediol (synthesized according to the method described in Reference Example 4. The C ^4- position stereoisomer 1: 4-mesylate (1: 1 mixture of C ⁴ stereoisomers, 54 mg) obtained from 1) was dissolved in 1 ml of dimethylformamide, and 1
0.5 ml of a 5% aqueous solution of methyl mercaptan was added, and the mixture was stirred at 50-60 ° C for 2 hours. Post-treatment was carried out in the same manner as in Example 1, and the obtained crude product was separated and purified by preparative silica gel thin-layer chromatography [developing solvent: ethyl acetate-hexane (3: 1)] to obtain the desired compound. 8 mg of stereoisomer A (2R ^* , 3S ^* , 4S ^* ) (low polarity) and 10 mg of stereoisomer B (2R ^* , 3S ^* , 4R ^* ) (high polarity) were obtained as oils, respectively.

NMR spectrum of stereoisomer A (CDCl ₃ ) δ ppm: 0.98 (3
H, d, J = 7 Hz); 1.03 (3H, d, J = 7 Hz); 2.80 (1H, quint,
4.19 (1H, quint, J = 7 Hz); 4.62 (1H, d, J = 1)
5 Hz); 5.12 (1H, d, J = 15 Hz); 7.31 (1H, dd, J = 9.2 H)
z); 7.46 (1H, d, J = 2 Hz); 7.71 (1H, d, J = 9 Hz); 7.90
(1H, s); 8.20 (1H, s). NMR spectrum of stereoisomer B (CDCl ₃ ) δ ppm: 0.92 (3
H, d, J = 7 Hz); 1.17 (3H, d, J = 7 Hz); 3.17 (1H, quint,
J = 7 Hz); 4.59 (1H, quint, J = 7 Hz); 4.72 (1H, dd, J =
15 Hz); 5.15 (1H, d, J = 15 Hz); 7.20 (1H, dd, J = 9,1.5
Hz); 7.38 (1H, d, J = 1.5 Hz); 7.50 (1H, d, J = 9 Hz);
7.81 (1H, s); 8.13 (1H, s). Each of the oxetane compounds was dissolved in ether, and a 5% nitric acid-ether solution was added thereto under ice cooling according to a conventional method.
The nitrate crystals of the target compound were obtained.

Melting point of nitrate of stereoisomer A: 150-165 ° C Melting point of nitrate of stereoisomer B: 160-164 ° C Example 17 2- (2,4-difluorophenyl) -2-[(1H-1,2, Four
-Triazol-1-yl) methyl] -3,3,4-trimethyloxetane 2- (2,4-difluorophenyl) -3,3-dimethyl-
1- (1H-1,2,4-triazol-1-yl) -2,4-pentanediol (according to the method described in Reference Example 4,
(2,4-difluorophenyl) -3,3-dimethyl-1-
77 mg of 4-mesylate obtained from (the less polar stereoisomer synthesized from (1H-1,2,4-triazol-1-yl) -4-penten-2-ol) in 1.5 ml of tetrahydrofuran And hydrated under ice-cooling
10 mg was added and stirred. Add 0.1 ml of methanol and add 10
After a minute, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained crude product was purified by silica gel column chromatography. The target compound eluted with ethyl acetate-hexane (3: 2) was recrystallized from cyclohexane,
39 mg of pure product having a melting point of 112-113 ° C. were obtained.

NMR spectrum (CDCl ₃ ) δ ppm: 0.86 (3H, s); 1.24 (3H, d, J = 6 Hz); 1.36 (3H, s); 4.7
2 (1H, d, J = 15 Hz); 4.82 (1H, q, J = 6 Hz); 5.02 (1H,
d, J = 15 Hz); 6.5-7.4 (3H, m); 7.61 (1H, s); 7.94 (1
H, s). Example 18 2- (2,4-difluorophenyl) -2-[(1H-1,2,4
-Triazol-1-yl) methyl] -3,3,4-trimethyloxetane (stereoisomer at the C ⁴ position of Example 17) 2- (2,4-difluorophenyl) -3,3-dimethyl-
1- (1H-1,2,4-triazol-1-yl) -2,4-pentanediol (according to the method described in Reference Example 4,
(2,4-difluorophenyl) -3,3-dimethyl-1-
The 4-mesylate obtained from (1H-1,2,4-triazol-1-yl) -4-penten-2-ol, a more polar stereoisomer synthesized from (1H-1,2,4-triazol-1-yl), was obtained in the same manner as in Example 17. To give the desired compound. Recrystallization from benzene-hexane gave a pure product having a melting point of 93-94 ° C.

NMR spectrum (CDCl ₃ ) δ ppm: 0.93 (3H, d, J = 2 Hz); 1.34 (3H, s); 1.44 (3H, d, J = 6.
5 Hz); 4.50 (1H, q, J = 6.5 Hz); 4.81 (2H, s); 6.6-7.
1 (2H, m); 7.23 (1H, td, J = 9.6 Hz); 7.60 (1H, s); 7.9
6 (1H, s). Example 19 (2R ^* , 3S ^* , 4R ^* )-2- (4-trifluoromethoxyphenyl) -3,4-dimethyl-2-[(1H-1,2,4-triazol-1-yl) methyl Oxetane (2R ^* , 3S ^* , 4S ^* )-2- (4-trifluoromethoxyphenyl) -4- (methanesulfonyloxy) -3-
Methyl-1- (1H-1,2,4-triazol-1-yl)
-2-Pentanol (synthesized according to the method described in Reference Example 2. Among C ^4- position isomers, a compound derived from a low-polarity 4,5-epoxy compound. 250 mg) was used. Example 4
The above compound was treated in the same manner as in the above to give 82 mg of the desired compound as an oil.

Mass spectrum (m / z): 328 (M + 1), 308, 272, 245, 21
4,197,190,189,175,161,141,129,115,95,82. NMR spectrum (CDCl ₃ ) δ ppm: 0.70 (3H, d, J = 7.5 Hz); 1.16 (3H, d, J = 6.5 Hz); 3.18
(1H, quint, J = 7.5 Hz); 4.35 (1H, d, J = 14.5 Hz); 4.39
(1H, dq, J = 17.5,6.5 Hz); 4.70 (1H, d, J = 14.5 Hz); 7.
2-7.4 (4H, m); 7.93 (1H, s); 8.23 (1H, s). Infrared absorption spectrum ν _max (liquid film) cm ^-1 : 1610,1590,1500,1260,1160,1020. Example 20 (2R ^* , 3S ^* , 4R ^* )-2- (4-chlorophenyl) -3,
4-dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane (2R ^* , 3S ^* , 4S ^* )-2- (4-chlorophenyl)-
4- (methanesulfonyloxy) -3-methyl-1-
(1H-1,2,4-triazol-1-yl) -2-pentanol (synthesized according to the method described in Reference Example 2. Among the C ^4- position stereoisomers, low-polar 4,5- Compound (230 mg) derived from an epoxy compound was treated in the same manner as in Example 4 to obtain 112 mg of the desired compound having a melting point of 111-118 ° C.

Mass spectrum (m / z): 278 (M + 1), 256, 222, 197, 16
4,149,141,139,129,111,104. NMR spectrum (CDCl ₃ ) δ ppm: 0.70 (3H, d, J = 7.25 Hz); 1.17 (3H, d, J = 6.45 Hz);
16 (1H, quint, J = 7.25 Hz); 4.41 (1H, d, J = 14.5 Hz);
4.4−4.53 (1H, m); 4.76 (1H, d, J = 14.5Hz); 7.25 (2H,
d, J = 8.46 Hz); 7.36 (2H, d, J = 8.46 Hz); 7.98 (1H,
s); 8.42 (1H, s). Example 21 2- (4-chlorophenyl) -3,3-dimethyl-2-
[(1H-1,2,4-triazol-1-yl) methyl)]
Oxetane 2- (4-chlorophenyl) -3,3-dimethyl-4-
To a solution of methanesulfonyloxy-1- (1H-1,2,4-triazol-1-yl) -2-butanol (750 mg) in dimethylformamide (DMF, 12 ml) was added sodium hydride (about 60% oil, 160 mg). ) And stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with an aqueous ammonium chloride solution, and MgSO ₄
The residue was subjected to preparative thin-layer chromatography and developed with ethyl acetate / hexane (1/4) to obtain 170 mg of the desired product.

Yield 31%. 90-102 ° C.

NMR (CDCl ₃ ) δ ppm: 0.90 (3H, s), 1.38 (3H, s), 4.11
(1H, d, J = 6Hz); 4.50 (1H, d, J = 6Hz); 4.60 (1H, d, J =
14Hz); 5.00 (1H, d, J = 14Hz); 6.85-7.30 (4H, m), 7.5
6 (1H, s), 7.81 (1H, s). Mass spectrum (m / z): 277 (M ⁺ ), 222, 195, 139 The compounds of Examples 21 to 32 were obtained in the same manner as in Example 21.

Example 22 2- (2,4-difluorophenyl) 2-[(1H-1,2,4-
Triazol-1-yl) methyl] - oxetane yield 56%, oil _{NMR (CDCl 3) δppm: 2.66~2.77} (1H, m); 2.93~3.04 (1
H, m); 4.15-4.23 (1H, m); 4.34 (1H, d, J = 14.9Hz); 4.
43 ~ 4.52 (1H, m); 4.73 (1H, d, J = 14.9Hz); 6.81 ~ 6.93
(2H, m); 7.39 ~ 7.48 (1H, m); 7.94 (1H, s); 8.27 (1H,
s). Mass spectrum (m / z): 251 (M ⁺ ), 170,141 Example 23 2- (2,4-difluorophenyl) -3-methyl-2-
[(1H-1,2,4-triazol-1-yl) methyl] oxetane 73% yield, oil NMR (CDCl ₃ ) δ ppm: 0.93 (3H, dd, J = 7.2 Hz); 3.15 (1H,
sext, .J = 7Hz); 3.99 (1H, t, J = 7Hz); 4.37 (1H, dd, J =
7,6Hz); 4.48 (1H, d, J = 14.5Hz); 4.90 (1H, d, J = 14.5H
z); 6.8-7.0 (2H, m); 7.2-7.4 (1H, m); 7.90 (1H, m
s); 8.30 (1H, s). Mass spectrum (m / z): 265 (M ⁺ ), 247,232,224,184,18
3, Example 24 2- (2,4-difluorophenyl) -3-ethyl-2-
[(1H-1,2,4- triazol-1-yl) methyl] oxetane yield 39%, oil _{NMR (CDCl 3) δppm: 0.70} (3H, t, J = 7.5Hz); 1.03~1.15
(1H, m); 1.46-1.56 (1H, m); 2.87-2.98 (1H, m); 4.0
7 (1H, m); 4.34 (1H, m); 4.48 (1H, d, J = 14.5 Hz); 4.9
1 (1H, d, J = 14.5Hz); 6.80 ~ 6.94 (2H, m); 7.44 ~ 7.53
(1H, m); 7.88 (1H, s); 8.22 (1H, s). Mass spectrum (m / z): 279 (M ⁺ ), 224, 197, 141, 127 Example 25 2- (2,4-difluorophenyl) -3,3-dimethyl-2
-[(1H-1,2,4-triazol-1-yl) methyl]
Oxetane yield 72%, mp 78 ° C NMR (CDCl ₃ ) δ ppm: 1.04 (3H, s); 1.43 (3H, s); 4.18
(1H, d, J = 5.6Hz); 4.62 (1H, d, J = 5.6Hz); 4.79 (1H, d
d, J = 14.1, 1.6 Hz); 5.01 (1H, d, J = 14.1 Hz); 6.68-6.8
3 (2H, m); 7.1 (1H, ddd, J = 6.5,6.5,2.0Hz); 7.62 (1H,
s); 7.95 (1H, s). Mass spectrum (m / z): 279 (M ⁺ ), 261,226,197,179,16
7,149 Example 26 2- (2,4-difluorophenyl) -3-phenyl-2-
[(1H-1,2,4- triazol-1-yl) methyl] oxetane yield 50%, oil _{NMR (CDCl 3) δppm: 4.28} (1H, t, J = 7.5Hz); 4.53~4.62
(2H, m); 5.00 (2H, d, J = 14.9Hz); 6.37-6.45 (1H,
m); 6.83 ~ 6.90 (1H, m); 7.00 ~ 7.14 (5H, m); 7.47 ~ 7.
56 (1H, m); 7.98 (1H, s); 8.36 (1H, s) Example 27 2- (4-chlorophenyl) -3-ethyl-2-[(1H
1,2,4-triazol-1-yl) methyl] oxetane yield 40%, oil _{NMR (CDCl 3) δppm: 0.63} (3H, t, J = 7.3Hz); 0.91~1.01
(1H, m); 1.16-1.32 (1H, m); 2.84-2.93 (1H, m); 4.0
5 ~ 4.09 (1H, m); 4.22 ~ 4.27 (1H, m); 4.38 (1H, d, J = 1
4.74); 4.74 (1H, d, J = 14.7Hz); 7.25 ~ 7.39 (4H, m);
7.97 (1H, s); 8.32 (1H, s). Example 28 3,3-Dimethyl-2- (4-methylphenyl) -2-
[(1H-1,2,4-triazol-1-yl) methyl] oxetane 83% yield, mp 76-77 ° C. NMR (CDCl ₃ ) δ ppm: 0.93 (3H, s); 1.41 (3H, s); 2.29
(3H, s); 4.19 (1H, d, J = 5.6Hz); 4.56 (1H, d, J = 5.6H)
z); 4.63 (1H, d, J = 14.1 Hz); 5.07 (1H, d, J = 14.1 Hz);
6.99-7.02 (2H, m); 7.07-7.10 (2H, m); 7.69 (1H,
S); 7.80 (1H, s) Mass spectrum (m / z): 257 (M ⁺ ), 202,175 Example 29 2- (4-isopropylphenyl) -3,3-dimethyl-
2-[(1H-1,2,4-triazol-1-yl) methyl] oxetane 67% yield, oil NMR (CDCl ₃ ) δ ppm: 0.92 (3H, S); 1.21 (6H, d, J = 7.3H
z); 1.41 (3H, s); 2.80-2.90 (1H, m); 4.19 (1H, d, J =
5.6Hz); 4.55 (1H, d, J = 5.6Hz); 4.62 (1H, d, J = 14.3H)
z); 6.97 to 7.15 (4H, m); 7.69 (1H, s); 7.77 (1 H, s) Mass spectrum (m / z): 285 (M ⁺ ), 230, 203 Example 30 2- (4-methoxyphenyl) ) -3,3-Dimethyl-2-
[(1H-1,2,4-triazol-1-yl) methyl] oxetane 29% yield, oil NMR (CDCl ₃ ) δ ppm: 0.92 (3H, s); 1.41 (3H, s); 3.77
(3H, s); 4.56 (1H, d, J = 5.8Hz); 4.59 (1H, d, J = 5.8H)
z); 4.62 (1H, d, J = 14.3 Hz); 5.06 (1H, d, J = 14.3 Hz);
6.80 to 6.88 (2H, m); 6.96 to 7.24 (2H, m); 7.69 (1H,
s); 7.81 (1H, s) Mass spectrum (m / z): 273 (M ⁺ ), 218,191 Example 31 3-Ethyl-2- (4-fluorophenyl) -2-
[(1H-1,2,4-triazol-1-yl) methyl] oxetane 33% yield, mp 43-47 ° C. NMR (CDCl ₃ ) δ ppm: 0.66 (3H, t, J = 7.25 Hz); 0.87-1.0
1 (1H, m); 1.20-1.32 (1H, m); 2.81-2.92 (1H, m); 4.
08 (1H, t, J = 6.2Hz); 4.27 (1H, t, J = 6.2Hz); 4.39 (1
H, d, J = 14.9Hz); 4.76 (1H, d, J = 14.9Hz); 7.09 (2H, t,
7.30 to 7.34 (2H, dd, J = 8.9,2Hz); 7.98 (1
H, s); 8.37 (1H, s). Mass spectrum (m / z): 262 (M ⁺ ), 246,206,179 Example 32 2- (2,4-dichlorophenyl) -3,3-dimethyl-2-
[(1H-1,2,4-triazol-1-yl) methyl] oxetane 60% yield, mp 90-100 ° C. NMR (CDCl ₃ ) δ ppm: 1.12 (3H, s); 1.50 (3H, s); 4.13
(1H, d, J = 5.8Hz); 4.62 (2H, d, J = 5.8Hz); 5.02 (1H,
d, J = 14.3Hz); 5.27 (1H, d, J = 14.3Hz); 7.08 (1H, dd, J
= 1.95, 8.45Hz); 7.17 (1H, d, J = 8.45Hz); 7.35 (1H, d,
J = 1.95 Hz); 7.66 (1H, s); 8.05 (1H, s) Mass spectrum (m / z): 315 (M + 4) ⁺ , 313 (M + 2).
⁺ , 311 (M ⁺ ), 276,256,231,229,199,173 Example 33 (2R ^* , 3S ^* , 4S ^* )-2- (2,4-difluorophenyl) -4-ethyl-3-methyl-2-[(1H-1, 2,4-
Triazol-1-yl) methyl)] oxetane 2- (2,4-difluorophenyl) -4-methanesulfonyloxy-3-methyl-1- (1H-1,2,4-triazol-1-yl) -2 -Hexanol (77.9mg, 0.2mm
ol) in DMF (4.9 ml) was added sodium hydride (oil containing about 60%, 960 mg, 0.24 mmol) under ice-cooling and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was cooled with ice water (20 m
l), extracted with ethyl acetate (40 ml), washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (eluent: hexane / ethyl acetate = 2/1) to give the desired product in 13.0 m
g obtained.

Yield 22.2%. Oil NMR (CDCl ₃ ) δ ppm: 0.82 (3H, t, J = 7.5 Hz); 0.87 (3H,
dd, J = 2.42,6.9Hz); 1.18-1.34 (1H, m); 1.36-1.50
(1H, m); 2.76 (1H, quint, J = 6.9 Hz); 3.98 (1H, q, J =
6.91Hz); 4.39 (1H, d, J = 14.5Hz); 4.79 (1H, d, J = 14.5
Hz); 6.82-6.97 (2H, m); 7.56-7.65 (1H, m); 7.88 (1
H, s); 8.18 (1H, s). Mass spectrum (m / z): 294 (M + 1) ⁺ , 224,211 The compounds of Examples 34 and 35 were synthesized in the same manner as in Example 33.

Example 34 (2R ^* , 3S ^* , 4S ^* )-4-ethyl-2- (4-fluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl Oxetane yield 7.5%, oil NMR (CDCl ₃ ) δ ppm: 0.73 (3H, d, J = 7.1 Hz); 0.82 (3H,
t, J = 7.5Hz); 1.11 ~ 1.44 (2H, m); 2.68 (1H, quint, J =
7.1Hz); 4.01 (1H, q, J = 7.1Hz); 4.29 (1H, d, J = 14.9H
z); 4.59 (1H, d, J = 14.9Hz); 7.08-7.15 (2H, m); 7.31
7.37.38 (2H, m); 7.97 (1H, s); 8.26 (1H, s). Mass spectrum (m / z): 276 (M + 1) ⁺ , 193 Example 35 (2R ^* , 3S ^* , 4S ^* )-2- (4-chlorophenyl) -4
-Ethyl-3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxetane Yield 8.0%, Oil NMR (CDCl ₃ ) δ ppm: 0.69 (3H, d, J = 7.0Hz); 0.79 (3H,
t, 7.5Hz); 1.11 ~ 1.29 (1H, m); 1.31 ~ 1.44 (1H, m); 2.
69 (1H, quint, J = 7.0 Hz); 4.29 (1H, d, J = 14.9 Hz); 4.5
9 (1H, d, J = 14.9 Hz); 7.31 (2H, d, J = 8.7 Hz); 7.40 (2
H, d, J = 8.7 Hz); 7.97 (1H, s); 8.26 (1H, s). Mass spectrum (m / z): 292 (M + 1) ⁺ , 209 Example 36 2- (4-Fluorophenyl) -3-tert-butyl-2
-[(1H-1,2,4-triazol-1-yl) methyl]
Oxetane 2- (4-fluorophenyl) -5,5-dimethyl-1
-(1H-1,2,4-triazol-1-yl) -2,4-hexane-diol (1.54 g, 5 mmol) in dichloromethane (75
ml) solution, triethylamine (2.02 g, 20 mmol) and methanesulfonyl chloride (2.29 g, 20 mmol) were added under ice-cooling, and the mixture was stirred at the same temperature for 3 hours and further at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water (80 ml), extracted with dichloromethane (150 ml), washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 6/5) to obtain 113 mg of the desired product.

Yield 7.8%. Melting point 128 ° C NMR (CDCl ₃ ) δ ppm: 1.06 (9H, s); 2.28 (1H, dd, J = 12.
1,14.30Hz); 2.64 (1H, dd, J = 1.21,14.30Hz); 4.92 (1
H, d, J = 14.5Hz); 5.21 (1H, d, J = 14.5Hz); 4.97 (1H, d
d, J = 1.21,12.1Hz); 7.01 ~ 7.11 (4H, m), 7.77 (1H,
s), 7.80 (1H, s). Mass spectrum (m / z): 289 (M ⁺ ), 207 Example 37 2- (4-Chlorophenyl) -3-tert-butyl-2-
[(1H-1,2,4-Triazol-1-yl) methyl] oxetane The title compound was obtained in the same manner as in Example 36.

3.4% yield. Oil NMR (CDCl ₃ ) δ ppm: 1.10 (9H, s); 2.27 (1H, dd, J = 11.
7,13.9Hz); 2.26 (1H, brd, J = 13.9Hz); 4.96 (1H, d, J =
12.5Hz); 5.19 (1H, d, J = 12.5Hz); 7.16 (1H, d, J = 8.3H)
z); 7.30 (2H, d, J = 8.3 Hz); 7.81 (1H, brs); 7.86 (1H,
brs). Mass spectrum (m / z): 305 (M ⁺ ), 223 Example 38 2- (4-Chlorophenyl) -4-isopropyl-2-
[(1H-1,2,4-triazol-1-yl) methyl] oxetane 2- (4-chlorophenyl) -5-methyl-1- (1H
-1,2,4-triazol-1-yl) -2,4-hexane-
The same treatment as in Example 36 was carried out using diol (700 mg, 2.26 mmol) to obtain two stereoisomers at the C ⁴ position of the title compound.

Yield of low polar compound (A) 53,5 mg. Yield 8.1% Yield of high polar compound (B) 28.9 mg. Yield 4.4% Compound (A) Oil NMR (CDCl ₃ ) δ ppm: 1.06 (3H, d, J = 6.8Hz); 1.07 (3H,
d, J = 6.8 Hz); 1.96 (1H, sept, J = 6.8 Hz); 2.27 (1H, dd,
J = 12.1, 14.1 Hz); 2.65 (1H, dd, J = 1.8, 14.1 Hz); 4.99
(1H, d, J = 14.5Hz); 5.16 (1H, d, J = 14.5Hz); 4.99-5.
06 (1H, m); 7.04 (2H, d, J = 8.7Hz); 7.29 (2H, d, J = 8.7
Hz); 7.81 (1H, s); 7.88 (1H, s). Mass spectrum (m / z): 291 (M ⁺ ), 209. Compound (B) Oil NMR (CDCl ₃ ) δ ppm: 1.00 (3H, d, J = 7.3 Hz); 1.02 (3H,
d, J = 7.3 Hz); 1.88 to 2.00 (1H, m); 2.77 (1H, dd, J = 3.
2,14.5Hz); 2.94 (1H, dd, J = 12.1, 14.5Hz); 3.94 (1H, d
dd, J = 3.2,6.4,12.1Hz); 4.45 (1H, d, J = 14.3Hz); 4.70
(1H, d, J = 14.3Hz); 7.14 (2H, d, J = 8.7Hz); 7.32 (2H,
d, J = 8.7 Hz); 7.69 (1H, s); 7.92 (1H, s). Mass spectrum (m / z): 291 (M ⁺ ), 209 Example 39 2-Phenyl-2- (1H-1,2,4-triazole-1-
Yl) methyl-3,3,4-trimethyl-oxetane 2- (1H-1,2,4-triazol-1-yl) acetophenone (1.1 g, 5.88 mmol) in acetonitrile-benzene (2: 1 V / V, 15 ml) solution with 2-methyl-2-butene (4.
0 ml, 37.64 mmol) was added. This was irradiated at 15 ° C. with a medium pressure mercury lamp (450 W) manufactured by Hanovia for 15 hours. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to obtain 409.7 mg of the desired product.

Yield 27%. Melting point 102 ° C NMR (CDCl ₃ ) δ ppm: 0.76 (3H, s); 1.26 (3H, d, J = 6.4H)
z); 1.36 (3H, s); 4.64 (1H, d, J = 14.1 Hz); 4.82 (1H,
q, J = 6.4Hz); 5.10 (1H, d, J = 14.1Hz); 7.1 ~ 7.3 (5H, b
rm); 7.65 (1H, s); 7.76 (1H, s). Mass spectrum (m / z): 258 (M + 1) ⁺ , 188,175,152,1
44,129. In the same manner as in Example 39, the compounds of Examples 40-44 were obtained.

Example 40 2- (4-isopropylphenyl) -2- (1H-1,2,4
-Triazol-1-yl) -3,3,4-trimethyloxetane yield 4.4%, mp 53-60 ° C NMR (CDCl ₃ ) δ ppm: 0.76 (3H, s); 1.20 (6H, d, J = 6.85H)
z); 1.26 (3H, d, J = 6.45 Hz); 1.35 (3H, s); 2.84 (1H, s
ept, J = 6.85 Hz); 4.62 (1H, d, J = 14.1 Hz); 4.81 (1H, q,
J = 6.45 Hz); 5.10 (1H, d, J = 14.1 Hz); 6.96 to 7.12 (4H,
brm); 7.69 (1H, s); 7.74 (1H, s). Mass spectrum (m / z): 299 (M ⁺ ), 230, 217. Example 41 2- (4-methoxyphenyl) -2- (1H-1,2,4-triazol-1-yl) methyl-3,3, 4- trimethyl oxetane yield 2.5%, oil _{NMR (CDCl 3) δppm: 0.75} (3H, s); 1.26 (1H, d, J = 6.44H
z); 1.34 (3H, s); 3.76 (3H, s); 4.63 (1H, J = 14.1H)
z); 4.81 (1H, q, J = 6.44 Hz); 5.09 (1H, d, J = 14.1 Hz);
6.80 (2H, d, J = 8.87 Hz); 6.94 to 7.03 (2H, br); 7.69 (1
H, s); 7.83 (1H, s). Mass spectrum (m / z): 287 (M ⁺ ), 218,205,135 Example 42 2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-yl) methyl-3,3 , 4-Trimethyloxetane yield 3.2%, mp 85-104 ° C NMR (CDCl ₃ ) δ ppm: 0.92 (3H, S); 1.24 (3H, d, J = 6.45H)
z); 1.44 (3H, s); 4.81 (1H, q, J = 6.45 Hz); 5.00 (1H,
d, J = 14.3Hz); 5.26 (1H, d, J = 14.3Hz) 7.06 (1H, dd, J
= 2.02,8,86Hz); 7.16 (1H, d, J = 8.86Hz); 7.32 (1H, d,
J = 2.0Hz); 7.63 (1H, s); 7.94 (1H, s). Mass spectrum (m / z): 325 (M ⁺ ), 312,243,175 Example 43 2- (4-Fluorophenyl) -2- (1H-1,2,4-triazol-1-yl) methyl-3,3,3 4-trimethyloxetane yield 15%, mp 108 ° C NMR (CDCl ₃ ) δ ppm: 0.74 (3H, s); 1.26 (3H, d, J = 6.45H)
z); 1.36 (3H, s); 4.65 (1H, d, J = 14.1 Hz); 4.83 (1H,
q, J = 6.45 Hz); 5.08 (1H, d, J = 14.1 Hz); 6.92 to 7.07 (4
H, brm); 7.67 (1H, s); 7.90 (1H, s). Mass spectrum (m / z): 276 (M ⁺ ), 206,147 Example 44 2- (4-Chlorophenyl) -2- (1H-1,2,4-triazol-1-yl) methyl-3,3,4 - trimethyl oxetane yield 2%, mp111~114 ℃ NMR (CDCl 3) δppm: 0.72 (3H, s); 1.24 (3H, d, J = 6.35H
z); 1.33 (3H, s); 4.62 (1H, d, J = 14.2 Hz); 4.80 (1H,
q, J = 6.35 Hz); 5.06 (1H, d, J = 14.2 Hz); 6.8 to 7.24 (4
H, brm); 7.65 (1H, s); 7.91 (1H, s). Mass spectrum (m / z): 292 (M ⁺ ), 279,222,209 Example 45 2- (2,4-difluorophenyl) -3,3-dimethyl-2
-[(1H-1,2,4-triazol-1-yl) methyl]
Oxetane benzene (6 ml) was bubbled at 0 ° C. until the 2-methylpropene gas volume increased by about 25%. Here, acetonitrile (6 ml) and 2 ', 4'-difluoro-2- (1H-
1,2,4-triazol-1-yl) acetophenone (69
(5.2 mg, 3.115 mmol) to give a solution. This was irradiated at 15 ° C. with a medium pressure mercury lamp (450 W) manufactured by Hanovia for 15 hours. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1 /
The mixture was subjected to 1) to obtain a mixture (450 mg) of the target compound and raw materials. This mixture was made into a solution of methanol (5 ml), and sodium borohydride (200 mg, 5.27 mmo) was added thereto at 0 ° C.
l) was added. After stirring at the same temperature for 3 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give a pale yellow residue. This was subjected to silica gel column chromatography to obtain the desired compound (197.1 mg, 0.706 mmol).

Yield 23%, melting point 76-78 ° C. This was identical in all respects to the compound obtained in Example 25.

Example 46 2- (4-fluorophenyl) -3,3-dimethyl-2-
[(1H-1,2,4-triazol-1-yl) methyl] oxetane 2-methylpropene and 4'-fluoro-2- (1H-1,
The reaction was carried out in the same manner as in Example 39 using 2,4-triazol-1-yl) acetophenone to obtain the target compound in a yield of 2.0
%.

Melting point 110 ° C NMR (CDCl ₃ ) δ ppm: 0.92 (3H, s); 1.43 (3H, s); 4.20
(1H, d, J = 5.6Hz); 4.58 (1H, d, J = 5.6Hz); 4.64 (1H,
d, J = 14.1Hz); 5.06 (1H, d, J = 14.1Hz); 6.97 (2H, t, J
= 8.86Hz); 7.00 ~ 7.09 (2H, brm.); 7.68 (1H, s); 7.99
(1H, s). Mass spectrum (m / z): 261 (M ⁺ ), 179,123 Example 47 8- (2,4-difluorophenyl) -7-oxa-8-
(1H-1,2,4-triazol-1-yl) methyl-bicyclo [4.2.0] octane cyclohexene and 2 ', 4'-difluoro-2- (1H-
1,2,4-triazol-1-yl) subjected to the same reaction as Example 39 using acetophenone, about gum stereoisomer of the desired compounds for C ⁸ position of the 1: as a mixture of 1.
Yield 31% NMR (CDCl ₃ ) δ ppm: 1.0 to 2.2 (brm.); 2.64 (brdt., J =
4.1Hz); 3.03 (q, J = 1.15Hz); 4.52 (d, J = 14.5Hz); 4.
60 (m); 4.70 (d, J = 14.5 Hz); 4.89 (d, J = 14.5 Hz);
5.11 (d, J = 14.5 Hz); 6.65 to 6.96 (m); 7.31 (ddd, J =
1.61,8.05,8.05Hz); 8.17 (s); 7.95 (s); 7.81
(S). Example 48 2- (2,4-difluorophenyl) -3,3,4,4-tetramethyl-2-[(1H-1,2,4-triazol-1-yl)
Methyl] oxetane The reaction was carried out in the same manner as in Example 39 using 2,3-dimethyl-2-butene and 2 ', 4'-difluoro-2- (1H-1,2,4-triazol-1-yl) acetophenone. To give 85 mg of the desired compound.

Yield 15%. Melting point 100-101 ° C. NMR (CDCl ₃ ) δ ppm: 0.93 (3H, d, J = 1.61 Hz); 1.27 (3H,
s); 1.42 (3H, s); 1.58 (3H, s); 4.84 (1H, dd, J = 1.61
14.10Hz); 4.90 (1H, d, J = 14.10Hz); 6.65 to 6.82 (1H,
m); 7.20 (1H, ddd, J = 2.01, 9.01, 9.01 Hz); 7.60 (1H,
s); 7.91 (1H, s). Mass spectrum (m / z): 307 (M ⁺ ), 294,279,224,205,16
Example 49 (2R ^* , 4R ^* )-2- (4-fluorophenyl) -3,4-
Dimethyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxetane cis-2-butene and 4'-fluoro-2- (1H-1,2,
4-triazol-1-yl) acetophenone (950 mg,
5.68 mmol) and subjected to a reaction in the same manner as in Example 39.
80 mg of a mixture of about 1: 1 stereoisomers of the coordination with respect to the position were obtained.

Yield 5.3%. Oil.

NMR (CDCl ₃ ) δ ppm: 0.69 (d, J = 7.25 Hz); 1.16 (d, J =
6.45Hz); 1.37 (d, J = 6.45Hz); 2.79 (quint, J = 7.25H
z); 3.15 (quint, J = 7.25 Hz); 4.39 (d, 14.50 Hz); 4.50
(M); 4.60 (m), 4.59 (d, J = 14.1 Hz); 4.73 (d, J = 1
4.50Hz); 4.92 (d, J = 14.1Hz); 6.91 ~ 7.15 (m); 7.21
~ 7.32 (m); 7.76 (s); 7.94 (s); 7.98 (s); 8.27
(S). Mass spectrum (m / z): 261 (M ⁺ ), 206, 179, 148, 133, 12
3. Example 50 2- (4-Methylphenyl) -2-[(1H-1,2,4-triazol-1-yl) methyl)] oxetane dimethylsulfoxide (DMSO, 20 ml) was added to sodium hydride (about 20 ml). A 60% oil content, 0.98 g, 25.5 mmol) was added and stirred at 80 ° C. for 1 hour. The mixture was cooled with ice, trimethylsulfoxonium iodide (5.62 g, 25.5 mmol) was added, and the mixture was returned from ice cooling to room temperature and stirred for 30 minutes. Next, a solution of 4′-methyl-2- (1H-1,2,4-triazol-1-yl) acetophenone (2.2 g, 11.6 mmol) in DMSO (5 ml) was added, and the mixture was stirred at 50 ° C. for 6 hours. After cooling, the reaction mixture was poured into ice-water (20 ml), extracted with ethyl acetate (200 ml), washed twice with saturated saline (100 ml), dried over sodium sulfate, concentrated, and concentrated to 2.7 g. An oil was obtained. This was subjected to silica gel column chromatography (elution solvent: hexane /
Ethyl acetate = 1/1) to give 2.3 g of the desired product.

Yield 86.3% oil _{NMR (CDCl 3) δppm: 2.37} (3H, s); 2.6~2.7 (1H, m); 2.
91 ~ 2.98 (1H, m); 4.02 ~ 4.10 (1H, m); 4.29 (1H, d, J =
14.7Hz); 4.52 (1H, d, J = 14.7Hz); 4.38 to 4.46 (1H,
m); 7.22 (4H, s); 7.98 (1H, s); 8.22 (1H, s). Mass spectrum (m / z): 229 (M ⁺ ), 214,198,184,172,15
9,148,119. ▲ IRv ^liq _max ▼ cm ^-1 : 3140,2980,2950,1505,1271. The compounds of Examples 51-57 were synthesized in the same manner as in Example 50.

Example 51 2- (4-Chlorophenyl) -2-[(1H-1,2,4-triazol-1-yl) methyl] oxetane 61% yield, mp 74-75 ° C. NMR (CDCl ₃ ) δ ppm: 2.62- 2.75 (1H, m); 2.95 to 3.05 (1
H, m); 4.06 to 4.14 (1H, m); 4.30 (1H, d, J = 14.5Hz); 4.
39 to 4.49 (1H, m); 4.53 (1H, d, J = 14.5 Hz); 7.27 (2H,
d, J = 8.46 Hz); 7.38 (2H, d, J = 8.46 Hz); 7.98 (1H, s);
8.24 (1H, s). Mass spectrum (m / z): 249 (M ⁺ ), 169,139 Example 52 2- (2,4-difluorophenyl) -2-[(1H-1,2,4
- triazol-1-yl) methyl] oxetane 45% yield, oil _{NMR (CDCl 3) δppm: 2.66~2.77} (1H, m); 2.93~3.04 (1
H, m); 4.15-4.23 (1H, m); 4.34 (1H, d, J = 14.9Hz); 4.
43 ~ 4.52 (1H, m); 4.73 (1H, d, J = 14.9Hz); 6.81 ~ 6.93
(2H, m); 7.39 ~ 7.48 (1H, m); 7.94 (1H, s); 8.27 (1H,
s). Mass spectrum (m / z): 251 (M ⁺ ), 170, 141 Example 53 2- (4-isopropylphenyl) -2-[(1H-1,2.
4-triazol-1-yl) methyl] oxetane yield 87%, oil _{NMR (CDCl 3) δppm: 1.27} (6H, d, J = 7.3Hz); 2.17~2.72
(1H, m); 2.90 ~ 3.01 (2H, m); 4.02 ~ 4.07 (1H, m); 4.2
9 (1H, d, J = 14.7 Hz); 4.38 to 4.47 (1H, m); 4.52 (1H, d,
J = 14.7 Hz); 7.27 (4H, s); 7.99 (1H, s); 8.25 (1H,
s). Mass spectrum (m / z): 257 (M ⁺ ), 175,147 Example 54 2- (4-trifluoromethylphenyl) -2-[(1H
1,2,4-triazol-1-yl) methyl] oxetane 42%, oil _{NMR (CDCl 3) δppm: 2.66~2.72} (1H, m); 3.00~3.11 (1
H, m); 4.07 to 4.15 (1H, m); 4.32 (1H, d, J = 14.9 Hz); 4.
40 ~ 4.48 (1H, m); 4.57 (1H, d, J = 14.9Hz); 7.47 (2H, m
7.68 (2H, d, J = 8.1Hz); 7.99 (1H, s); 8.
27 (1H, s). Mass spectrum (m / z): 283 (M ⁺ ), 201,173 Example 55 2- (4-Fluorophenyl) -2-[(1H-1,2,4-
Triazol-1-yl) methyl] oxetane 55% yield, mp 65-66 ° C. NMR (CDCl ₃ ) δ ppm: 2.61-2.81 (1H, m); 2.94-3.04 (1
H, m); 4.06 to 4.16 (1H, m); 4.30 (1H, d, J = 14.7Hz); 4.
40 ~ 4.48 (1H, m); 4.53 (1H, d, J = 14.7Hz); 7.06 ~ 7.12
(2H, m); 7.27 ~ 7.33 (2H, m); 7.99 (1H, s); 8.25 (1H,
s). Mass spectrum (m / z): 233 (M ⁺ ), 151,123 Example 56 2- (4-methoxyphenyl) -2-[(1H-1,2,4-
Triazol-1-yl) methyl] oxetane yield 46%, mp66~67 ℃ NMR (CDCl 3) δppm: 2.61~2.71 (1H, m); 2.90~3.02 (1
H, m); 3.82 (3H, s); 4.04-4.14 (1H, m); 4.30 (1H, d, J
= 14.7Hz); 4.44-4.47 (1H, m); 4.51 (1H, d, J = 14.7H
z); 6.93 (2H, d, J = 8.86 Hz); 7.25 (2H, d, J = 8.86 Hz);
7.98 (1H, s); 8.21 (1H, s). Mass spectrum (m / z): 245 (M ⁺ ), 163,135 Example 57 2- (4-Chloro-2-fluoromethylphenyl) -2
-[(1H-1,2,4-triazol-1-yl) methyl]
Oxetane yield 59%, oil NMR (CDCl ₃ ) δ ppm: 2.66 to 2.77 (1H, m); 2.94 to 3.04 (1
H, m); 4.08 to 4.23 (1H, m); 4.34 (1H, d, J = 14.7Hz); 4.
39 ~ 4.51 (1H, m); 4.73 (1H, d, J = 14.7Hz); 7.08 ~ 7.18
(2H, m); 7.37-7.43 (1H, m); 7.94 (1H, s); 8.27 (1H,
s). Mass spectrum (m / z): 245 (M ⁺ ), 163,135 Example 58 2- (4-Methylphenyl) -2- [1- (1,2,4-triazol-1-yl) ethyl] oxetane 4 ' -Methyl-2- (1H-1,2,4-triazole-1
Treatment with -yl) propylphenone in the same manner as in Example 50 afforded an approximately 2: 1 mixture of isomers with respect to the configuration of the triazole group of the title compound.

Yield 49.3% Oil NMR (CDCl ₃ ) δ ppm: 1.33 (d, J = 7.25 Hz); 2.37 (s),
2.44 to 2.53 (m); 2.70 to 2.80 (m); 3.98 to 4.06
(M); 4.37-4.47 (m); 4.74 (q, J = 7.25Hz); 7.20
(S); 7.99 (s); 8.34 (s). Mass spectrum (m / z): 243 (M ⁺ ), 228, 213, 147, 119. Example 59 2- (2,4-difluorophenyl) -2-[(1H-1,2,4
-Triazol-1-yl) methyl)] oxetane Sodium hydride (oil containing about 60%, 101 mg, 4.2 mmol) was added to DMSO (10 ml), and the mixture was stirred at 80 ° C for 30 minutes, cooled with ice, and then trimethyl iodide. Sulfoxonium (928mg, 4.2mmo
l) and the temperature is returned from ice cooling to room temperature. After stirring for 30 minutes, 2- (2,4
-Difluorophenyl) -2-[(1H-1,2,4-triazol-1-yl) methyl)] oxolane (501 mg, 2.11
mmol), and the mixture was heated and stirred at 50 ° C. for 16 hours. After cooling, the reaction mixture was poured into ice water (50 ml), and ethyl acetate (100 ml) was added.
The mixture was extracted with l), washed with brine, dried over sodium sulfate, concentrated, and subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/3) to obtain 238 mg of the desired product.

This was in all respects the same as the compound obtained in Example 52.

Example 60 5-oxa-4-phenyl-4-[(1,2,4-triazol-1-yl) methyl] spiro [2,3] hexane 1-phenyl-1- {1- (methanesulfonyloxymethyl) ) -Cyclopropan-1-yl} -2- (1H-1,
2,4-Triazol-1-yl) ethanol (69.8 mg, 0.9%
Sodium hydride (oil containing about 60%, 33.2 mg, 0.496 mmol) was added to a DMF solution of 207 mmol) under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water, washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by preparative silica gel chromatography (developing solvent: hexane / ethyl acetate = 1/1). By subjecting to 1), 5 mg of the desired product was obtained.

Yield 9.9%. Oil NMR (CDCl ₃ ) δ ppm: 0.3-0.9 (4H, m); 4.37 (1H, d, J =
5.46Hz); 4.44 (1H, d, J = 14.80Hz); 4.54 (1H, d, J = 5.4
6Hz); 4.85 (1H, d, J = 14.80Hz); 7.19 to 7.41 (5H, m);
7.88 (1H, s); 8.32 (1H, s). Mass spectrum (m / z): 242 (M ⁺ ), 188, 172, 159 Example 61 (2R ^* , 3S ^* , 4S ^* )-2- (4-chlorophenyl) -3,
4-dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane (2R ^* , 3S ^* , 4R ^* )-2- (4-chlorophenyl)-
3-methyl-4-methanesulfonyloxy-1- (1H-
1,2,4-triazol-1-yl) -pentanol (200
Sodium hydride (oil containing about 60%, 28 mg, 1.003 mmol) was added to a solution of DMF (5 ml) in ice-cooling and stirred for 1.5 hours. After completion of the reaction, the reaction product was treated in the same manner as in Example 60 to obtain 32.2 mg of the desired product.

Yield 19.7%. Oil NMR (CDCl ₃ ) δ ppm: 0.73 (3H, d, J = 7.25 Hz); 1.06 (3H,
d, J = 6.04 Hz); 2.66 (1H, quint, J = 7.25 Hz); 4.26 (1H,
m); 4.31 (1H, d, J = 14.9 Hz); 7.30 (2H, d, J = 8.66 Hz);
7.40 (2H, d, J = 8.66 Hz); 8.01 (1H, s); 8,38 (1H, s). Mass spectrum (m / z): 278: (M + 1) ⁺ , 222, 195, 139. The compounds of Examples 62 to 66 were synthesized in the same manner as in Example 61.

Example 62 (2R ^* , 3R ^* , 4S ^* )-2- (4-chlorophenyl) -3,
4-dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane yield 8.0% mp 75-118 ° C NMR (CDCl ₃ ) δ ppm: 1.39 (3H, d, J = 6.04 Hz); 1.42 (3H,
d, J = 4.88 Hz); 3.14 (1H, quint, J = 7.66 Hz); 4.60 (1H,
d, J = 14.5Hz); 4.74 (1H, d, J = 14.5Hz); 4.92 (1H, quin
t, J = 6.54 Hz); 7.10 (2H, d, J = 8.46 Hz); 7.26 (2H, d, J
= 8.46Hz); 7.83 (1H, s); 8.13 (1H, s). MS (m / z): 277 (M ⁺ ), 222,195,139 Example 63 (2R ^* , 3R ^* , 4R ^* )-2- (4-chlorophenyl) -3,
4-dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane Yield 70.0% mp 113-121 ° C. NMR (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 5.64 Hz); 1.38 (3H,
d, J = 7.65 Hz); 2.77 (1H, quint, J = 7.25 Hz); 4.51 to 4.6
4 (1H, m); 4.59 (1H, d, J = 14.3 Hz); 4.93 (1H, d, J = 14.
3 Hz); 7.08 (2H, d, J = 8.46 Hz); 7.25 (2H, d, J = 8.46 H)
z); 7.78 (1H, s); 8.05 (1H, s). Mass spectrum (m / z): 278 (M + 1) ⁺ , 222,195,139 Example 64 (2R ^* , 3S ^* , 4R ^* )-2- (4-bromophenyl) -3,
4-dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane Yield 62.3% Oil NMR (CDCl ₃ ) δ ppm: 0.70 (3H, d, J = 7.66 Hz); 1.16 (3H,
d, J = 6.45 Hz); 3.16 (1H, quint, J = 7.66); 4.38 (1H, d,
J = 14.5Hz); 4.40 ~ 4.54 (1H, m); 4.72 (1H, d, J = 14.5H
z); 7.19 (2H, d, J = 8.66 Hz); 7.52 (2H, d, J = 8.66 Hz);
7.95 (1H, s); 8.30 (1H, s). Mass spectrum (m / z): 322 (M + 1) ⁺ , 303,266,241,1
85 Example 65 (2R ^* , 3S ^* , 4R ^* )-2- (4-trifluoromethylphenyl) -3,4-dimethyl-2-[(1H-1,2,4-triazol-1-yl) Methyl] oxetane 46% yield, oil NMR (CDCl ₃ ) δ ppm: 0.71 (3H, d, J = 7.7 Hz); 1.17 (3H,
d, J = 6.4Hz); 3.23 (1H, quint, J = 7.7Hz); 4.40 (1H, d,
J = 14.5Hz); 4.43-4.48 (1H, m); 4.75 (1H, d, J = 14.5H
z); 7.44 (2H, d, J = 8.1Hz); 7.65 (2H, d, J = 8.1Hz); 7.
95 (1H, s); 8.30 (1H, s). Mass spectrum (m / z): 312 (M + 1) ⁺ , 229,173 Example 66 (2R ^* , 3R ^* )-2- (4-chloro-2-fluoromethylphenyl) -3,4-dimethyl-2-[( 1H-1,2,4-triazol-1-yl) methyl] oxetane 93% yield, mp 115-116 ° C. NMR (CDCl ₃ ) δ ppm: 1.30-1.41 (6H, m); 2.72-2.84 (1
H, m); 4.54 to 4.8 (1H, m); 4.65 (1H, d, J = 13.31 Hz);
95 (1H, d, J = 13.31 Hz); 6.98 to 7.38 (3H, m); 7.72 (1H,
s); 8.07 (1H, s) Mass spectrum (m / z): 296 (M + 1) ⁺ , 256,240,215,1
59 Example 67 (2R ^* , 3S ^* , 4R ^* )-2- (4-chlorophenyl) -3,
4-dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane nitrate (2R ^* , 3S ^* , 4R ^* )-2- (4-chlorophenyl)-
3,4-dimethyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxetane (300 mg, 1.08 mmol) in a mixed solution of ether (5 ml) and methanol (1 ml) was added with concentrated nitric acid (containing about 61%, 0.19 ml), and the solvent was distilled off. The mixture was added, and the precipitated crystals were collected by filtration to obtain the desired compound (351 mg).

Yield 95.4% Melting point 129-142 ° C Elemental analysis: C ₁₄ H ₁₇ ClN ₄ O ₄ Calculated: C, 49.35; H, 5.03; Cl, 10.40; N, 16.44 Analytical value: C, 49.28; H, 5.15; Cl, 10.32; N, 16.64 Example 68 (2R ^* , 3S ^* , 4R ^* )-2- (4-chlorophenyl) -3,
4-dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane oxalate. (2R ^* , 3S ^* , 4R ^* )-2- (4-chlorophenyl)-
3,4-dimethyl-2-[(1H-1,2,4-triazole-1
-Yl) methyl] oxetane (300 mg, 1.08 mmol) in ethyl acetate (5 ml) was added dropwise with a solution of oxalic acid (97.2 ml) in ethyl acetate, and the precipitated crystals were collected by filtration, dried and dried to give the desired compound (22
9 mg).

Yield 57.7%. 135-144 ° C _{NMR (CMSO-d 6) δppm} : 0.61 (3H, d, J = 7.25Hz); 1.09
(3H, d, J = 6.45 Hz); 3.18 (1H, quint, J = 7.65 Hz); 3.37
(Brs); 4.51 (1H, t, J = 7.25 Hz); 4.60 (1H, d, J = 14.5H)
z); 4.89 (1H, d, J = 14.5 Hz); 7.34 (2H, d, J = 8.86 Hz);
7.41 (2H, d, J = 8.86 Hz); 7.88 (1H, s); 8.34 (1H, s). Example 69 (2R ^* , 3S ^* , 4R ^* )-2- (4-chlorophenyl) -3,
4-dimethyl-2-[(1H-1,2,4-triazole-1-
Yl) methyl] oxetane 2- (4-chlorophenyl) -3,4-dimethyl-2-
Methanesulfonyloxymethyloxetane (107mg, 0.35
1 mmol), 1H-1,2,4-triazole (51.5 mg, 0.746 mmo
l) and sodium iodide (45.6 mg, 0.304 mmol) in dimethylimidazolidinone (10 ml) were added at 0 ° C. with sodium hydride (about 60% in oil, 38 mg, 0.950 mmol). Stirred for minutes. After further stirring at 90 ° C for 12 hours,
An aqueous solution of sodium thiosulfate was added. The mixture was extracted with ethyl acetate-hexane (1: 1, V / V), washed with water, and dried over anhydrous magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1),
The target compound (76.3 mg) was obtained.

This was in all respects consistent with the compound obtained in Example 20.

Example 70 2- (2,4-dichlorophenyl) -3,3,4-trimethyl-
2-[(1H-1,2,4-triazol-1-yl) methyl] oxetane 2- (2,4-dichlorophenyl) -3,3-dimethyl-4
-Mesyloxy-1- (1H-1,2,4-triazole-1
-Yl) -2-pentanol (400 mg, 0.95 mmol) in DMF
Sodium hydride (60% oil, 8
4 mg, 2.1 mmol) and stirred at 90 ° C. for 2 hours. After cooling,
The mixture was poured into ice water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, evaporated, and the residue was washed with hexane.
2.4 mg of crude product was obtained. This was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 220.7 mg of the desired product.

Yield: 71.4% Melting point: 118-125 ° C This compound is a stereoisomer of the compound obtained in Example 42 and coordination at the C4 position.

NMR (CDCl ₃ ) δ ppm: 1.06 (3H, s) 1,42 (3H, s); 1.49 (3
H, d, J = 6.3Hz); 4.36 (1H, q, J = 6.3Hz); 4.83 (1H, d, J
= 14.2Hz); 5.36 (1H, d, J = 14.2Hz); 7.10 (1H, dd, J =
2.2, 8.4Hz); 7.28 (1H, d, J = 8.4Hz); 7.35 (1H, d, J = 2.
7.63 (1H, s); 7.99 (1H, s) Mass spectrum (m / z): 328,326,290,256,243,173 Example 71 (2R ^* , 3S ^* , 4S ^* )-2- (2,4-difluorophenyl)- 4-isopropyl-3-methyl-2-[(1H-1,
2,4-Triazol-1-yl) methyl] oxetane
Succinate (A) (2R ^* , 3R ^* , 4S ^* )-2- (2,4-difluorophenyl) -4-isopropyl-3-methyl-2-[(1H-1,
2,4-Triazol-1-yl) methyl] oxetane
Succinate (B) (2R ^* , 3R ^* , 4R ^* )-2- (2,4-difluorophenyl) -4-isopropyl-3-methyl-2-[(1H-1,
2,4-Triazol-1-yl) methyl] oxetane (C) The title compound was produced in the same manner as in Example 1.

(A) melting point 140-145 ° C NMR (CDCl ₃ ) δ ppm: 0.69 (3H, d, J = 7 Hz); 0.88 (3H, dd,
J = 7.25 Hz); 0.90 (3H, d, J = 7 Hz); 1.25 (1H, m); 2.79
(1H, m); 3.61 (1H, dd, J = 7.5,9.5Hz); 4.40 (1H, d, J =
14.5Hz); 4.78 (1H, d, J = 14.5Hz); 6.8-7.0 (2H, m);
7.60 (1H, td, J = 9.7 Hz); 7.87 (1H, s); 8.19 (1 H, s) (B) Melting point 151-154 ° C. NMR (acetone-d6) δ ppm: 0.81 (3H, d, J = 6.5Hz); 1.0
2 (3H, d, J = 6.5 Hz); 1.47 (3H, d, J = 7.5 Hz); 2.29 (1H,
m); 3.19 (1H, m); 4.17 (1H, dd, J = 10.5,8.5Hz); 4.65
(1H, d, J = 13Hz); 4.92 (1H, d, J = 13Hz); 6.7−7.2 (3
H, m); 7.52 (1H, s); 8.13 (1H, s) (C) Oil NMR (CDCl ₃ ) δ ppm: 0.77 (3H, d, J = 7 Hz); 0.93 (3H, d, J)
= 7Hz); 1.40 (3H, dd, J = 7.5,1Hz); 1.76 (1H, m); 2.84
(1H, m); 4.09 (1H, dd, J = 8.7 Hz); 4.67 (1H, dd, J = 14,
1.5Hz); 4.90 (1H, d, J = 14Hz); 6.6-6.8 (2H, m); 7.07
(1H, td, J = 8.5, 6.5 Hz); 7.66 (1H, s); 8.03 (1H, s) Example 72 (2R ^* , 3S ^* , 4R ^* )-2- (4-chlorophenyl) -3,
4-dimethyl-2-[(1H-1,2,4, -triazole-1
-Yl) methyl] oxetane 2- (4-chlorophenyl) -2-chloromethyl-3,
4-dimethyl-oxetane (4S ^* : 4R ^* = 3: 1 mixture, 24
1H-1,2,4-triazole (26 mg, 0.38 mmol) and potassium carbonate (26 mg, 0.19 mmol) were added to a DMF solution (2 ml) of 5 mg, 1 mmol), and the mixture was stirred at 130 ° C. for 5 hours. After cooling, the mixture was poured into ice water, extracted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution, dried over sodium sulfate, and the solvent was distilled off to obtain 260 mg of a residue. This was subjected to silica gel column chromatography to obtain 56.2 mg (yield 81%) of the desired product.

This was in all respects consistent with the compound obtained in Example 20.

Example 73 (2R ^* , 3S ^* , 4R ^* )-2-phenyl-3,4-dimethyl-
2-[(1H-1,2,4-triazol-1-yl) methyl] oxetane The procedure described in Example 69 was followed using 2-phenyl-3,4-dimethyl-2-methanesulfonyloxymethyloxetane. The title compound was obtained accordingly.

NMR (CDCl ₃ ) δ ppm: 0.61 (3H, d, J = 7.4 Hz); 1.08 (3H,
d, J = 6.5Hz); 3.09 (1H, m); 4.32 (1H, m); 4.28 (1H, d,
J = 14.7Hz); 4.67 (1H, dJ = 14.7Hz); 7.21-7.34 (5H,
m); 7.85 (1H, s); 8.15 (1H, s) Mass spectrum (m / z): 244 (M + 1) ⁺ , 227,188,161 Reference example 1 (3S ^* , 4R ^* )-4- (2,4-difluoro) Phenyl) -3
-Methyl-5- (1H-1,2,4-triazol-1-yl) -1,4-pentanediol and (2R ^* , 3S ^* )-2- (2,4-difluorophenyl) -3
-Methyl-1- (1H-1,2,4-triazol-1-yl) -2,4-pentanediol (2R ^* , 3S ^* )-2- (2,4-difluorophenyl)-
3-methyl-1- (1H-1,2,4-triazol-1-yl) -4-penten-2-ol [synthesized according to the method described in JP-A-60-36468] 200 mg ( 0.72 mmol
e) is dissolved in 5 ml of tetrahydrofuran, and stirred under ice-cooling.
2.2 ml (4.4 mmole) of M borane-dimethyl sulfide complex tetrahydrofuran solution was added. The mixture was returned to room temperature and stirred for 15 minutes, and then at 50 ° C. for 20 minutes. The reaction solution was ice-cooled again, and 1 ml of a 15% aqueous sodium hydroxide solution and 1 ml of a 30% aqueous hydrogen peroxide solution were added. After stirring at room temperature for 30 minutes and then at 50-60 ° C for 2 hours, ethyl acetate was added, and the mixture was washed with saturated saline. After drying, the solvent was distilled off, and the oil obtained was subjected to column chromatography using silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (5: 1-10: 1) to elute the desired compound (the latter). mg was obtained as an oil. This substance is N
As a result of MR spectrum analysis, about 1: 1 of C ^4- position isomers A and B
Was a mixture of Main peak NMR spectrum of [isomer A] (CDCl ₃ ) δ ppm: 0.80 (3H, dd, J = 7,3.5 Hz); 1.1
8 (3H, d, J = 6 Hz); 4.90 (2H, s); 5.97 (1H, s); 7.79
(1H, s); 8.05 (1H, s). Main peak NMR spectrum of [Isomer B] (CDCl ₃ ) δ ppm: 0.76 (3H, dd, J = 7,1.5 Hz); 1.27 (3H, d, J = 6 Hz); 5.4
7 (1H, s); 7.70 (1H, s); 7.93 (1H, s). Further, with ethyl acetate, 1% methanol-ethyl acetate,
Elution was performed successively to obtain 139 mg of the desired compound (former).
A pure product having a temperature of 22 ° C. was obtained.

NMR spectrum (CDCl ₃ ) δ ppm: 0.78 (3H, dd, J = 7.1 Hz); 1.6−2.0 (2H, m); 2.4 (1H,
m); 3.3-4.0 (3H, m); 4.62 (1H, d, J = 14 Hz); 4.93 (1
H, dd, J = 14,1 Hz); 5.52 (1H, br.); 6.5-7.0 (2H, m);
7.43 (1H, td, J = 9.7 Hz); 7.73 (1H, s); 7.97 (1H,
s). Reference Example 2 (2R ^* , 3S ^* , 4S ^* )-2- (2,4-difluorophenyl) -4- (methanesulfonyloxy) -3-methyl-
1- (1H-1,2,4-triazol-1-yl) -2-pentanol a) (2R ^* , 3S ^* )-2- (2,4-difluorophenyl) -4,5-epoxy-3 -Methyl-1- (1H-1,2,4-
Triazol-1-yl) -2-pentanol (2R ^* , 3S ^* )-2- (2,4-difluorophenyl)-
960 mg of 3-methyl-1- (1H-1,2,4-triazol-1-yl) -4-penten-2-ol (synthesized according to the method described in JP-A-60-36468) 3.44 mmol
e) was dissolved in 30 ml of methylene chloride, and 1.360 mg (6.19 mmole) of m-chloroperbenzoic acid (80% purity) was added at 0 ° C. After 5 minutes, the mixture was returned to room temperature and stirred overnight. The reaction solution was diluted with ethyl acetate, and washed sequentially with an aqueous sodium sulfite solution, an aqueous sodium hydrogen carbonate solution, and a saturated saline solution. After drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography, and separated and purified with a mixed solvent of ethyl acetate-hexane (1: 2) to give stereoisomer A (low polarity) as the target compound, ( 2R ^* , 3S ^* , 4S ^* ) 320 mg (melting point 160-180 ° C)
And stereoisomer B (highly polar), (2R ^* , 3S ^* , 4R ^* ) 206
mg was obtained as an oil.

NMR spectrum of stereoisomer A (CDCl ₃ ) δ ppm: 0.82 (3
H, d, J = 7.3 Hz); 1.74 (1H, quint, J = 7.3 Hz); 2.54 (1
H, dd, J = 4.0,2.8 Hz); 2.89 (1H, t, J = 4.4 Hz); 3.3−
3.4 (1H, m); 4.90 (2H, AB-d, J = 14.5 Hz); 5.06 (1H, b
rs); 6.6-6.8 (2H, m); 7.3-7.5 (1H, m); 7.79 (1H, m
s); 7.80 (1H, s). NMR spectrum of stereoisomer B (CDCl ₃ ) δ ppm: 0.94 (3
H, d, J = 6.9 Hz); 1.86 (1H, quint, J = 6.9 Hz); 2.74 (1
H, dd, J = 4.8,2.8 Hz); 2.95 (1H, t, J = 4.8 Hz); 3.2−
3.3 (1H, m); 4.80 (2H, AB-d, J = 13.7 Hz); 4.92 (1H,
s); 7.6-7.8 (2H, m); 7.3-7.5 (1H, m); 7.78 (1H, m
s); 7.86 (1H, s). b) (2R ^* , 3S ^* , 4S ^* )-2- (2,4-difluorophenyl) -3-methyl-1- (1H-1,2,4-triazol-1-yl) -2,4- (2R ^* , 3S ^* , 4S ^* )-2- (2,4-difluorophenyl) -4,5-epoxy-3-methyl-1- obtained from pentanediol a)
320 mg (1.08 mmole) of (1H-1,2,4-triazol-1-yl) -2-pentanol (stereoisomer A) was dissolved in 20 ml of ether, and the mixture was stirred under ice-cooling and stirring under a nitrogen atmosphere. 84 mg of lithium aluminum hydride (2.16 mmol
e) was added. After 10 minutes, the reaction was refluxed for 1 hour. After cooling, 2 ml of water was slowly added, and the mixture was stirred for 10 minutes. The insoluble matter was removed by filtration using Celite, and the mixture was extracted with ethyl acetate. After drying, the solvent was distilled off, and the obtained oil was subjected to silica gel column chromatography, and eluted with a mixed solvent of ethyl acetate-chloroform-hexane (5: 5: 1) to obtain 240 mg of the desired compound.

NMR spectrum (CDCl ₃ ) δ ppm: 0.80 (3H, dd, J = 6.9, 3.0 Hz); 2.00 (1H, qd, J = 6.9, 1.6)
Hz); 3.86 (1H, qd, J = 6.9, 1.6 Hz); 4.62 (1H, d, J = 14
Hz); 4.93 (2H, s); 6.7-6.9 (2H, m); 7.50 (1H, td, J
= 8.9,6.5 Hz); 7.82 (1H, s); 8.13 (1H, s). c) (2R ^* , 3S ^* , 4S ^* )-2- (2,4-difluorophenyl) -4- (methanesulfonyloxy) -3-methyl-1- (1H-1,2,4-triazole-1 -Il) -2
-Pentanol b), (2R ^* , 3S ^* , 4S ^* )-2- (2,4-difluorophenyl) -3-methyl-1- (1H-1,2,4-triazole-1- Yl) -2,4-pentanediol213 m
g (0.72 mmole) was dissolved in 4 ml of pyridine, and 140 mg (1.22 mmole) of methanesulfonyl chloride was added at 0 ° C.
Stirred for 2.5 hours. After completion of the reaction, pyridine was distilled off under reduced pressure, a diluted aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. After drying, the solvent is distilled off to give the desired compound
270 mg was obtained as an oil.

NMR spectrum (CDCl ₃ ) δ ppm: 0.79 (3H, dd, J = 6.5, 0.8 Hz); 1.49 (3H, d, J = 6.5 H)
z); 2.6-2.8 (1H, m); 3.08 (3H, s); 4.85 (2H, AB-d, J
= 13.9 Hz); 5.3-5.4 (1H, m); 6.6-6.8 (2H, m); 7.2
-7.4 (1H, m); 7.76 (1H, s); 7.81 (1H, s). Reference Example 3 (2R ^* , 3R ^* )-2- (2,4-difluorophenyl) -4,
5-epoxy-3-methyl-1- (1H-1,2,4-triazol-1-yl) -2-pentanol (2R ^* , 3R ^* )-2- (2,4-difluorophenyl)-
514 mg of 3-methyl-1- (1H-1,2,4-triazol-1-yl) -4-penten-2-ol [synthesized according to the method described in JP-A-60-36468] 1.84 mmol
e) was dissolved in 15 ml of methylene chloride, and 635 mg (3.13 mmole) of m-chloroperbenzoic acid (85% purity) was added at 0 ° C. After 5 minutes, the mixture was returned to room temperature and stirred for 2 hours. The reaction solution was diluted with ethyl acetate, and washed sequentially with an aqueous solution of sodium sulfite, aqueous sodium hydrogen carbonate, and saturated saline. After drying, the solvent was distilled off, and the residue was subjected to column chromatography using silica gel, and eluted with a mixed solvent of ethyl acetate-hexane (2: 1) to obtain 472 mg of the desired compound as a solid.

The substance was an approximately 3: 1 mixture of two stereoisomers for the C ⁴ position.

Recrystallize from a mixed solvent of ethyl acetate-hexane,
The main isomer (melting point 106-109 ° C) was separated.

NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J = 6 Hz); 1.90 (1H, br, quint); 2.00 (1H,
2.35 (1H, t, J = 4 Hz); 2.85 (1H, m);
4.53 (1H, d, J = 14 Hz); 4.89 (1H, dd, J = 14,1.5 Hz);
4.9 (1H, br.); 6.5-7.0 (2H, m); 7.3-7.7 (1H, m); 7.
79 (1H, s); 7.91 (1H, s). Reference Example 4 (2R ^* , 3R ^* , 4S ^* )-2- (2,4-difluorophenyl) -3-methyl-1- (1H-1,2,4-triazole-
1-yl) -2,4-pentanediol (2R ^* , 3R ^* )-2- (2,4-difluorophenyl)-
4,5-epoxy-3-methyl-1- (1H-1,2,4-triazol-1-yl) -2-pentanol (C ⁴ isomer about 3:
207 mg (0.70 mmole) of 1) was dissolved in 4 ml of ether, and 53 mg (1.40 mmole) of lithium aluminum hydride was added thereto while stirring with ice cooling under a nitrogen atmosphere. After 10 minutes, the reaction was refluxed for 1 hour. After cooling, 1 ml of water was slowly added, and the mixture was stirred for 10 minutes. The insoluble matter was removed by filtration using Celite, and extracted with ethyl acetate. After drying, the solvent was distilled off, and the resulting oil was subjected to column chromatography using silica gel, and eluted with a mixed solvent of ethyl acetate-chloroform-hexane (5: 5: 1) to obtain 160 mg of the desired compound. Was.

The substance was an approximately 3: 1 mixture of two stereoisomers for the C ⁴ position.

The product was recrystallized from a benzene-hexane mixed solvent to separate an isomer (melting point: 145-146 ° C) as a main component.

NMR spectrum (CDCl ₃ ) δ ppm: 1.05 (3H, d, J = 6.5 Hz), 1.25 (3H, d, J = 6.5 Hz); 2.2
0 (1H, qd, J = 6.5, 1 Hz); 3.03 (1H, br.s); 3.74 (1H, b
rq, J = 6.5 Hz); 4.51 (1H, d, J = 14 Hz); 4.77 (1H, dd,
J = 14.1 Hz); 5.33 (1H, s); 6.5-7.0 (2H, m); 7.1-7.
6 (1H, m); 7.65 (1H, s); 7.89 (1H, s). Reference Example 5 (2R ^* , 3S ^* )-3- (2,4-dichlorophenyl) -3-
Hydroxy-2-methyl-4- (1H-1,2,4-triazol-1-yl) -butanal and (2S ^* , 3R ^* )-3- (2,4-dichlorophenyl) -3-
Hydroxy-2-methyl-4- (1H-1,2,4-triazol-1-yl) -butanal (2R ^* , 3R ^* )-4- (2,4-dichlorophenyl) -3
-Methyl-1- (1H-1,2,4-triazol-1-yl) -4-penten-2-ol and its (2R ^* , 3R ^* )
139 mg (0.45 mmole) of a 1: 1 mixture of isomers [synthesized by the method described in JP-A-60-36468] was dissolved in 2.8 ml of a mixed solvent of tetrahydrofuran-water (5: 2), and metaperiodine was added. 290 mg (1.32 mmole) of sodium silicate and 1 mg of osmium tetroxide were added, and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated saline. After drying, the solvent was distilled off, and the resulting oil was subjected to column chromatography using 4 g of silica gel to give ethyl acetate-hexane (4: 5).
Elution with a mixed solvent, the desired compound (2R ^*, 3R ^*) - isomer ^{27 mg, (2R *, 3R} *) - isomer and (2S ^*, 3R ^*) - mixture 25 mg of the isomer, followed by ( 2S ^* , 3R ^* )-isomer 31 m
g was obtained.

The separated (2R ^* , 3R ^* )-isomer was recrystallized from benzene to give a pure product having a melting point of 150-151 ° C.

The (2S ^* , 3R ^* )-isomer was recrystallized from a mixed solvent of benzene and ethyl acetate to obtain a pure product having a melting point of 155-157 ° C.

^{. [(2R *, 3R *} ) - isomer] Infrared absorption spectrum ^{_{ν max (CHCl 3) cm -}} 1: 3400,1715 NMR spectrum _{(CDCl 3) δppm: 0.96 (} 3H, d, J = 7 Hz); 3.47 (1H, qd, J = 7.3 Hz); 4.64
(1H, d, J = 14 Hz); 5.30 (1H, br.); 5.42 (1H, d, J = 14
Hz); 7.11 (1H, dd, J = 8.2 Hz); 7.31 (1H, d, J = 2 Hz);
7.52 (1H, d, J = 8 Hz); 7.77 (1H, s); 7.85 (1H, s); 9.8
8 (1H, d, J = 3 Hz). ^{[(2S *, 3R *)} - isomer] NMR spectrum _{(CDCl 3) δppm: 1.40 (} 3H, d, J = 7 Hz); 3.52 (1H, qd, J = 7,1.5 Hz); 4.5
0 (1H, d, J = 14 Hz); 5.42 (1H, d, J = 14 Hz); 5.5 (1H, b
r.); 7.11 (1H, dd, J = 8.2 Hz); 7.35 (1H, d, J = 2 Hz);
7.54 (1H, d, J = 8 Hz); 7.77 (1H, s); 7.68 (1H, s); 9.3
9 (1H, d, J = 1.5 Hz). Reference Example 6 (2S ^* , 3R ^* )-3- (2,4-dichlorophenyl) -2-
Methyl-4- (1H-1,2,4-triazol-1-yl)
-1,3-butanediol and (2R ^* , 3R ^* )-3- (2,4-dichlorophenyl) -2-
Methyl-4- (1H-1,2,4-triazol-1-yl)
-1,3-butanediol (2R ^* , 3R ^* )-3- (2,4-dichlorophenyl) -3
-Hydroxy-2-methyl-4- (1H-1,2,4-triazol-1-yl) butanal and its (2S ^* , 3R ^* )-
Dissolve 85 mg of a 1: 1 mixture of isomers in 1.5 ml of methanol,
Under ice cooling and stirring, 15 mg of sodium borohydride was added. 1
0 minutes later, ethyl acetate was added to the reaction solution, and the mixture was washed with saturated saline. The crude product obtained by distilling off the solvent was silica gel 3
g, and eluted with ethyl acetate to give (2R ^* , 3R ^* )-isomer of the target compound in 31 g.
mg.

Recrystallized from a benzene-hexane mixed solvent to give a melting point of 120.
A pure product having -122 ° C was obtained.

Then, elution was performed with a 7% methanol-ethyl acetate mixed solvent to obtain 33 mg of the (2S ^* , 3R ^* )-isomer of the target compound.

Recrystallization from a benzene-hexane mixed solvent gave a melting point of 176.
A pure product having a temperature of -177 ° C was obtained.

^{[(2R *, 3R *)} - isomer] NMR spectrum _{(CDCl 3) δppm: 1.39 (} 3H, d, J = 7 Hz); 2.85 (1H, m); 3.40 (1H, s); 3.4
5 (1H, s); 4.50 (1H, d, J = 14 Hz); 5.31 (1H, d, J = 14 H
z); 7.05 (1H, dd, J = 8.2 Hz); 7.25 (1H, d, J = 2 Hz);
7.52 (1H, d, J = 8 Hz); 7.66 (1H, s); 7.91 (1H, s). [(2S ^* , 3R ^* )-isomer] Infrared absorption spectrum ν _max (nujol) cm ^- 1: 3400,3
140. NMR spectrum [CDCl ₃ : CD ₃ OD (1: 1)] δppm: 0.77 (3H,
d, J = 7 Hz); 2.9 (1H, m); 3.6-4.3 (2H, m); 4.74 (1H, m)
d, J = 14.5 Hz); 5.44 (1H, d, J = 14.5 Hz); 7.04 (1H, d
7.30 (1H, d, J = 2 Hz); 7.48 (1H, d, J = 9)
Hz); 7.67 (1H, s); 8.07 (1H, s). Reference Example 7 (2R ^* , 3S ^* )-2- (2,4-dichlorophenyl) -4-
(Methanesulfonyloxy) -3-methyl-1- (1H-
1,2,4-triazol-1-yl) -2-butanol (2S ^* , 3R ^* )-3- (2,4-dichlorophenyl) -2
-Methyl-4- (1H-1,2,4-triazol-1-yl) -1,3-butanediol 74 mg (0.231 mmole)
After dissolving in 2 ml of methylene chloride, 61 mg (0.61 mmole) of triethylamine and 64 mg (0.56 mmole) of methanesulfonyl chloride were added while stirring at 0 ° C. After 15 minutes, dilute aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and the solvent was distilled off to obtain 92 mg of a crude product.

NMR spectrum (CDCl ₃ ) δ ppm: 0.70 (3H, d, J = 7 Hz); 3.07 (3H, s); 2.9-3.4 (1H,
m); 4.22 (1H, dd, J = 10.5 Hz); 4.59 (1H, d, J = 14.5H
z); 4.71 (1H, dd, J = 10,7 Hz); 5.18 (1H, br.); 5.51
(1H, d, J = 14.5 Hz); 7.04 (1H, dd, J = 8.2 Hz); 7.27
(1H, d, J = 2 Hz); 7.43 (1H, d, J = 8 Hz); 7.73 (1H,
s); 7.81 (1H, s). Reference Example 8 (2R ^* , 4R ^* ) 2- (4-chlorophenyl) -3,4-dimethyl-2-ethoxycarbonyl-oxetane benzene (200 ml) at 0 ° C. and 2-butene in a volume of about 1.
I blew it up to 25 times. Ethyl 4-chlorophenylglyoxylate (24.3 g, 114.09 mmol) was added thereto, and the mixture was irradiated with a 450 W medium pressure mercury lamp manufactured by Hanovera at 15 ° C. for 3 hours. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired product as an oil (23.4 g).

Yield: 76%. Boiling point: 141 to 142 ° C./2.7 torr NMR revealed that the product was a mixture of α: β ≒ 1: 1 for the coordination at C ₃ position.

_{NMR (CDCl 3) δppm: 0.76} (d, J = 7.66Hz); 1.23~1.31
(M); 1.34 (d, J = 6.04 Hz); 2.83 (quint, J = 7.25H
z); 3.55 (quint, J = 7.25 Hz); 4.16-4.32 (m); 4.56
(Quint, J = 6.45 Hz); 5.06 (quint, J = 7.25 Hz); 7.26 ~
7.47 (m). Mass spectrum (m / z): 268 (M ⁺ ), 224,213,195,178,16
7. Reference Example 9 (2R ^* , 3S ^* , 4R ^* )-2- (4-chlorophenyl) -3,
4-dimethyl-2-hydroxymethyl-oxetane (A) and (2R ^* , 3R ^* , 4R ^* )-2- (4-chlorophenyl) -3,
4-dimethyl-2-hydroxymethyl-oxetane (B) 2- (4-chlorophenyl) -3,4-dimethyl-2-
Ethoxycarbonyl-oxetane (920 mg, 3.42 mmol, 1: 1 of (2R ^* , 3R ^* , 4R ^* ) and (2R ^* , 3S ^* , 4R ^* ))
Was added dropwise at 0 ° C. to a solution of lithium aluminum hydride in tetrahydrofuran (7 M), and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution and then 1N-hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give (2R ^* , 3S ^* , 4R ^* ) of the target compound A (336.4 mg) and (2R ^* , 3R ^* , 4R) ^* ) The desired compound B (349.5 mg) was obtained.

Compound A NMR (CDCl ₃ ) δ ppm: 0.70 (3H, d, J = 7.66 Hz); 1.24 (3H,
d, J = 6.44 Hz); 3.33 (1H, d, J = 7.66 Hz); 3.63 (1H, d, J
= 12.08Hz); 3.87 (1H, d, J = 12.08Hz); 4.96 (1H, dq, J
= 6.44,7.66Hz); 7.25 (2H, d, J = 8.46Hz); 7.35 (2H, d,
Mass spectrum (m / z): 223,195,181,167,153,139 Compound B NMR (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.04 Hz); 1.36 (3H,
d, J = 7.25 Hz); 2.18 (1H, brdd, J = 5.53, 7.25 Hz); 2.65
(1H, quint, J = 7.25 Hz); 3.71 (1H, dd, J = 5.53, 12.09H
z); 4.02 (1H, dd, J = 7.25, 12.09 Hz); 4.56 (1H, dq, J =
6.04, 7.25 Hz); 7.24 (2H, d, J = 8.46 Hz); 7,33 (2H, d, J
= 8.46Hz). Mass spectrum (m / z): 195,167,139,129,125,115 Reference Example 10 2- (4-chlorophenyl) -3,4-dimethyl-2-methanesulfonyloxymethyl-oxetane 2- (4-chlorophenyl) -3,4-dimethyl-2-
To a solution of hydroxymethyl-oxetane (123 mg, 0.543 mmol) in dichloromethane (10 ml) at 0 ° C. was added methanesulfonyl chloride (0.13 ml, 1.68 mmol) and then triethylamine (0.24 ml, 1.708 mmol), and the mixture was stirred for 4 hours at room temperature. The temperature was raised to To the reaction mixture was added saturated sodium bicarbonate and extracted with dichloromethane. After drying over anhydrous magnesium sulfate and concentration, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired compound (107 mg).

Yield 65% NMR (CDCl ₃ ) δ ppm: 0.72 (3H, d, J = 7.25 Hz); 1.21 (3H,
d, J = 6.44 Hz); 3.02 (3H, s); 3.25 (1H, quint, J = 7.25H)
z); 4.33 (1H, d, J = 11.68 Hz); 4.60 (1H, d, J = 11.68H)
z); 5.04 (1H, dq, J = 6.44, 7.25 Hz); 7.28 (2H, d, J = 8.8
6.37); 7.37 (2H, d, J = 8.86 Hz). Reference Example 11 (2R ^* , 4R ^* )-2- (4-chlorophenyl) -2-chloromethyl-3,4-dimethyl-oxetane At 0 ° C., 2-butene was added to benzene (180 ml) at a volume of about 1.2.
I blew it up to 5 times. 4-Chlorophenacyl chloride (15 g, 79.34 mmol) was added thereto, and irradiated with a Hanovia 450 W, medium pressure mercury lamp at 15 ° C. for 15 hours. The reaction mixture was concentrated and distilled under reduced pressure to obtain 15.24 g of the target compound.

From NMR, it was a mixture of α: β = 3: 1 for the C ₃ position coordination.

NMR (CDCl ₃ ) δ ppm: 0.72 (d, J = 7.00 Hz), 1.24 (d, J =
6.40Hz), 1.33 (d, J = 7.00Hz), 1.34 (d, J = 6.40Hz),
2.74 (dq, J = 7.00, 7.00 Hz), 3.24 (dq, J = 7.54, 7.54H
z), 3.82 (d, J = 11.62 Hz), 3.90 (d, J = 11.62 Hz), 3.91
(D, J = 11.62 Hz), 4.00 (d, J = 11.62 Hz), 4.55 (dq, J =
6.40,7.00Hz), 5.05 (dq, J = 6.40,7.00Hz), 7.23 ~ 7.40
(M). Mass spectrum (m / z): 246 [(M + 2) ⁺ ], 244
(M ⁺ ), 195,191,190,165,151,141,139 Reference Example 12 (2R ^* , 3R ^* )-3-methyl-2- (4-chlorophenyl) -2- (trimethylsilyloxy) -1- (1H-1,
2,4-triazol-1-yl) -4-pentene (2R ^* , 3R ^* )-3-methyl-2- (4-chlorophenyl) -1- (1H-1,2,4-triazol-1-yl )
20 ml of DMF solution of -2-pentanol (900 mg, 3.24 mmol)
To the mixture were added trimethylsilyl chloride (2.47 ml, 19.4 mmol) and imidazole (1.7 g, 24.3 mmol), and the mixture was stirred at 50 ° C. for 4 hours. After completion of the reaction, the mixture was poured into water, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off to obtain 1.3 g of an oily crude product.

_{NMR (CDCl 3) δppm: 0.17} (9H, s); 0.88 (3H, d, J = 6.7H
z), 2.7 ~ 2.85 (1H, m), 4.47 (1H, d, J = 14.7Hz), 4.82
(1H, d, J = 14.7Hz), 5.05-5.2 (2H, m), 5.5-5.7 (1H,
m), 7.2-7.3 (4H, m), 7.54 (1H, s), 7.78 (1H, s). Reference Example 13 (2R ^* , 3R ^* )-3-methyl-2- (4-chlorophenyl) -2-trimethylsilyloxy-1- (1H-1,2,4
-Triazol-1-yl) -butanal (2R ^* , 3R ^* )-3-methyl-2- (4-chlorophenyl) -2- (trimethylsilyloxy) -1- (1H-
1,2,4-Triazol-1-yl) -4-pentene (190
Oxygen was blown into a methanol solution (10 ml) of methanol (0.5 mg, 0.54 mmol) while cooling with dry ice / acetone. The end point of the reaction was confirmed by thin-layer chromatography, and then an appropriate amount of KI powder was added and stirred. An aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of hibo, washed with water, dried over magnesium sulfate, and the solvent was distilled off to obtain 140 mg of an oil. NMR (CDCl ₃ ) δ ppm: 0.17 (9H, s); 1.28 (3H, d, J = 6.9H)
z), 3.04 (1H, q, J = 6.9Hz), 4.48 (1H, d, J = 15Hz), 4.6
7 (1H, d, J = 15Hz), 7.04 (2H, d, J = 8.6Hz), 7.27 (2H,
d, J = 8.6Hz); 7.55 (1H, s); 7.88 (1H, s); 9.325 (1H, s
d, J = 1.26 Hz) Reference Example 14 (2R ^* , 3R ^* )-3-methyl-2- (4-chlorophenyl) -2-trimethylsilyloxy-1- (1H-1,2,4
-Triazol-1-yl) -4-pentanol (2R ^* , 3R ^* )-3-methyl-2- (4-chlorophenyl) -2- (trimethylsilyloxy) -1- (1H-
1,2,4-triazol-1-yl) -butanal (111.1
mg, 0.316 mmol) in THF solution (10 ml) and diethylaluminum chloride (0.84 mol in hexane solution, 0.45 ml, 0.38
mmol) The mixture was cooled to an internal temperature of -78 ° C with dry ice-acetone, and methylmagnesium bromide (0.82 mol of an ether solution, 1.39 ml, 1.14 mmol) was added. After stirring at the same temperature for 3 hours, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, washed with brine, dried over magnesium sulfate, and the solvent was distilled off to obtain 85.4 mg of an oil. .

73% storage ratio The obtained compound was identified by NMR as having a coordination of about 1: 5 at the C4 position.
Was a mixture of

NMR (CDCl ₃ ) δ ppm: 0.087 (s), 0.284 (s), 0.77 (d,
J = 6Hz), 0.94 (d, J = 6.5Hz), 1.08 (d, J = 6Hz), 1.28
(D, J = 6.9Hz), 2.0 to 2.1 (m), 3.5 to 3.65 (m), 4.14
(D, J = 13.8 Hz), 4.69 (d, J = 13.8 Hz), 4.7 to 4.85
(M), 6.74 (d, J = 8.67 Hz), 7.2 to 7.35 (m), 7.88
(S). Reference Example 15 (2R ^* , 3R ^* )-3-methyl-2- (4-chlorophenyl) -1- (1H-1,2,4-triazol-1-yl)-
2,4-pentadiol (2R ^* , 3R ^* )-3-methyl- obtained in Reference Example 14
2- (4-chlorophenyl) -2-trimethylsilyloxy-1- (1H-1,2,4-triazol-1-yl)-
4-pentanol (85.4 mg, 0.233 mmol) in THF solution (2.5
ml) in tetrabutylammonium fluoride (1mol
THF solution, 0.35 ml, 0.35 mmol) was added with stirring at room temperature.
Stirred for 0 minutes. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off.
64 mg of the desired product was obtained. The yield was 93%. According to NMR, the compound (2R ^* , 3R ^* , 4S ^* ) and (2R ^* , 3R)
^* , 4R ^* ) was an approximately 5: 1 mixture of bodies.

NMR (CDCl ₃ ) δ ppm: 0.81 (d, J = 7 Hz), 1.01 (d, J = 7H
z), 1.12 (d, J = 7 Hz), 1.25 (d, J = 7 Hz), 1.99 (q, J = 7
Hz), 3.68 (q, J = 7 Hz), 4.44 (AB-d, J = 15 Hz), 4.75
(AB-d, J = 15 Hz), 7.1 to 7.4 (m), 7.68 (s), 7.74
(S), 8.00 (s). Reference Example 16 ethyl 3- (4-chlorophenyl) -2,2-dimethyl-
3-hydroxy-4- (1H-1,2,4-triazole-1
-Yl) butanoate In a THF suspension (30 ml) of zinc (2.0 g, 30 mmol) and CuBr (0.14 g, 1 mmol), Et ₂ Al Cl (1.0 M in hexane, 30 ml, 30 m
mol) was added. 4'-Chloro-2- (1H
A THF solution (30 ml) of -1,2,4-triazol-1-yl) acetophenone (1.33 g, 6 mmol) and ethyl-2-bromoisobutyrate (6.7 g, 30 mmol) was added dropwise. At room temperature
After stirring for 18 hours, water and 1N hydrochloric acid were added, and the precipitated precipitate was separated by filtration using celite, the precipitate was washed with ethyl acetate, and the filtrate was washed with 1N hydrochloric acid, an aqueous ammonium chloride solution and saturated saline. After washing, drying and concentration, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate).
1.89 g of an oil was obtained.

NMR (CDCl ₃ ) δ ppm: 1.21 (3H, s); 1.21 (3H, t, J = 7H)
z); 1.23 (3H, s); 4.10 (1H, q, J = 7Hz); 4.63 (1H, d, J
= 14Hz); 5.13 (1H, d, J = 14Hz); 5.37 (1H, bs); 7.05-
7.40 (4H, m); 7.65 (1H, s); 7.92 (1H, s). Mass spectrum (m / z): 337 (M ⁺ ), 292, 252, 222, 139 The compounds of Reference Examples 17 to 32 were obtained in the same manner as in Reference Example 16.

Various data of the compounds of Reference Examples 17 to 32 are described in a table after the description of Reference Example 33.

Reference Example 33 3- (4-Chlorophenyl) -2,2-dimethyl-4- (1
H-1,2,4-triazol-1-yl) -1,3-butanediol ethyl-3- (4-chlorophenyl) -2,2-dimethyl-3-hydroxy-4- (1H-1,2, To a solution of 4-triazol-1-yl) butanoate (1.75 g, 5.2 mmol) in methanol (25 ml) was added NaBH ₄ (1.9 g, 50.2 mmol).
After heating under reflux for 3 hours, the temperature was returned to room temperature, the reaction solution was poured into ice water, and extracted with ethyl acetate. The extract was washed with an aqueous ammonium chloride solution, dried and concentrated to obtain 1.5 g of the desired product.

Yield 98% boiling point _{120~135 ℃ NMR (CDCl 3) δppm} : 0.82 (3H, s); 0.90 (3H, s); 3.23~
3.30 (3H, s); 4.56 (1H, d, J = 14.7Hz); 5.27 (1H, d, J =
14.7Hz); 5.59 (1H, s); 7.24 ~ 7.48 (4H, m); 7.70 (1H, s
s); 8.25 (1H, s). Mass spectrum (m / z): 295 (M ⁺ ), 222, 139, 83. The compounds of Reference Examples 34 to 44 were synthesized in the same manner as in Reference Example 33.

Various data of the compounds of Reference Examples 34-44 are shown in Reference Examples 17-32.
After the table of the compound of the above, a table is described.

General formula of the compound of Reference Examples 17 to 32 General formula of compounds of Reference Examples 34-44 (Formulation Example 1) (Wettable powder) 10% of the compound of Example 1 (free), Emulgen 810
(Surfactant manufactured by Kao Corporation) 0.5%, Demol N
(Surfactant manufactured by Kao Corporation) 0.5%, Kunilite 201
(Diatomaceous earth manufactured by Kunimine Industries Co., Ltd.) 20%, Siegrite
69% of CA (Clay manufactured by Siegrite Mining Co., Ltd.) was uniformly mixed and pulverized to obtain a wettable powder.

(Formulation Example 2) (Wettable powder) 25% of the compound of Example 1 (free), 2.5% of dodecylbenzenesulfonate, 2.5% of ligninsulfonate and 70% of diatomaceous earth were mixed and pulverized to obtain a wettable powder.

(Formulation Example 3) (Emulsion) 15% of the compound of Example 1 (free), 35% of cyclohexanone
%, Polyoxyethylene nonyl phenyl ether 11%,
An emulsion was prepared by uniformly dissolving 4% of calcium dodecylbenzenesulfonate and 35% of methylnaphthalene.

(Formulation Example 4) (Emulsion) 30% of the compound of Example 1 (free), emulsifier Solpol SM
An emulsion was prepared by thoroughly mixing 10% of 100 (a surfactant manufactured by Toho Chemical Co., Ltd.) and 60% of xylene.

(Formulation Example 5) (Granules) 5% of the compound of Example 1 (nitrate), 2% of sodium salt of lauryl alcohol sulfate, 5% of sodium ligninsulfonate, 2% of sodium salt of carboxymethyl cellulose and 86% of clay And crushed.
16 parts by weight of water was added to 100 parts by weight of this mixture, kneaded, granulated using an extrusion-type granulator, dried, and then sieved using a 14-mesh and a 32-mesh sieve to obtain granules.

(Formulation Example 6) (Granules) 5% of compound (nitrate) of Example 1, bentonite 30
%, Talc 62%, sodium ligninsulfonate 2% and sodium dodecylbenzenesulfonate 1% are uniformly mixed and ground. 18 parts by weight of water was added to 100 parts by weight of this mixture, kneaded, granulated using an extruder and dried, and then dried.
The mixture was sieved using a mesh and a 32 mesh sieve to obtain granules.

(Formulation Example 7) (Granules) Compound (nitrate) 4% of Example 1, bentonite 30
%, Clay 63%, polyvinyl alcohol 1% and sodium alkylbenzenesulfonate 2% are uniformly mixed and pulverized. 20 parts by weight of water was added to 100 parts by weight of this mixture, kneaded, granulated using an extruder and dried, and then sieved using a 14 mesh and 32 mesh sieve to obtain granules.

(Formulation Example 8) (Granules) 4% of the compound of Example 1 (nitrate), 35% bentonite
%, Talc 58%, alkylnaphthalenesulfonic acid 2% and dioctylsulfosuccinate 1% are uniformly mixed and ground. 20 parts by weight of water was added to 100 parts by weight of this mixture, kneaded, granulated using an extruder and dried, and then sieved using a 14 mesh and 32 mesh sieve to obtain granules.

(Formulation Example 9) (Granules) 5% of the compound (nitrate) of Example 1, 1% of white carbon, 5% of ligninsulfonate, 84% of clay and 5% of sodium salt of carboxymethylcellulose are pulverized and mixed well. 17 parts by weight of water was added to 100 parts by weight of this mixture, kneaded, granulated using an extruder and dried, and then sieved using a 14-mesh and a 32-mesh sieve to obtain granules.

(Formulation Example 10) (Dust) 2% of the compound (nitrate), 5% of diatomaceous earth and 93% of clay of Example 1 were uniformly mixed and pulverized to give a dust.

(Formulation Example 11) (Wettable powder) A hammer mill was prepared by mixing the compound of Example 1 (nitrate) 80%, sodium alkylnaphthalene sulfonate 2%, sodium lignin sulfonate 2%, synthetic amorphous silica 3%, and kaolinite 13%. And then mix again and package.

(Formulation Example 12) (Granules) Infiltration powder 15%, gypsum 69%, potassium sulfate of Formulation Example 11
16% in a rotary or fluidized bed mixer,
Water was sprayed to granulate. When most of the granules reach 1.0-0.42 mm, the granules are taken out, dried and sieved to a particle size of 0,0.
The 42-1.0 mm section was sorted.

(Formulation Example 13) (High concentration concentrate) 98.5% of the compound of Example 1 (nitrate), 0.5% of silica airgel, and 1.0% of synthetic amorphous fine silica were mixed.
Then pulverize with a hammer mill.
A highly concentrated concentrate was produced that passed through a 0.044 mm sieve.

(Formulation Example 14) (Aqueous suspension) 25% of the compound of Example 1 (nitrate), 3% of hydrated attapulgite, 10% of crude calcium lignin sulfonate,
Sodium dihydrogen phosphate 0.5%, water 61.5%
Milled together in a ball mill, sand mill or roller mill until reduced to submicron diameter to give an aqueous suspension.

(Formulation Example 15) (Solution) 30% of the compound of Example 1 (free) and 70% of dimethylformamide were combined and stirred to obtain a solution.

(Formulation Example 16) (Emulsion) Combine 15% of the compound of Example 1 (free), 25% of a blend of calcium sulfonate and a nonionic surfactant, and 60% of xylene, and stir to dissolve the active ingredient. An emulsion was obtained.

(Formulation Example 17) (Hard capsule) 100 mg each in a standard bisecting hard gelatin capsule
Of a powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate to prepare a unit capsule, which was washed and dried.

Formulation Example 18 (Soft Capsule) A mixture of the active ingredients in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected into gelatin with a positive displacement pump to give 100 mg of the active ingredient. Was obtained, washed, and dried.

(Formulation Example 19) (Tablet) According to a conventional method, 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275
mg microcrystalline cellulose, 11 mg starch and 98.8 mg
Of lactose. If desired, a coating was applied.

(Formulation Example 20) (Injection) 1.5% by weight of an active ingredient was stirred in 10% by volume of propylene glycol, then made up to a constant volume with water for injection, and then sterilized to produce.

(Formulation Example 21) (Suspension) In 5 ml, 100 mg of micronized active ingredient, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (Japanese Pharmacopoeia) and
Manufactured to contain 0.025 ml of vanillin.

Formulation Example 22 (Cream) 5 g cream consisting of 40% white petrolatum, 3% microcrystalline wax, 10% lanolin, 5% span 20, 0.3% tween 20, and 41.7% water 100 m inside
It was prepared by incorporating g of the micronized active ingredient.

(Formulation Example 23) (Cream) Active ingredient, 2 parts by weight, 1,2-propanediol, 5 parts by weight, glycerol stearate, 5 parts by weight, spermaceti,
A mixture of 5 parts by weight, isopropyl myristate, 10 parts by weight, polysorbate, and 4 parts by weight was heated, cooled, and then, with stirring, water and 69 parts by weight were added to prepare a cream.

(Formulation Example 24) (Solution for application) Active ingredient, 1 part by weight, polyethylene glycol 300, 9
The mixture was mixed with 9 parts by weight to prepare a coating solution.

(Formulation Example 25) (Ointment) Active ingredient, 2 parts by weight, polyethylene glycol 400, 4
0 parts by weight, polyethylene glycol 1500 and 58 parts by weight were mixed and dissolved while heating, and then cooled to produce an ointment.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hiroshi Ota 1041 Yasu-cho, Yasu-cho, Yasu-gun, Shiga Pref. Kuki Kajino 1041 Yasu-cho, Yasu-cho, Yasu-gun, Shiga Pref. (72) Inventor Hiroyuki Ito 1041 Yasu-cho, Yasu-cho, Yasu-gun, Shiga pref. 58 Sankyo Co., Ltd. (72) Inventor Noriko Takeda 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Tonoyuki Konosu 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock within the company (72) inventor Hiroshi Yasuda Shinagawa-ku, Tokyo Hiromachi 1-chome, No. 2 58 No. Sankyo Co., Ltd. in the (58) investigated the field (Int.Cl. ^7, DB name) C07D 405/06 CA (ST ) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) General formula [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. R ² represents a hydrogen atom or a lower alkyl group. R ³ represents a hydrogen atom, a lower alkyl group or a phenyl group. R ⁴ represents a hydrogen atom or a lower alkyl group. At this time, R ¹ and R ⁴ may together form a saturated ring having 5 to 6 carbon atoms together with the two carbon atoms to which they are bonded. Alternatively, R ³ and R ⁴ may together form a saturated ring having 3 to 6 carbon atoms together with one carbon atom to which they are bonded. R ⁵ , R ⁶ and R ⁷ are the same or different and represent a hydrogen atom, a lower alkyl group, a halogen atom, a halogeno lower alkyl group, a lower alkoxy group or a halogeno lower alkoxy group. R ⁸ represents a hydrogen atom or a lower alkyl group. ] The compound represented by these, and its salt. 2. The general formula [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group. R ² represents a hydrogen atom or a lower alkyl group. R ³ represents a hydrogen atom, a lower alkyl group or a phenyl group. R ⁴ represents a hydrogen atom or a lower alkyl group. At this time, R ¹ and R ⁴ may together form a saturated ring having 5 to 6 carbon atoms together with the two carbon atoms to which they are bonded. Alternatively, R ³ and R ⁴ may together form a saturated ring having 3 to 6 carbon atoms together with one carbon atom to which they are bonded. R ⁵ , R ⁶ and R ⁷ are the same or different and represent a hydrogen atom, a lower alkyl group, a halogen atom, a halogeno lower alkyl group, a lower alkoxy group or a halogeno lower alkoxy group. R ⁸ represents a hydrogen atom or a lower alkyl group. R ⁹ represents a hydrogen atom or a protecting group for a hydroxyl group. Y represents a halogen atom, a lower alkanesulfonyloxy group, a halogeno lower alkanesulfonyloxy group or an arylsulfonyloxy group. The method for producing a compound or a salt thereof according to claim 1, wherein the compound represented by the formula (I) is treated with a base. 3. An agricultural fungicide comprising the compound according to claim 1 or a salt thereof as an active ingredient.