JPH02191262A - Triazole derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [Ar is (substituted) phenyl; R<1> is alkyl; R<1> may be H when R<3> and Xm-Yn-R<2> together form a group of formula II (R<2>' is alkyl, phenyl, etc.; p and q are 0 or 1); X is alkylene, alkenylene; m is 0 or 1; Y is N(R<5>)CO (R<5> is H or alkyl), OCO, SCO, etc.; R<3> is H or together with Xm-Yn-R<2> forms group of formula II; is 0 or 1; R<2> is azido, phthalimide, protected OH, OSO2R<4> (R<4> is alkyl, phenyl, etc.), etc., when n=0 and is R<2>' when n=1]. EXAMPLE:(2R,3R)-2-(2,4-dichlorophenyl)-3-(4-fluorobenzoylamino)-1-(1H- 1,2,4- triazol-1-yl)-2-butanol. USE:An antimycotic agent for pharmaceutical and agricultural use. PREPARATION:For example, a diol compound of formula III is made to react with a compound of formula R<4>SO2-O-SO2R<4> or R<4>SO2-Z (Z is eliminable group) to obtain the corresponding sulfonyl compound of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION [Objective] (Industrial Application Field) The present invention relates to a novel triazole derivative having excellent antifungal activity that can be used as a medicine and an agrochemical.

That is, since the compound of the present invention has an ergosterol biosynthesis inhibitory effect, it can be used as a pharmaceutical therapeutic agent for local or deep mycoses (for example, fungal diseases such as candidiasis), or for agricultural purposes against fungal damage to plants. This invention relates to novel triazole derivatives that can be used as prophylactic or therapeutic agents.

(Prior art) 1-(1,2,4-triazol-1-yl)-2-aryl-3-(substituted amino)-2-propatol derivatives have antifungal activity, as disclosed in Japanese Patent Application Laid-open No. 59-6257
It is described in Publication No. 4.

In addition, compounds similar to some of the compounds of the present invention are listed in the abstracts of the 8th Medicinal Chemistry Symposium,
9, Osaka (1986).

(Problems to be Solved by the Invention) As a result of extensive research over many years on the synthesis of derivatives having triazole derivatives and their pharmacological activities, the present inventors have discovered that the structure is completely different from the known propatool derivatives mentioned above. The novel butanol derivative has excellent antifungal activity based on the inhibitory effect on ergosterol biosynthesis, and can be used as a pharmaceutical treatment for local or deep mycoses (for example, fungal diseases such as candidiasis) or as a plant agent. The present invention has been completed based on the discovery that the present invention can be used as an agricultural preventive or therapeutic agent against damage caused by fungi.

[Structure] The novel triazole derivative of the present invention has the general formula (wherein Ar is a phenyl group optionally substituted with 1 to 2 substituents (the substituents include a halogen atom or trifluoromethyl ), and R1 represents a lower alkyl group, or R3 and the formula -X
The groups having m-Yn-R' together form the general formula [wherein R2/ is a lower alkyl group, a halogenated lower alkyl group, an optionally substituted phenyl group (the substituents include the following: 1 selected from substituent groups (a) and (b)
The above groups are shown below. ), a naphthyl group, or an optionally substituted 5- to 6-membered heterocyclic group (the substituents include 1 to 3 groups selected from the substituent group (a) below).
, p represents O to 1, and q represents 0 to 1. ] indicates a hydrogen atom or a lower alkyl group.

X is a lower alkylene group, a lower alkenylene group, a lower alkynylene group, a cycloalkylene group, a cycloalkenylene group, a (lower alkylene-cycloalkylene) group, or (
Cycloalkylene (lower alkylene) group.

m represents 0 to 1.

Y is a group having the formula -N(R5)Co- (wherein R5 represents a hydrogen atom or a lower alkyl group), a group having the formula -N(R5)Co- (wherein R5 represents a hydrogen atom or a lower alkyl group);
') CO-CH=CH- (in the formula, R5 has the same meaning as above), a group having the formula -〇〇〇-, a group having the formula -
It represents a group having 0CO-CH=CH-, a group having the formula -5CO- or a group having the formula -3CO-CH=CH-.

R3 represents a hydrogen atom or together with a group having the formula -Xm-Yn-R' represents the general formula (wherein R21, p and q have the same meanings as above), and n is , O to 1, and when n is 0, R2 is a group having the formula R2' [wherein R2'' is an azide group, an optionally substituted butarimide group (the substituent is, represents one or more groups selected from the following substituent groups (a) and (b)), an optionally substituted 1-oxo-2,3-dihydro-2-isoindolyl group (the substituents include: represents one or more groups selected from the following substituent groups (a) and (b)), a protected hydroxyl group, or a group having the formula -05O2R4 [wherein R4 is a lower alkyl group, a halogenated lower alkyl group] or an optionally substituted phenyl group (the substituent is 1 selected from the following substituent group (a))
The above groups are shown below. ) is shown. ]. ].

When n is 1, R2 represents the same group as R2/ above.

However, compounds in which R1 is a methyl group, m is O, n is O, and R' is a protected hydroxyl group or a group having the formula -08O□R4 (R4 has the same meaning as above) are excluded. ) Further, the pharmaceutical or agricultural composition used as an antifungal agent mainly contains the compound of the present application or a salt thereof.

Substitution 11(1)a Nitro group, cyano group, halogen atom, lower alkyl group, and halogenated lower alkyl group.

[Substituted] lower alkoxy group, halogenated lower alkoxy group, hydroxyl group, benzyloxy group, hydroxymethyl group, formula -CH
2-0CO-R' (wherein, R6 represents a lower alkyl group or a halogenated lower alkyl group), a group having the formula -Go-R6 (wherein, R6 has the same meaning as above)
A group having the formula -GOOR' (wherein R6 has the same meaning as above), a group having the formula -3o, R' (wherein R
6 indicates the same meaning as above, and r indicates O to 2. )
, an amino group, a mono- or di-lower alkyl-substituted amino group, and an acylamino group.

In the above general formula (I), the "halogen atom" in the definitions of Ar and [substituent group (a)] refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom. It is.

R1, R2/, R4, R5, R6 and [substituent group (a)
] In the definition of "lower alkyl group", 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. age methylbutyl, l, 2
-dimethylbutyl, 1,3-dimethylbutyl, 2,3-
It represents a straight or branched alkyl group having 1 to 6 carbon atoms such as dimethylbutyl, preferably an alkyl group having 1 to 4 carbon atoms.

The "halogenated lower alkyl group" in the definitions of R'l/, R4, R6 and [substituent group (a)] means trifluoromethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, Pentafluoroethyl, tricumylomethyl, pentachloroethyl, tribromomethyl, pentabromoethyl,
2,2.2-trichloroethyl, 2,2.2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2
-Fluoroethyl, 2,2-difluoroethyl, 2,2
-dibromoethyl, 2,2-dichloroethyl, 3-chloropropyl, 3,3-dichloropropyl, 3,3.3-
Trichloropropyl, 3,3,3,2,2-pentachloropropyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3.3-trifluoropropyl, 3.
3,3,2,2-pentafluoropropyl, 4-chlorobutyl, 4-fluorobutyl, 4-iodobutyl, 4-
It refers to a group in which a halogen atom is substituted on a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as bromobutyl, and preferably a group in which a halogen atom is substituted in an alkyl group having 1 to 4 carbon atoms. .

The "optionally substituted 5- to 6-membered heterocyclic group" in the definition of Hfi/ refers to a 5- to 6-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms, and/or nitrogen atoms,
For example, furyl, thienyl, pyrrolyl, morpholinyl, thiomorpholinyl, pyrazolyl, imidazolyl, oxasilyl, isoxazolyl, thiazolyl, isothiazolyl,
Examples include 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and partially or completely reduced groups corresponding to these groups, and preferred are furyl, Mention may be made of thienyl, pyrrolyl, imidazolyl, oxasilyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl and partially or completely reduced groups corresponding to these groups.

The "lower alkylene group" in the definition of -1 carbon number such as -ethylethylene, -methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene, 2-propylethylene, 1-isopropylethylene, hexamethylene
Mention may be made of from 6 straight-chain or branched alkylene groups, preferably methylene, methylmethylene, ethylene, trimethylene or tetramethylene.

The "lower alkenylene group" in the definition of X means the above "
"Lower alkylene group" refers to a group having one or more double bonds in a part of the carbon chain, such as vinylene, 1-propenylene, 2-propenylene, 1-methylvinylene, 2-methylvinylene, 1-butenylene, 2 -butenylene, 3-butenylene, Examples include linear or branched alkenylene groups having 2 to 6 carbon atoms, preferably 1-propenylene, 2-methylvinylene or 2-butenylene.

The "lower alkynylene group" in the definition of X means the above "
"lower alkylene group" refers to a group having one or more triple bonds in a part of the carbon chain, such as ethynylidene, 1-provinylidene, 2-provinylidene, 1-butynylidene, 2
- such as putynylidene, 3-putynylidene, 1-pentynylidene, 2-pentynylidene, 3-pentynylidene, 4-pentynylidene, 1-hexynylidene, 2-hexynylidene, 3-hexynylidene, 4-hexynylidene, 5-hexynylidene Examples include straight chain or branched alkynylene groups having 2 to 6 carbon atoms, and preferably,
1-provinylidene.

"Cycloalkylene group" in the definition of It represents a divalent 3- to 7-membered saturated cyclic hydrocarbon group such as silene, 1,3-cyclohexylene, and 1,4-cyclohebutylene, preferably a divalent 5- to 7-membered saturated cyclic hydrocarbon group. be.

The "cycloalkenylene group" in the definition of 1.3-cyclobutenylene, 1,2-cyclopentenylene, 1.3-cyclopentenylene, 2,3-cyclopentenylene, 3,4-cyclopentenylene, 1,2-cyclohexenylene, 1,
3-carbon atoms such as 3-cyclohexenylene, 1,4-cyclohexenylene, 2,3-cyclohexenylene, 3,4-cyclohexenylene, 1,4-cyclohebutenylene
7 to 7 cycloalkenylene groups can be mentioned.

"(Lower alkylene-cycloalkylene) group" and "(cycloalkylene group-lower alkylene) group" in the definition of
Refers to a group formed by the bonding of a lower alkylene group, such as cyclopropylene methylene, methylmethylene-cyclopropylene, cyclopropylene ethylene, propylene-cyclopropylene, cyclopropylene trimethylene, tetramethylene-cyclopropylene, Cyclopropylenepentamethylene, hexamethylene-
Cyclopropylene, methylene-cyclobutylene, cyclobutylene-methylmethylene, ethylene-cyclobutylene, cyclobutylene-propylene, trimethylene-cyclobutylene, cyclobutylene-tetramethylene, pentamethylene-cyclobutylene, cyclobutylene-hexamethylene, methylene-cyclo Pentylene, cyclopentylene-methylene, methylmethylene-cyclopentylene, cyclopentylene-ethylene, propylene-cyclopentylene, cyclopentylene-trimethylene, tetramethylene-cyclopentylene, cyclopentylene-pentamethylene, hexa methylene-cyclopentylene, methylene-cyclohexylene, cyclohexylene-methylmethylene,
Mention may be made of groups such as ethylene-cyclohexylene, cyclohexylene-propylene, trimethylene-cyclohexylene, cyclohexylene-tetramethylene, cyclohexylene-pentamethylene, hexamethylene-cyclohexylene, preferably methylene-2- Cyclopentylene or 2-cyclopentylenemethylene.

In addition, as the X fund, methylene, ethylene,
Methylmethylene, 1-propenylene, 2-methylvinylene, 2-butenylene, 1-provinylidene, methylene-
2-cyclopentenylene or 2-cyclopentenylene methylene.

The protecting group for the "protected hydroxyl group" in the definition of R2'' refers to a protecting group in a reaction, a group for prodrug formation when administered to a living body, or a group for activation when used as an agricultural chemical. , for example, alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl, tridecanoyl, no(lumitoyl, stearoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, Aliphatic acyl groups such as halogenated alkylcarbonyl groups such as trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, and unsaturated alkylcarbonyl groups such as (E)-2-methyl-2-butenoyl; benzoyl , α-naphthoyl,
Arylcarbonyl groups such as β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl, lower alkylated arylcarbonyl groups such as 2,4.6-trimethylbenzoyl and 4-toluoyl, Lower alkoxylated arylcarbonyl groups such as 4-anisoyl, 4-nitrobenzoyl,
Aromatic acyl groups such as nitrated arylcarbonyl groups such as 2-nitrobenzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl, and arylated arylcarbonyl groups such as 4-phenylbenzoyl. groups; such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; Tetrahydropyranyl or tetrahydrothiopyranyl group; Tetrahydrofuranyl or tetrahydrothiofuranyl group such as tetrahydrofuran-2-yl, te-1-rahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t- tri-lower alkylsilyl groups such as butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl; Silyl groups such as tri-lower alkylsilyl groups substituted with aryl groups; such as methoxymethyl, 1,agemethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl lower alkoxymethyl group, lower alkoxylated lower alkoxymethyl group such as 2-methoxyethoxymethyl, 2
, 2,2-trichloroethoxymethyl, alkoxymethyl groups such as halogenated lower alkoxymethyl such as bis(2-chloroethoxy)methyl; 1-ethoxyethyl,
Lower alkoxylated ethyl groups such as 1-(isopropoxy)ethyl, halogenated ethyl groups such as 2,2.2-trichloroethyl, arylzelenenylated ethyl groups such as 2-(phenylzelenenyl)ethyl Substituted ethyl groups such as groups; substituted with 1 to 3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl; lower alkyl group,
4-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, piperonyl, etc., where the aryl ring is substituted with a lower alkyl, lower alkoxy, nitro, halogen, or cyano group. aralkyl groups such as lower alkyl groups substituted with 1 to 3 aryl groups; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl;
2,2゜Alkoxycarbonyl groups such as lower alkoxycarbonyl groups substituted with halogen or tri-lower alkylsilyl groups such as 2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; alkenyls such as vinyloxycarbonyl and allyloxycarbonyl Oxycarbonyl group; benzyloxycarbonyl,
The aryl ring has 1 to 2 lower alkoxy or nitro groups, such as 4-methoxybenzyloxycarbonyl, 3,4-dume-1-xybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl. Protective groups for reactions such as optionally substituted aralkyloxycarbonyl groups; protecting groups that are easily hydrolyzed in vivo for prodrug formation when administered to living organisms, such as pivaoyloxymethyloxycarbonyl; The lower alkyl group; lower alkanesulfonyl group such as methanesulfonyl, ethanesulfonyl, ■-propanesulfonyl; fluorinated lower alkanesulfonyl group such as trifluoromethanesulfonyl, pentafluoroethanesulfonyl, or benzenesulfonyl, P-toluenesulfonyl Examples include arylsulfonyl groups such as, and preferred are tetrahydropyranyl, tetrahydrofuranyl, and alkoxyalkyl groups.

The "lower alkoxy group" in the definition of substituent group (b) includes, 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-methylpentoxy, 3,3-dimethylbutoxy, 2
, 2-dimethylbutoxy, 1,1-dimethylbutoxy,
(2) represents a straight or branched alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as 2-dimethylbutoxy, 1,3-dimethylbutoxy, and 2,3-dimethylbutoxy; is an alkoxy group.

The "halogenated lower alkoxy group" in the definition of [substituent group (b)] refers to difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, pentachloroethoxy, pentabromoethoxy, 2.2.2-trichloroethoxy, 2. , 2,2-trifluoroethoxy, 2-bromoethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2-dibromoethoxy, 2,2-dichloroethoxy, 3-chloropropoxy, 3,3-dichloropropoxy, 3.3,3-trichloropropoxy, 2,2,3.3-tetrafluoropropoxy, 3,3,3,2,2-pentachloropropoxy, 3,3,3,2, Carbon such as 2-pentafluoropropoxy, 3-fluoropropoxy, 3,3-difluoropropoxy, 3,3.3-trifluoropropoxy, 4-chlorobutoxy, 4-fluorobutoxy, 4-bromobutoxy, 4-isobutoxy It refers to a group in which a halogen atom is substituted on a linear or branched alkoxy group having 1 to 6 carbon atoms, preferably a group in which a halogen atom is substituted in an alkoxy group having 1 to 4 carbon atoms.

The "mono- or di-lower alkyl-substituted amino group" in the definition of [substituent group (b)] refers to a group in which one or two of the above-mentioned "lower alkyl groups" are substituted with an amino group, for example,
Methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, propylamino, isopropylamino, dipropylamino, diisopropylamino, methylpropylamino, ethylpropylamino,
Butylamino, isobutylamino, S-butylamino,
Mention may be made of groups such as 1-butylamino, dibutylamino, methylbutylamino, ethylbutylamino, propylbutylamino, pentylamino, dipentylamino, hexylamino, dihexylamino.

"Acylamino group" in the definition of [substituent group (b)]
The "acyl group" herein refers to the same group as the aliphatic acyl group and the aromatic acyl group.

Compound (I) of the present invention can be made into a salt, and such salts are preferably salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide. hydrohalides, nitrates, perchlorates.

Inorganic acid salts such as sulfates and phosphates and methanesulfonates,
Lower alkanesulfonates such as trifluoromethanesulfonate and ethanesulfonate, arylsulfonates such as benzenesulfonate and P-toluenesulfonate, fumarate, oxalate, maleate, etc. Organic acid salts may be mentioned.

Compound (I) of the present invention has an asymmetric carbon in the molecule, and stereoisomers exist in which each has an S configuration and an R configuration, and those with a double bond have an E type or Geometric isomers of the Z form exist, and each of them or a mixture thereof is encompassed by the present invention.

Optical isomers can be separated using common optical resolution techniques, and diastereomers can be separated using common separation methods such as chromatography.
.

Furthermore, if it is desired to produce individual isomers, they can be produced stereoselectively or enantioselectively, as described below.

In the compound (I) of the present invention, preferred compounds include (1) a compound in which Ar is a phenyl group substituted with a halogen atom or/and a trifluoromethyl group (2) a compound in which the substitution position in (1) above is Compound (3) where Ar is at the 2-position or/and 4-position, 4-(trifluoromethyl)phenyl,
4-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-bromophenyl, 2-fluoro-4-iodophenyl.

Compound (4) Ar which is 2.4-dichlorophenyl, 2,4-difluorophenyl, 4-chlorophenyl or 2-fluoro-4-(trifluoromethyl)phenyl,
4-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, Z, 4-dichlorophenyl, 2,4-difluorophenyl or 4-
Compound (5) R" which is chlorophenyl is a linear or branched alkyl group having 1 to 4 carbon atoms. (6) Compound (7) R" where R1 is methyl, ethyl, propyl or isopropyl. Compound (8)R is methyl or ethyl
" is a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogenated lower alkoxy group, a lower alkoxy group, a nitro group, a cyano group, the formula -GOOR' (in the formula,
R6 has the same meaning as above. ), formula-3o, R6 (wherein R6 has the same meaning as above, and r represents 0 to 2) or/and acylamino group, substituted with 1 to 5 groups selected from Compound (9) that is a phenyl group
R" is a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a halogenated lower alkoxy group, a lower alkoxy group, a nitro group, a cyano group, the formula -COOR6 (wherein R1' has the same meaning as above) ), formula-3O,R'
(In the formula, R6 has the same meaning as above, and r is 0 to 2
shows. ) or/and a phenyl group substituted with 1 to 3 groups selected from acylamino groups (
10) R" is a halogen atom, lower alkyl group, halogenated lower alkyl group, halogenated lower alkoxy group, lower alkoxy group, nitro group, cyano group, formula -50, R6
(In the formula, R6 has the same meaning as above, and r is 0 to 2
shows. ) or/and an acylamino group, the compound (11) Compound (12) R'', which is a phenyl group substituted with 1 or 2 selected from the groups, is 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 2,4-difluorophenyl, 3, 4-difluorophenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, pentafluorophenyl, 3-(trifluoromethyl)phenyl, 4
-(trifluoromethyl)phenyl, 4-(trichloromethyl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl Fluoromethyl)phenyl, 4-(difluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl, 4-(2
,2,2-trifluoroethoxy)phenyl,4-(2
,2,3,3-tetrafluoropropoxy)phenyl,
3-nitrophenyl, 4-nitrophenyl, 2-fluoro-4-nitrophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 2
-Chloro-4-cyanophenyl, 4-(methoxycarbonyl)phenyl, 2-fluoro-4-(ethoxycarbonyl)phenyl, 4-(methylthio)phenyl, 4-(
Compound (13)R'' which is methylsulfinyl)phenyl, 4-(methylsulfonyl)phenyl or 4-(dichloroacetamido)phenyl is 4-fluorophenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 4- cyanophenyl, 3-(trifluoromethyl)phenyl,
4-(trifluoromethoxy)phenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or 2-
Compound (14)R'', which is fluoro-4-(trifluoromethyl)phenyl, is an optionally substituted pyridyl, furyl, thienyl, thiazolyl or pyrimidinyl group, and compound (15)R'' is 6-chloro- 3-pyridyl, 6-(trifluoromethyl)-3-pyridyl, 5-(trifluoromethyl)-2-pyridyl, 5-chloro-2-pyridyl, 5-(trifluoromethyl)-2-furyl, 5- (trifluoromethyl)-2-thienyl, 5-chloro-2-
thienyl, 5-(trifluoromethyl)-2-thiazolyl, 2-(trifluoromethyl)-5-thiazolyl, 5
-(trifluoromethyl)-2-pyrimidinyl or 2-
Compound (16) which is (trifluoromethyl)-5-pyrimidinyl, as a group having the formula -(CH=CH)q-R'', 4-fluorophenylvinyl, 4-chlorophenylvinyl, 2,4-difluorophenylvinyl, 3,4-difluorophenylvinyl, 2,4-dichlorophenylvinyl, 3-(trifluoromethyl)phenylvinyl, 4
-(trifluoromethyl)phenylvinyl, 4-(trichloromethyl)phenylvinyl, 2-fluoro-4-(
trifluoromethyl)phenylvinyl, 3-nitrophenylvinyl, 4-nitrophenylvinyl, 3-cyanophenylvinyl, 4-cyanophenylvinyl, 6-chloro-3-pyridylvinyl, 6-(trifluoromethyl)-
3-pyridylvinyl, 5-(trifluoromethyl)-2
- Compound (17) R2 which is furylvinyl, 5-chloro-2-thienylvinyl or 5-(trifluoromethyl)-2-thienylvinyl Compound (18) R4 where R2'' is an azido group
is a methyl group or a phenyl group. Compound (19) Y is a group having the formula -0CO-, the formula -0CO-CH=CH-
a group having the formula -5CO-, a group having the formula -3CO-CH=CH-, a group having the formula -N(R5)
A group having Co- (in the formula, R5 is a hydrogen atom or a group having 1 carbon number)
It represents from 4 straight chain or branched chain alkyl groups. ) or a group having the formula -N(R5)Co-CH=CH- (wherein R5 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms) (20 ) Compounds in which X is a linear or branched alkylene group having 1 to 2 carbon atoms can be mentioned.

Representative compounds of the present invention include, for example, Tables 1 to 2.
Compounds listed in the table may be mentioned, but the present invention is not limited to these compounds.

In addition, in the table below.

rAcJ is acetyl, riBuJ is isobutyl, rtBuJ is t-butyl, rBzJ is benzyl, rEtJ is ethyl, rEtcJ is ethoxycarbonyl, rFurJ is furyl, rHxJ is hexyl, rMeJ is methyl, rMocJ is methoxycarbonyl, rNPJ is naphthyl, rOD IIJ is 1-oxo-2,3-dihydro-2-isoindolyl, rPhJ is phenyl, rPhtJ is phthalimide, rPrJ is propyl, rcPrJ is cyclopropyl, riPrJ is isopropyl, rPyazJ is pyrazolyl, rPymJ is pyrimidinyl, rpyrJ is pyridyl, rTfmJ is tri- fluoromethiJ, rTbiJ represents thienyl, and rThizJ represents thiazolyl.

Figure 1 r 1-19 4-CIPh 1-20 4-CIPh IX Me -4-CLPh Me -4-TfmPh Number r IX 1-42 2-F-4-TfmPh l-434-TfmPh 1-44 2- F-4-TfmPh Me -4-FPh Me -4-CIPh Me -4-TfmPh NHCO- NHCO- NHCO- NHCO- -N)ICO- r RI X 2-F-4-CIPh Me -4-CIPh NHCO- -FPh Me 2-F-4-TfmPh NHCO- 1-664-CIPh 1-67 4-CIPh Me -4-CNPh Me -3-Tf+oPh NHCO- NHCO- r IX r IX r RI X lX Ar 1-1472- F-4-(1:IPh e-2-F-4-TfmPh NHCO- 1-1514-CIPh Me-2-F-4-CNPh-Nl(CO- 1-1834-F-2-C:lPh 1 -1844-FPh 1-1854-BrPh 1-1862-F-4 (Ph 1-1664-F-2-C:IPh -CIPh NHCO- Ar IX Ar 1-2252-F-4-C:lPh 1-2262 -C1-4-FPh l-2274-TfmPh t - Me - Me - (CHz)z- 4-τft+Ph -CIPh N3 NHCO- -N)ICO- r R1 Fig. 2 1-2352, 4-diclPh l-2364 -FPh 1-2374-BrPh 1-2384-CIPh 2-16 2-F-4-TfmPh H2-174
-CIPh H4-MeSOzPh -CNPh r 2,4-diFPh 2.4-diFPh 2.4-diclPh 2.4-diFPh 2-F-4-Tfn+Ph 4-NPh4- N02Ph4- -CIPh 2,4-diFPh 2. 4-diFPh 2.4-dicIPh 2.4-diclPh 2.4-dicIPh 4-TfmOPh -CNPh -CIPh 4-TfmPh -CNPh 2-31 2,4-diFPh Me2-32 2
,4-diclPh Me2-33 2,4-di
cIPh Me4-MeSOzPh 4-MocPh 4-NO! Ph 2-37 4-CIPh Me 4-F
Ph2-38 2.4-diFPh Me 4-
CIPh2-39 2,4-diFPhMe
4-FPh2.4-diFPh 5-Tfm-2-Thir R1 r q -FPh -CIPh -CIPh -CIPh -CIPh -CIPh -CIPh -CIPh -CIPh -CIPh -CIPh -CIPh -CIPh -CIPh -CIPh 2, 4-diclPh 4-TfmPh 4-TfmPh 3(fmPh -CIPh 2-F-4=Tfn+Ph -CIPh 4-TfmPh 3-TfmPh 2-F-4-TfmPh -CNPh 4-NO2Ph 6-Cl-3-Pyr 5- Tfm-2-Thi 5-Tfm-2-Thiz 5-CI-2-Pym -CIPh 2-107 4-TfmPh Mg2-108
2-F-4-TfmPh Mg3-CIPh 3-Tfn+Ph Among the above exemplary compounds, preferred compounds include 1-2
, ■-5, 1-20, 1-23, 1-24, ■-25,
1-26, ■-27, ■-32, ■-66, ■-68,
1-89, 1-117, 1-124, 1-127, 1-
145, 1-154, 1-168, 1-179, ii
ao, 1-181, 1-182, 1-183, 1-18
7, 1-189, 1-190, 1-191.

1-193, 1-228, 1-229, 1-230, 1
-231, 1-232, 1-233, 1-234, 1-
235, 1-236, 1-237, 2-40.

Mention may be made of the compounds 2-41, 2-80, 2-99 or 2-100.

More suitable compounds for pharmaceutical use include 1-2, 1
-20, 1-24, ■-26, l-32, 1-66, 1
-68, 1-89, 1-117, 1-124, 1-12
7, 2-40, 2-41, 2-80, 2-99 or 2-
100 compounds can be mentioned, and the more suitable compounds for agricultural chemicals include 1-2, 1-5, 1-23,
■-25, 1-26, 1-27, 1-127, 1-14
5, 1-154, 1-168, 1-179, i-180
, 1-181, 1-182, 1-183, 1-187,
1-189, 1-190, 1-191, 1-193, 1
-228, 1-229, 1-230, 1-231, 1-
Mention may be made of the compounds 232, 1-233, 1-234 or 1-235.

Furthermore, the most suitable compound for pharmaceutical use is l-
20, 1-24, 1-26, ■-32, 1-68, 1-
89, 1-117, 1-124 or 1-127, and the most suitable compounds for use as agricultural chemicals include ■-5, 1-127.
-26, 1-145, 1-181, 1-182, 1-1
87, 1-189, 1-190, 1-191, 1-19
3 or 1-235 may be mentioned.

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

In the following steps, a compound in which R2'' is a protected hydroxyl group can be produced by protecting a corresponding compound having a hydroxyl group according to a conventional method.For example, in the review of Green et al.
in Organic Synthesis “Chapter 2,
Hydroxyl groups protected with various protecting groups can be prepared according to Wiley-Interscience Publishing).

[Method A] In the above formula, Ar, R1 and R4 have the same meanings as above (in the formula, RflI has the same meanings as above).

[Method A] is a sulfonyl compound (
AII), azido alcohol (Am) or amide alcohol (AVI) production method.

Seventh item: The compound having the formula R45O2-0-5OJ4 (wherein R4 has the same meaning as above) or the formula R
A step of producing compound (AII) by reacting with a compound having '5O2-Z (wherein R4 has the same meaning as above, and Z represents a leaving group such as the halogen atom) It is.

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 aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, halogenated hydrocarbons such as chloroform; esters such as ethyl acetate, propyl acetate; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane, or amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide I can list several types.

The base used is not particularly limited as long as it is used as a base in normal reactions, but preferably alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, etc. Inorganic bases; triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, 1,5-
Diazabicyclo[4,3,0]non-5-ene, ■, 4
-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]undec-7-ene (DB
Mention may be made of organic bases such as U) or organometallic bases such as butyllithium, lithium diisopropylamide.

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

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

In step A-2, compound (AII) is mixed in a solvent with 1 equivalent of a base, an azide such as sodium azide or lithium azide; sodium hydride, potassium hydride,
Alkali metal hydrides such as lithium hydride; alkali metal cyanides such as lithium cyanide and sodium cyanide; alkali metal hydroxides such as sodium hydroxide, lithium hydroxide, and potassium hydroxide; sodium carbonate , alkali metal carbonates such as potassium carbonate; 1,
5-diazabicyclo[4,3,0]non-5-ene, ■
, 4-diazabicyclo[2,2,2]octane, 1,8
-diazabicyclo[5,4-01undec-7-ene (
I) This is a process for producing an epoxy compound (AIII) by reacting with an organic base such as BU) or an organometallic base such as butyllithium or lithium diisopropylamide.

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 aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, halogenated hydrocarbons such as chloroform; esters such as ethyl acetate, propyl acetate; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane; methanol, ethanol, n-propanol, isopropanol, n- Mention may be made of alcohols such as butanol, isobutanol and isoamyl alcohol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide or nitriles such as acetonitrile.

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

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 10 minutes to 1 hour.

At the end of the experiment, the epoxy compound (AIII) was added in a solvent.
It is a process for producing an azide alcohol compound (Am) by reacting with one or more equivalents of an alkali metal azide compound such as sodium azide or lithium azide in the presence of one or more equivalents of ammonium halide such as ammonium chloride. .

The solvent to be used is not particularly limited as long as it is a polar solvent that does not inhibit the reaction and dissolves the starting material and the alkali metal azide compound to some extent, but dimethylformamide, dimethylacetamide, hexamethylphosphorotriate is preferably used. Mention may be made of amides such as amides or sulfoxides such as dimethylsulfoxide.

The reaction temperature is 50°C to 130°C, and the reaction time is usually 1 to 15 hours, although it varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used.

In Step A-2, compound (AII) is reacted with 2 equivalents or more of an alkali metal azide compound in the presence of 1 equivalent or more of ammonium halide such as ammonium chloride in a solvent to form an epoxy compound. Compound (A
Via III)' as an intermediate, the azidoalcohol compound (Am) can be prepared in one step.

However, even when one equivalent or more of such alkali metal azide compound is used, compound (AIII) can be produced if the reaction is completed in a short time.

W is an azide alcohol compound (AIV) in a solvent,
This is a process of reducing to produce an amino alcohol compound (AV).

Reduction is usually carried out by catalytic reduction, and the catalyst used is not particularly limited as long as it is normally used for catalytic reduction, and preferably palladium-carbon, platinum, Raney nickel, etc. Mention may be made of metal catalysts.

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 aromatic hydrocarbons such as benzene, toluene, and xylene; ethyl acetate, Esters such as propyl acetate; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane, or alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol. can be mentioned.

Alternatively, it is reacted with hydrogen sulfide or mercaptans such as 1,3-propanedithiol in a solvent such as a halogenated hydrocarbon such as methylene chloride or chloroform, in the presence of an organic base such as triethylamine or diisopropylethylamine. It can also be reduced by

The reaction temperature is 0°C to 50°C, but preferably,
It is at room temperature.

The reaction time varies mainly depending on the reaction temperature, raw material compound, reducing agent, or type of solvent used, but is usually 30 minutes to 5 hours.

lΣ1 represents an amino alcohol compound (AV) with the formula R7
-0H (in the formula, R7 has the same meaning as above) or a reactive derivative thereof, to produce an amide alcohol compound (AVI).

The solvent used is not particularly limited as long as it is a polar solvent that does not inhibit the reaction and dissolves the starting material to some extent.
Preferably, aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform; esters such as ethyl acetate, propyl acetate; ether, tetrahydrofuran, dioxane, dimethoxyethane. nitrites such as acetonitrile, propionitrile, or pyridine.

Formula R'-0H (wherein, R7 has the same meaning as above)
When reacting using a compound having , a condensing agent is used. The condensing agent is not particularly limited as long as it is normally used as a condensing agent, but carbodiimides such as dicyclohexylcarbodiimide can be preferably used.

Formula R'-0H (wherein, R7 has the same meaning as above)
When carrying out the reaction using a reactive derivative of a compound having the formula R'-OH, for example, a compound having the formula R'-OH (wherein R7 has the same meaning as above) can be easily reacted using a conventional method. A compound having the formula R'-Z' to be synthesized (wherein,
R7 has the same meaning as above, and 2' is the halogen atom; a lower alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy, or a halogen lower alkanesulfonyl group such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy. Indicates a leaving group such as an oxy group. ) or the formula R'-0-R
7 (wherein R7 has the same meaning as above).

) in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine.

The reaction temperature is -20''C to 50℃,
The temperature is preferably 0°C to room temperature.

The reaction time varies mainly depending on the reaction temperature, raw material compound, reducing agent, or type of solvent used, but is usually 10 minutes to 1 hour.

[Method B] [Method C] In the above formula, Ar, R' and R7 have the same meanings as above.

rBB method] is a method for producing ester alcohol (BI), which is a compound of the present invention.

The seventh step is a step of esterifying the hydroxyl group of the compound (AI) to produce the compound (BI) of the present invention.

The reaction consists of pyridine, triethylamine, 4-(N,N-
It is carried out analogously to the procedure of step A-5 in the presence of an organic base such as dimethylamino)pyridine.

In the above formula, Ar, R' and R7 have the same meanings as above.

R8 represents an aralkyl group such as 4-methoxybenzyl or the aforementioned aliphatic acyl group.

[Method C] is a method for producing a thioester alcohol compound (CIII), which is a compound of the present invention.

rJl on l is a thiolate derivative (1 to 3 molar amount) synthesized by reacting an equimolar amount of a mercapto compound or thiocarboxylic acid derivative R85H (wherein R8 has the same meaning as above) and a base. , an epoxy alcohol derivative (AIII) is added and reacted in a solvent to produce a thioether or thioester derivative (CI).

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 ethers such as tetrahydrofuran, dioxane, dimethoxyethane; methanol, ethanol, n
-propanol, isopropanol, n-butanol,
Mention may be made of alcohols such as isobutanol and isoamyl alcohol, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, or sulfoxides such as dimethylsulfoxide.

Examples of bases that can be used include inorganic bases such as alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride, and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and barium hydroxide. Among them, sodium hydride is preferred.

The reaction temperature is 40°C to 130°C, and the reaction time is usually 30 minutes to 5 hours, although it varies mainly depending on the reaction temperature, the raw material compound, the type of solvent used, etc.

In addition, by reacting compound (AII) with 2 molar equivalents or more of a thiolate derivative, epoxy alcohol (
The thioether alcohol derivative (CI) can be synthesized in one step without isolating AIII).

U is a thioether or a thioester derivative (C
This is a step of converting I) into a mercapto derivative (CII).

For example, when the R8 group is an aralkyl group such as 4-methoxybenzyl, in the presence of an appropriate amount of anisole,
This is achieved by treatment with trifluoromethanesulfonic acid-trifluoroacetic acid.

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

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 10 minutes to 3 hours.

Furthermore, when the R8 group is an aliphatic acyl group, it can be removed by treatment with a base in the presence of a solvent. The base is not particularly limited as long as it does not affect other parts of the compound, but preferably metal alcoholades such as sodium methoxide, alkali metals such as aqueous ammonia, sodium carbonate, and potassium carbonate. It is carried out using carbonates, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or concentrated ammonia-methanol. The solvent used is not particularly limited as long as it is used in ordinary hydrolysis reactions, and includes water, alcohols such as methanol, ethanol, and n-propanol, and ethers such as tetrahydrofuran and dioxane. An organic solvent or a mixed solvent of water and an organic solvent is suitable.

The reaction temperature and reaction time vary depending on the starting materials, the base used, etc. and are not particularly limited, but in order to suppress side reactions, they are usually at 0°C to 150°C for 1 to 10 hours.

In addition, when compound (AIII) is reacted with an alkali metal sulfide such as sodium sulfide, compound (CII) can be produced in one step.

fi acylates a mercapto compound (CII) according to Step B-1 to form a thioester compound (CIII).
).

[Method D] (AL, 1) CDI) CD'I I) In the above formula, Ar, R' and R7 have the same meanings as above.

R9 and RIG are the same or different and represent a hydrogen atom, a lower alkyl group, or an aryl group.

[Method D] is a method for producing an N-substituted amide derivative (IMI:L), which is a compound of the present invention.

m is an amino alcohol compound (AV), 1 to 1.5
equivalent of an aldehyde or ketone compound R9R1°C20 (wherein R9 and RIO have the same meanings as above).

) in a solvent to form an oxazolidine compound (D
This is a process for producing I).

The aldehyde or ketone compound is not particularly limited, but preferably aldehyde compounds such as formaldehyde (formalin or paraformaldehyde is used), acetaldehyde, propionaldehyde, benzaldehyde, or acetone, methyl ethyl ketone, methyl isopropyl ketone, Ketone compounds such as methyl isobutyl ketone.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene, or tetrahydrofuran and dioxane are preferably used. and ethers such as dimethoxyethane.

The reaction temperature is 50° C. to the boiling point of the solvent, and the reaction time is usually 30 minutes to 3 hours, although it varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used.

The seventh Lr group reductively opens the oxazolidine compound (DI) in a solvent to form an N-substituted amino compound (DII).
).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene, ether, and tetrahydrofuran are preferably used. , dioxane and dimethoxyethane.

As a method of reduction, reduction using a metal hydride compound is preferred, and is achieved, for example, by reaction with an alkali metal hydride such as lithium aluminum hydride.

The reaction temperature is 0°C to the boiling point of the solvent, preferably room temperature to 50°C.

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

The seventh stop is a step of producing an N-substituted amide compound (DIII) by acylating the nitrogen atom of the N-substituted amino compound (DII) in the same manner as in step A-5.

[Method E] In the above formula, Ar, R'', R9 and RIG have the same meanings as above.

R11 represents a group having the formula R2/ (wherein R2/ has the same meaning as above).

[Method E] is a method for producing an N-substituted oxazolidine derivative (EII), which is a compound of the present invention.

For the sake of laughter, add an epoxy compound (AIII) to 1 to 5
molar equivalents of a compound having the formula R''NH2, where R11
indicates the same meaning as above. ) in the presence or absence of a solvent to produce an amino alcohol compound (EI).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene, or tetrahydrofuran and dioxane are preferably used. , and ethers such as dimethoxyethane.

The reaction temperature is 50°C to 150°C, and the reaction time is usually 30 minutes to 3 hours, although it varies mainly depending on the reaction temperature, raw material compound, or type of solvent used.

In addition, the amino alcohol compound (EI) is a compound having the formula R11-Z (wherein R11 and 2 have the same meanings as above) by protecting the amino compound (AV) as desired and then preparing it according to a conventional method. It can also be produced by reacting with the compound, alkylating, arylating, etc., and deprotecting if desired.

U represents an amino alcohol compound (EI), 1 to 3 equivalents of an aldehyde or ketone compound R9R"C=O (wherein R9 and RIG have the same meanings as above).

) in a solvent to form an oxazolidine compound (E
This is the process of manufacturing II).

The aldehyde or ketone compound is not particularly limited, but preferably aldehyde compounds such as formaldehyde (formalin or paraformaldehyde is used), acetaldehyde, propionaldehyde, benzaldehyde, or acetone, methyl ethyl ketone, methyl isopropyl ketone, Ketone compounds such as methyl isobutyl ketone.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene, or tetrahydrofuran and dioxane are preferably used. , and ethers such as dimethoxyethane.

The reaction temperature is 50° C. to the boiling point of the solvent, and the reaction time is usually 30 minutes to 3 hours, although it varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used.

Note that water produced by the reaction can also be removed as an azeotrope, and this may be preferable in some cases.

[Method E] In the above formula, Ar, R', R7, R9 and RIO have the same meanings as above.

UF method] is a method for producing N-acyloxazolidine derivatives (FI), which are the compounds of the present invention.

U is a step of producing an N-acyl oxazolidine derivative (FI) by acylating the oxazolidine derivative (DI) according to Step A-5.

[Method G] [Method G] is a method for producing a compound of the present invention having one more carbon number in the side chain than the compounds described in [Method A to [Method F].

The first step is a step of oxidatively decomposing a vinyl compound (GI) in a solvent to produce an aldehyde compound (GII).

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 halogenated hydrocarbons such as methylene chloride and chloroform; ethyl acetate and acetic acid are used. Esters such as propyl; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane or methanol, ethanol, n-propanol, isopropanol;
Mention may be made of alcohols such as n-butanol, inbutanol, isoamyl alcohol.

Reagents used in oxidation reactions are usually those that can oxidatively decompose double bonds and convert them into aldehydes.
There is no particular limitation, but it is preferable to pass through an oxidizing agent such as ozone in a halogenated hydrocarbon or ester solvent at -78°C to room temperature, and then treat with a sulfide such as dimethyl sulfide. Alternatively, in a mixed solvent of ethers such as tetrahydrofuran or alcohols such as methanol and water at 0 to 50°C, 2 to 4 equivalents of an alkali metal salt of metaperiodate such as sodium metaperiodate and a catalyst. Add a quantity of osmium oxide such as osmium tetroxide and react.

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 3 to 10 hours.

The third step is to reduce the aldehyde group of the aldehyde compound (GII) to produce the alcohol compound (GIII).

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 ethers such as tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol,
n-proper tool can be mentioned.

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

The reaction temperature is -30°C to room temperature, and the reaction time is:
Although it varies mainly depending on the reaction temperature, raw material compound, or type of solvent used, it is usually 5 to 30 minutes.

The step is to sulfonylate the primary hydroxyl group of the diol compound (GIII) according to Step C-1, and then convert the generated sulfonyloxy group to an azide group to produce an azide compound (GIV). It is.

The latter azidation step is achieved by reacting with one or more equivalents of an alkali metal azide compound such as sodium azide or lithium azide in a solvent.

The solvent used is not particularly limited as long as it is a polar solvent that does not inhibit the reaction and dissolves the starting material to some extent.
Suitable examples include amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, and sulfoxides such as dimethylsulfoxide.

The reaction temperature is 70°C to 130°C, preferably 90°C to 100°C.

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 1 to 15 hours.

In addition, the produced azide compound (GIV) is subjected to the steps after step C-1 of [Method A] to produce a compound according to the present invention that has one more carbon number than the compound described in [Method A]. Compounds can be produced.

In addition, a compound having one more carbon number, which is produced in the above process and corresponds to the compound (AV), is used as a raw material,
By subjecting the compound to the steps of [Method F], [Method F], and/or [Method F], a corresponding compound of the present invention having one more carbon number than the compound described in each method can be produced.

Furthermore, the produced diol compound (GIII) is subjected to Step 8-1 of [Method F] to produce a corresponding compound of the present invention having one more carbon number than the compound described in [Method F]. can.

On the other hand, by sulfonylating the secondary hydroxyl group of this diol compound (GIII), protecting the tertiary hydroxyl group, and reacting according to the conditions of Step C-1, the compound described in [Method C] is obtained. A corresponding thiol compound having one more carbon number can be produced, which is subjected to steps C-2 and subsequent steps of [Method C], and optionally deprotected to produce the compound described in [Method C]. Accordingly, a corresponding compound of the present invention having one more carbon number can be produced.

[Method G'] [Method G'] is a method for producing a compound of the present invention having two more carbon atoms in the side chain than the compounds described in [Method A] to [Method F].

In the first step, a vinyl compound (GI) is subjected to a hydroboration reaction in a solvent to form an alcohol compound (GV
) and (GVI).

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 ethers such as ether, tetrahydrofuran, dioxane, and dimethoxyethane are preferably used. can.

The hydroboration reaction is preferably carried out using diborane (B
2H2), borane-dimethylsulfide complex (BH3.
5(CH3), 9-borabicyclononane (9-BBN
This is achieved by reacting a borane reagent such as > and then applying hydrogen peroxide under alkaline conditions to oxidatively eliminate boron.

The reaction temperature is from -20°C to 80°C, preferably from room temperature to 50°C.

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

After the reaction, the amphoteric acid is easily separated by column chromatography.

Alcohol compound (GV) or (G
VI) according to step C-3,
This is a process for producing an azide compound (GVII) or (GVIII).

In addition, the produced azide compound (GVII) or (GV
By subjecting III) to the C-2 and subsequent steps of [Method A], a corresponding compound of the present invention having two more carbon atoms than the compound described in [Method A] can be produced.

In addition, a compound having two more carbon atoms, which is produced in the above process and corresponds to the compound (AV), is used as a raw material,
By subjecting to the steps of [Method B], [Method B] and/or [Method B], a corresponding compound of the present invention having two more carbon atoms than the compound described in each method can be produced.

Furthermore, the produced diol compound (GV) or (GV
By subjecting T) to Step 8-1 of [Method B], a corresponding compound of the present invention having two more carbon atoms than the compound described in [Method B] can be produced.

On the other hand, this diol compound (GV) or (GVI)
After sulfonylating the secondary hydroxyl group of , protecting the tertiary hydroxyl group and reacting according to the conditions of Step C-1, a compound having two more carbon atoms than the compound described in [Method C],
A corresponding thiol compound can be produced, which is produced by [Method C]
The corresponding compound of the present invention, which has two more carbon atoms than the compound described in [Method C], is obtained by subjecting it to the steps after Step C-2 and deprotecting the tertiary hydroxyl group, if desired. Can be manufactured.

[G'' method ]GIX) C6su I] In the description, Ar and R1 have the same meanings as above.

[G'' method], above, secondary alcohol compound (G'/I)
This is a separate, position-selective manufacturing method.

The molding step is a step in which a vinyl compound (GI) is epoxidized in a solvent to produce a compound (GIX).

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 suitable examples include halogenated hydrocarbons such as methylene chloride and chloroform. .

The epoxidation reagent is usually not particularly limited as long as it can oxidize double bonds to epoxy, but organic peracids such as peracetic acid and 3-chloroperbenzoic acid are preferably used. 1 to 1.
5 equivalents are used.

The reaction temperature is 0°C to 50°C, preferably room temperature.

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

The process is a process for producing a secondary alcohol compound (GVI) by reducing an epoxy compound (GIX).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but suitable examples include ethers such as tetrahydrofuran, dioxane, and dimethoxyethane.

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

The reaction temperature is -30°C to room temperature, and the reaction time is:
Although it varies mainly depending on the reaction temperature, raw material compound, or type of solvent used, it is usually 5 to 30 minutes.

In the above [Method A to Method G''], the compound synthesized as a racemate is obtained by adding a well-known resolving reagent, for example, an optically active acid such as 1-camphorsulfonic acid, to the racemate. By forming a crystalline salt and performing optical resolution, only one optically active substance can be extracted.

In the raw material compound (AI), a compound in which R1 is a hydrogen atom can be prepared by, for example, a known method (JP-A-58-12838
3), and compounds in which R1 is a methyl group can be easily produced by a known method [8th Medicinal Chemistry Symposium Abstracts, page 9 (1986)]. .

Further, the raw material compound (GI) can be easily produced, for example, according to a known method (method described in JP-A-60-36468).

The following method is a method for producing an optically active compound of the present invention. For example, the compound of the present invention in which R1 is a methyl group is an optically active compound produced from an optically active α-hydroxycarboxylic acid such as lactic acid. It is synthesized by using the active compound (HI) as a raw material.

In addition, a racemate corresponding to the optically active compound (HI),
Even when used as a raw material, optically active compounds of the present invention can be produced according to the following method by carrying out the optical resolution described above at an appropriate stage.

[Method H] In the above formula, Ar, R' and R4 have the same meanings as above.

[Method H] is a method for producing an optically active compound of the present invention.

7th above [Yoshi reacts compound (HI) with a halogenating agent such as oxalyl chloride or thionyl chloride to form an acid halide, and then reacts the compound (HI) with an acid halide in the presence of excess aluminum chloride and in the presence or absence of a solvent. This is a step of producing an acyl compound (l(II)) in which a sulfonyloxy group is converted into a chlorine atom by performing a Friedel-Craf reaction with an aryl compound.

The reaction temperature is 0°C to room temperature, and the reaction time is usually 5 to 20 hours, although it varies mainly depending on the reaction temperature or the type of raw material compound.

After the reaction has ended, the product is purified by distillation after a conventional work-up.

Episode ±L consists of a Grignard reagent synthesized from chloromethyltrimethylsilane in a solvent and a ketene compound (
HII), the resulting silyl alcohol intermediate is treated with 0.1 to 1 equivalent of boron trifluoride ether complex in a solvent, and desilylated alcohol is produced to produce an olefin compound (HIII). be.

In the first reaction, the solvent used is not particularly limited as long as it does not inhibit the reaction, but ethers such as ether, tetrahydrofuran, dioxane, and dimethoxyethane can be preferably used.

The reaction temperature is -50°C to room temperature, and the reaction time is usually 10 minutes to 1 hour, although it varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used.

In the latter reaction, the solvent used is not particularly limited as long as it does not inhibit the reaction, but aromatic hydrocarbons such as benzene, toluene, and xylene; and aromatic hydrocarbons such as methylene chloride and chloroform are preferably used. Examples of halogenated hydrocarbons include esters or ethers such as ethyl acetate and propyl acetate, and ethers such as tetrahydrofuran, dioxane and dimethoxyethane.

The reaction temperature is 0° C. to room temperature, and the reaction time is usually 30 minutes to 3 hours, although it varies mainly depending on the reaction temperature, raw material compound, or type of solvent used.

The first generation method is to prepare an olefin compound (HIII) in a solvent in the presence of 1 equivalent of water, a catalytic amount of osmium tetroxide, and 1 to 1.5 equivalents of N-methylmorpholine N-oxide, triethylamine N- This is a process for producing diol compounds (HIV) by oxidizing organic amines such as oxides with N-oxide compounds.

The solvent used is not particularly limited as long as it does not inhibit the reaction, but preferably halogenated hydrocarbons such as methylene chloride and chloroform; esters or ethers such as ethyl acetate and propyl acetate; Mention may be made of ethers such as tetrahydrofuran, dioxane and dimethoxyethane.

The reaction temperature is 0°C to 50°C, preferably room temperature.

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 5 to 20 hours.

Incidentally, stereoisomers produced in small amounts can be easily separated by column chromatography.

No. 1-2 [The animals received the 4-diolyl compound (HIV) from No. A-
By treating according to step 1 and sulfonylating,
This is a process for producing compound (HV).

The alkali metal salt of triazole (2 to 4 equivalent) and compound (HV)
This is a step of producing compound (HVI) by reacting with

The solvent to be used is not particularly limited as long as it does not inhibit the reaction, but suitable examples include amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, and sulfoxides such as dimethylsulfoxide. be able to.

The reaction temperature is from room temperature to 100°C, and the reaction time is usually 1 to 15 hours, although it varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used.

The seventh step is a step of producing an optically active azide compound (HVII) by reacting an epoxy compound (HVI) in the same manner as in step A-3.

In addition, the produced optically active azide compound (HVII),
The corresponding optically active compound of the present invention can be produced by performing the steps after Step A-4 of [Method A].

Alternatively, by using an optically active compound corresponding to compound (AV) produced in the above process as a raw material and subjecting it to the steps of [Method D], [Method E] and/or [Method F] , corresponding optically active compounds of the present invention can be produced.

Furthermore, by subjecting the produced epoxy compound (HVI) to the step of [Method C], an optically active corresponding compound of the present invention can be produced.

On the other hand, a diol compound produced by treating the epoxy compound (LV) described later in the same manner as in Step L-7 is subjected to the step of [Method B] to obtain an optically active corresponding compound of the present invention. can be manufactured.

EJ method] Ar (JL, II) In the above formula, Ar, R' and R4 have the same meanings as above.

R7' represents a group similar to the aliphatic acyl group or aromatic acyl group, R14 represents a group similar to the tetrahydropyranyl group among the protecting groups for the "protected hydroxyl group", DMPS stands for dimethylisopropoxysilyl group.

[Method J] is a separate method for producing the optically active compound (HVI).

In the second and second sections, the compound (JI) is reacted with a halogenating agent such as oxalyl chloride or thionyl chloride to form an acid halide, and then using 2 to 3 equivalents of a Lewis acid catalyst,
In the presence or absence of a solvent, a Friedel-Craf reaction is carried out with 1 to 2 equivalents of an aryl compound, and the product is further deacylated (removal of the R7' group) to form a compound (J
This is the process of manufacturing II).

The solvent that can be used is not particularly limited as long as it does not inhibit the reaction, but suitable examples include halogenated hydrocarbons such as methylene chloride and chloroform, and carbon disulfide.

The catalyst to be used is not particularly limited as long as it is normally used in the Friedel-Crach reaction, but preferred examples include Lewis acids such as aluminum chloride, iron chloride, and titanium tetrachloride. More preferably, it is aluminum chloride.

The reaction temperature is 0° C. to room temperature, and the reaction time is usually 5 to 20 hours, although it varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used.

The deacylation reaction can be removed by treatment with an acid in the presence of a solvent.

In this case, removal under basic conditions, which is usually carried out, cannot be used because the carbonyl group will be transferred.

The acid that can be used is not particularly limited as long as it does not affect other parts of the compound, but preferably sulfuric acid,
Inorganic acids such as hydrochloric acid and nitric acid, usually methanol,
It is carried out in an alcoholic solvent such as ethanol.

The reaction temperature and reaction time vary depending on the starting materials and the acid used, etc., and are not particularly limited, but are usually 0°C to 50°C,
0.5 to 10 hours.

After the reaction has ended, the product is purified by distillation after a conventional work-up.

mi is compound (JIII) by sulfonylating compound (JII) in the same manner as in step A-1.
This is the process of manufacturing.

1: Mystery is to dissolve the compound (JIII) in a solvent and gradually add 1 equivalent of lithium hydroxide dropwise to it, thereby inverting the steric configuration of the hydroxyl group by a substitution reaction.
This is a process for producing compound (JIV).

The solvent used is not particularly limited as long as it mixes with water and dissolves the starting material, but preferably ethers such as tetrahydrofuran and dioxane; methanol, ethanol, n-propanol, etc. na arco=
Examples include amides such as dimethylformamide and sulfoltriamide, and sulfoxides such as dimethyl sulfoxide.

The reaction temperature is carried out at -78°C to 0°C, preferably -15°C to 0°C.

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 1 to 10 hours.

Daijojo: The hydroxyl group of compound (JIV) was protected with tetrahydropyranyl groups according to a conventional method, and the compound (JIV) was protected with tetrahydropyranyl groups.
JV) and is achieved, for example, by reaction with dihydropyran in a halogenated hydrocarbon such as methylene chloride using a catalyst such as pyridinium p-toluenesulfonate.

Step U is a step of producing a compound (JVI) by reacting a Grignard reagent synthesized from chloromethyldimethylisopropoxysilane with a ketone compound (JV) in a solvent.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction, but suitable examples include ethers such as ether, tetrahydrofuran, dioxane, and dimethoxyethane.

The reaction temperature is -20°C to room temperature°C, and the reaction time is usually 5 minutes to 1 hour, although it varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used.

Step U is a step of oxidatively desilylating compound (JVI) with hydrogen peroxide in a solvent in the presence of a base to convert it into a hydroxyl group to produce compound (JVII).

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 ethers such as tetrahydrofuran, dioxane, dimethoxyethane; methanol, ethanol, n
- Alcohols such as propatool: Examples include water or a mixed solvent thereof, and more preferably a mixed solvent of ethers such as tetrahydrofuran and alcohols such as methanol.

The base to be used is not particularly limited as long as it is used as a base in normal reactions, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate, or sodium hydrogen carbonate and potassium hydrogen carbonate. Examples include alkali metal hydrogen carbonates such as

The hydrogen peroxide solution used is preferably 35% hydrogen peroxide solution.

The reaction temperature is from room temperature to 70°C, and the reaction time is:
Although it varies mainly depending on the reaction temperature, raw material compound, or type of solvent used, it is usually 30 minutes to 2 hours.

m is a step of removing the hydroxyl protecting group R12 of compound (JVII) to produce compound (JVIII).

It can usually be removed by treatment with an acid in a solvent, and the acid used is preferably hydrochloric acid, acetic acid-sulfuric acid, p-1-luenesulfonic acid or acetic acid. The solvent to be used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, or a mixed solvent of these organic solvents and water may be used. suitable. The reaction temperature and reaction time vary depending on the starting materials and the type of acid used, but are usually 0°C to 50°C.
The duration is from 10 minutes to 18 hours.

Step U is a step of producing compound (JIX) by reacting compound (JVIII) with 2 equivalents or more of a sulfonylating agent according to step A-1.

No. U is sodium hydride, lithium hydride, in a solvent,
A compound (HVI) is produced by reacting an alkali metal salt of a triazole (2 to 4 equivalents) obtained by mixing an alkali metal hydride such as potassium hydride and a triazole at a ratio of 1:1 with a compound (JIX). This is the process of

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 dimethylformamide, dimethylacetamide,
Mention may be made of amides such as hexamethylphosphorotriamide or sulfoxides such as dimethylsulfoxide.

The reaction temperature is from room temperature to 100°C, and the reaction time is usually 1 to 5 hours, although it varies depending on the reaction temperature, raw material compound, or type of solvent used.

[Method K] In the above formula, Ar, R', R4 and HB- have the same meanings as above.

[Method K] is a separate method for producing the optically active compound (HVI).

The first step is to react compound (JV) with vinylmagnesium bromide in a solvent to produce compound (KI).

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 ethers such as ether, tetrahydrofuran, dioxane, and dimethoxyethane are preferably used. can.

The reaction temperature is -78°C to room temperature, preferably -50°C to -30°C.

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 10 to 30 minutes.

(Sadan closure is the protecting group H12 of the hydroxyl group of the compound (KI)
This is the step of removing , in the same manner as step J-7.

The hydroxyl group of the compound (KII) is sulfonylated by reacting according to Step A-1, and the hydroxyl group of the compound (KII) is sulfonylated.
This is a process for producing I).

Seventh Part: In a solvent, alkali metal hydrides such as sodium hydride, lithium hydride, potassium hydride (
1 to 1.5 equivalents) and compound (KIII) to produce compound (KIV).

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 ethers such as ether, tetrahydrofuran, dioxane, and dimethoxyethane; dimethylformamide, Mention may be made of amides such as dimethylacetamide, hexamethylphosphorotriamide or sulfoxides such as dimethylsulfoxide.

The reaction temperature is 0° C. to room temperature, and the reaction time is usually 1 to 10 hours, although it varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used.

The seventh IR group is the G-
In this step, the compound (KV) is produced by converting it into an aldehyde group by performing an oxidation reaction according to Step 1.

The seventh main group is the aldehyde group of the compound (KV).
This is a process of reducing and producing an alcohol compound (KVI) by carrying out a reaction according to Step -2.

The kI block is the A-1 hydroxyl group of the compound (KVI).
In this step, the compound (KVTI) is produced by sulfonylation according to the process.

Second, on the R floor, alkali metal salts of triazoles (1 to 3 equivalents ) and the compound (KVI
This is a step of producing compound (HVI) by reacting with I).

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 dimethylformamide, dimethylacetamide,
Mention may be made of amides such as hexamethylphosphorotriamide or sulfoxides such as dimethylsulfoxide.

The reaction temperature is 50°C to 120°C, preferably 80°C to 100'C.

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 0.5 to 3 hours.

[L Method] Ar (LI) Self (LU) In the above formula, Ar, R', R4, R7' and R1'- have the same meanings as above.

[Method L] is a separate method for producing the optically active compound (HVI).

First and foremost: the hydroxyl group of compound (JII).

This is a step of protecting with protecting group R14 in the same manner as Step J-4.

U reacts a Grignard reagent (1 to 1.5 equivalents) synthesized from chloromethyltrimethylsilane with a ketone compound (LI) in a solvent, and reacts the resulting silyl alcohol intermediate in a catalytic amount in a solvent. This is a process for producing an allyl alcohol compound (LI process) by treating with P-toluenesulfonic acid to simultaneously deprotect the hydroxyl group and generate a double bond by desilyl alcoholation.

In the first-stage 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 ethers such as ether, tetrahydrofuran, dioxane, and dimethoxyethane are preferably used. I can list several types.

The reaction temperature is 0°C to 50°C, preferably 0°C to room temperature.

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 30 minutes to 1 hour.

In the latter 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 alcohols such as methanol, ethanol, and n-propanol are preferably used. I can list several types.

The reaction temperature is 0°C to 50°C, preferably room temperature.

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 1 to 15 hours.

U stereoselectively oxidizes an allyl alcohol compound (LI) using a vanadium catalyst such as vanadium acetylacetate and t-butyl hydroperoxide (1 to 2 equivalents) to produce an epoxy compound (LIII). This is a manufacturing process.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene are preferably used. can.

The reaction temperature is 0°C to 50°C, preferably room temperature.

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 5 to 15 hours.

The first method is to invert the steric configuration of the hydroxyl group of the epoxy compound (LIII) through the Mitsunobu reaction to form the compound (LIV).
).

The Mitsunobu reaction can be carried out according to conventional methods, for example,
In a solvent, in the presence of 1 to 2 equivalents each of a phosphine such as triphenylphosphine and azodicarboxylic acid diethyl ester, a compound of the formula R''O)! (wherein R7/ has the same meaning as above) This is achieved by reacting a carboxylic acid derivative with

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 ethers such as ether, tetrahydrofuran, dioxane, and dimethoxyethane are preferably used. can.

The reaction temperature is -20°C to 50°C, preferably 0°C to room temperature.

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

The third element is R? of the group having the formula -0R7' in compound IV). / group, which can be removed by treatment with a catalytic amount of base in the presence of a solvent.

In this case, if the removal is performed using an acid, the epoxy may be cleaved, which is not preferable.

The base is not particularly limited as long as it does not affect other parts of the compound, but preferably metal alcoholades such as sodium methoxide; alkali metals such as aqueous ammonia, sodium carbonate, and potassium carbonate. Carbonates; carried out using alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or concentrated ammonia-methanol.

The solvent to be used is not particularly limited as long as it is used in ordinary hydrolysis reactions, and includes water; alcohols such as methanol, ethanol, and n-propanol; and ethers such as tetrahydrofuran and dioxane. An organic solvent or a mixed solvent of water and an organic solvent is suitable.

The reaction temperature and reaction time vary depending on the starting materials and the base used and are not particularly limited, but in order to suppress side reactions, they are usually at -20°C to 50°C and for 1 to 12 hours.

Chopsticks t, -6 step is the hydroxyl group of the compound (LV>)
In this step, compound (LVI) is produced by sulfonylation according to Step 1.

Step d is a triazole alkali metal salt (1 to 3 equivalents) obtained by mixing an alkali metal hydride such as sodium hydride, lithium hydride, or potassium hydride and a triazole in a 1=1 ratio in a solvent. and the compound (LVI
) to produce compound (1-IVI).

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 dimethylformamide, dimethylacetamide,
Mention may be made of amides such as hexamethylphosphorotriamide or sulfoxides such as dimethylsulfoxide.

The reaction temperature is from room temperature to 100°C, preferably from 50°C to 70°C.

The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 30 minutes to 10 hours.

In all of the above steps, the compound of the present invention has the formula -5o, R6 (wherein r represents 1 or 2, and RG
indicates the same meaning as above. ),
or/and in the case of having a group having the formula -5O2R4 (wherein R4 has the same meaning as above) as a substituent,
It can also be produced by oxidizing a compound having a group having the formula -5R' or -5R' at the corresponding position with an organic peracid such as peracetic acid or 3-chloroperbenzoic acid according to a conventional method. can.

Note that, unless otherwise specified, after the completion of the reaction, the target compound of the reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is immiscible with water to the reaction mixture, washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography.

[effect] Below, we investigated various effects.

In addition, as a control compound, Ar=2,4-diclPh,
R1=H1X=single bond, R2=4-CIPh, Y=
A racemic compound of -NHCO- was used.

This compound has the strongest antifungal activity among the compounds described in JP-A-59-62574.

In the three-dimensional representation of the compounds below, wood indicates a racemic body, but details will be explained in the Examples section.

Antifungal activity is due to Candida albicans (Candida albicans)
20 mg/kg of the drug was administered orally to mice (10 mice per group) that had been inoculated with 7 to 9 x 10' of A. albicans) at 2, 4 and 24 hours after the inoculation, and 9 to 9 days after infection.
It is expressed as the survival rate on day.

The survival rate on the second day of the non-administration group was 0%.

A r = 2.4-diclPh, Compound -FPh -CIPh -CIPh 4 (fmPh -CIPh 4-TfmPh 4-TfmPh R1=methyl group, X = single bond.

NHCO- NHCO- NHCO- NHCO- 0CO- 5CO- NHCO- Conformation survival rate (illusion) 2nd place 3rd place Compound -CNPh 4-NO, Ph 2.4-diFPh Ketoconazole control compound A r = 2.4-diFPh, Compound -CIPh 4-TfmPh 3-TfmPh Conformation survival rate (illusion) 2nd place 3rd place -NHCO-R”　　R” -NHCO-R”　　R” -NHCO-R”　　R” R1=methyl group, X=single bond.

Conformity survival rate (%) 2nd place 3rd place -3CO-R”　　R” -3CO-R”　　R” -3CO-R”　　R” A r = 4-CIPh, R1=methyl group, X = single bond.

Compound 2-F-4-TfmPh -5CO-(4-
CIPh)-CH=CH--3CO-(4-TfmPh
)-CH=CH--NHCO-(3-TfmPh)-C
H=CH--NHCO-(4-CIPh)-CH=CH
--NHCO-4-TfmPh -N(Me
)C,0-20-2-F-4-Tf-N(Me
)CO-(4-CIPh)-CH=CH--N(Me)
CO-2-F-4-TfmPh -NHCO
-3-TfmPh -NHCO-4-
CNPh-NHCO-4-TfmP
h -NHCO-4-TfmPh
-NHCO- Ketoconazole control compound steric survival rate (%) 2nd place 3rd place Compound 4-TfmPh 2-F-4-TfmPh 2-F-4-TfmPh Ketoconazole control compound steric survival rate (%) 2nd place 3 Position -NHCO-R"R"-NHCO-R"R" -NHCO-RR A r = 2.4-dicIPh, Compound -CIPh -CIPh Ketoconazole control compound R1 = methyl group, p = 1° Conformational viability (%) 4th place 5th place OR"R" ORR A r = 2,4-diFPh.

Compound -CIPh 4-TfmPh 2-F-4-TfmPh -CIPh 4-TfmPh Ketoconazole control compound R1: methyl group, p=l.

Conordination survival rate (phantom 4th position 5th position A r = 4-CIPh, compound R1 = methyl group, p = 1° Conordination survival rate (%) 4th position 5th position 2-F-4-TfmPh Ketoconazole control compound Candida albicans (Candidaa)
lbicans) 7-9X were inoculated, and 1, 4 and 24 hours after the inoculation, each drug was orally administered,
The 1EDso value was determined 14 days after infection.

A r = 2,4-diclPh, Compound R1 = methyl group.

X = single bond.

3D configuration EDs.

2nd place 3rd place -CIPh -CIPh Ketoconazole-NHCO-R"R" -NHCO-RR 7,07 <2.5 44.51 Trial 1 Candida albicans (Candidaa
1.4 and 24 hours after inoculation, each drug was orally administered, and the oral EDSO level was determined 15 days after infection.

A r = 2,4-diFPh, compound (4-CIPh) -CH=CH- -CNPh 4-Tfu+Ph 4-TfmPh 2-F-4-TfmPh A r = 2,4-dicIPh, R' = methyl group, X = single bond.

R1=methyl group, X=single bond.

Stereocoordination EDSO 2nd place 3rd place 5CO- NHCO- NHCO- -N(Me)GO- NHCO- 1,22 1,25 0,86 17,66 <0.625 Compound steric coordination 2nd place 3rd place E　D　s　.

A r = 4-CIPh, R1=methyl group, X = single bond.

4-TfmPh 5CO- R′g 0.73 Compound steric coordination 2nd place 3rd place EDs.

4-TfmPh NHCO- 0,48 From the above test examples, it can be seen that the compounds of the present invention have much stronger antifungal activity than the commercially available ketoconazole and control compounds.

As described above, the novel triazole derivative of the present invention is
It has excellent antifungal activity not only as a topical agent but also as an oral agent, and is useful as a therapeutic agent for deep mycoses such as candidiasis.

Examples of the administration form of the compound of the present invention include oral administration in the form of tablets, capsules, granules, powders, syrups, etc., or parenteral administration in the form of injections, half-open tablets suitable for topical use, creams, ointments, etc. Can be done. These formulations include excipients, diluents, dispersants, binders, disintegrants, lubricants, and stabilizers.

It is manufactured by a well-known method using additives such as flavoring agents.

Dose and frequency of administration vary depending on symptoms, age, body weight, administration form, etc., but in the case of oral administration, 50 to 200 doses per day.
0 mg, preferably 100-600 mg, can be administered to adults usually once a day or in divided doses.

B++1 Rice seedlings (variety: Kofu) at the 4-5 leaf stage were infected with rice blast fungus (P
yricularia oryzae) was inoculated by spraying. After inoculation, rice seedlings are kept at a temperature of 20-22℃.
After leaving the pots in a room with a relative humidity of 100% for 24 hours, a 10 ppl solution of the test compound was sprayed at a rate of 30 ml per 3 pots.

Next, rice seedlings were left in the same room for 6 days to develop the disease, and the top 2
Control efficacy was investigated based on the number of lesions formed on leaves.

In addition, the control efficacy (same in the following test examples) was determined by visually observing the degree of disease onset of the test plants, and expressed according to the following criteria.

5: No disease onset observed.

4: The degree of disease onset is 10% or less of the untreated group (if no test compound is used, the same applies hereinafter).

3: The degree of disease onset is 10% or more and 30% or less of the untreated area.

2: The degree of disease onset is 30% or more of the untreated plot and 5 or less.

1: The degree of disease onset is 50% or more and 70% or less of the untreated plot.

0: The degree of disease onset is 70'1 or more than the untreated plot, and no difference is observed from the untreated plot.

1 of the test compound was applied to rice seedlings (variety Nihonbare) at the 4-5 leaf stage.
00 ppm solution was sprayed at a rate of 30 ml per 3 pots. 24 hours after spraying the chemical solution, the rice sheath blight fungus (Rhi
4 to 5 oat grains cultured with zoctonia 5olani were placed near the ground of rice seedlings and placed in a room at a temperature of 25 to 27° C. and a relative humidity of 100 degrees Fahrenheit for 5 days to induce disease. Control efficacy was investigated based on the height of lesions formed on leaf sheaths.

The results are shown in Table 7.

Oat grains in which Rhizoctonia 5olani had been cultured in advance were added to the soil of rice seedlings (variety: Nipponbare) at the 4-5 leaf stage at 4-5'F1. I left it there and inoculated it. After inoculation, the rice seedlings were placed in a room at a temperature of 25-27°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. continue,
Rice seedlings were left in the same room for 5 days to develop the disease, and the control efficacy was investigated based on the height of lesions formed on the leaf sheaths.

The results are shown in Table 8.

Rice seedlings at the 3-4 leaf stage grown in pots (variety Nipponbare)
The pot was kept submerged in water at a depth of 1 cm, and the test compound was applied to the pot in an amount of 100 g/10a of active ingredient. After the rice seedlings were placed in a glass greenhouse for 7 days, 4 to 5 oat grains in which the rice sheath blight fungus (Rhizoctonia 5olani) had been cultured were inoculated at the ground level of the rice seedlings. After the plants were placed indoors at a temperature of 25-27°C and a relative humidity of 100% for 5 days to develop the disease, the control efficacy was investigated based on the height of lesions formed on the leaf sheaths.

The results are shown in Table 9.

Inadaka Nae disease fungus (Gi
10 g of diseased seeds obtained by spray inoculation with a conidial suspension of Bberella fujikuroi were immersed in 20 ml of 1100PP solution of the test compound for 3 days. Next, the seeds are sown densely in the soil in the pot, covered with soil, and kept at a temperature of 2.
Seedlings were grown for 3 weeks in a glass greenhouse at 0-30°C, and the control efficacy was investigated based on the number of infected bacteria.

The results are shown in Table 10.

Test Example 9 Wheat seedlings (variety: Norin No. 61) at the 1.5-leaf stage were sprinkled with spores of wheat rust (Puccinia recondita) and inoculated. After inoculating the bacteria, the wheat seedlings were kept at a temperature of 20°C.
After being placed indoors at -22°C and 100% relative humidity for 24 hours, it was then transferred to a glass greenhouse at 15-20°C for 2 days.
30 ml of 3 ppm solution of test compound per 3 pots
It was distributed at a rate of .

Next, wheat seedlings were placed in a glass greenhouse for 100 days to develop the disease, and the control efficacy was investigated based on the area of lesions formed on the first leaves.

The results are shown in Table 11.

Barley powdery mildew fungi (Erysiphe gran+1nis f, sp,
hordei) was sprinkled with conidia to inoculate. After inoculation, the barley seedlings were placed in a glass greenhouse at a temperature of 15-20℃ for 24 hours.
After standing for a period of time, 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 100 days to develop the disease, and the control efficacy was investigated based on the area of lesions formed on the first leaves.

The results are shown in Table 12.

A 300 ppm solution of the test compound was sprayed on cucumber seedlings (variety: Sumo Hanshiro) at the 3-4 leaf stage at a rate of 30 ml per 3 pots. 24 hours after spraying the chemical solution, cucumber powdery mildew bacteria (Sphaerotheca fuligine)
The conidia of a) were sprinkled and inoculated. After inoculation, the cucumber seedlings were placed in a glass greenhouse at a temperature of 20-30° C. for 7 days to develop the disease, and the control efficacy was investigated based on the area of lesions formed on the 3rd and 4th leaves.

The results are shown in Table 13.

PM solution was sprayed at a rate of 30ml per 3 pots. 24 hours after spraying the chemical solution, the apple scab fungus (Venturia
inaequalis) was inoculated by spraying with a conidial suspension.

After inoculation, apple seedlings were kept at a temperature of 20-22℃ and a relative humidity of 10℃.
The plants were placed in a 0% room for 3 days, then placed in a glass room at 20-22°C for 100 days to develop the disease, and the control efficacy was investigated based on the area of lesions formed on the 34th leaf.

The results are shown in Table 14.

In addition, in the table below, abbreviations have the same meanings as above.

In addition, rTHPJ represents a tetrahydropyranyl group 3-4
300 ρ blasts of the test compound A r = 2,4-diclPh on apple seedlings at leaf stage.

A r = 2.4-diFPh, Me -CIPh -N)! GO- R” A r = 2-F-4-CIPh, 4-TfmPh -CIPh 2-F-4-TfmPh NHCO- NHCO- NHCO- N3 CH2- Me A r = 2.4-diFPh, Itto 1a Me 4-CIPh Me 31FPh -NHCO-R’　　R”　　5 -NHCO-R”　　　R”　4 A r = 2.4-diclPh, 2-F-4-TfmPh -CNPh 4-TfmOPh Bu -PJHCO- -Nl(CO= -ToJHCO- -N)ICO- 4-AePh 4-BzOPh -NHCO-R" R" 5 -NHCO-R”　　　R”　4 4-TfmPh 4-TfmPh -NHCO-R”　　R” -NHCO-RR A r 22-F-4-CIPh, 4-CIPh 2-F-4-TfnPh Ar = 214-diclPh, 4-TfiPh −ω− -Nl(CO- oxalate A r = 4-CIPh, A r = 4-FPh, -CIPh -THP -NHCO-R”　　P,” -FJ,　　　　　R”　R” -O-R”　　R” A r = 4-BrPh, -N.

Ar = 2.4-diFPh, -CIPh 2.4-diFPh 2.5-diFPh 4-Tf old ph 2-F-4-TfiPh 4-CIPh 4-TfmOPh -CIPh 4-BzOPh -N) (CO- NHCO - -NF(CQ- -PIHCO- NHCO- NHCO- NHCQ- -N1(CO- -N)ICQ- R"R"5' R5 R"S" 4 Et Me Et 2-TIP -Prompt t-R"R" 5 -0- R"R" 4A r =
2-F-4-CLPh.

A　　　　”4-CIPhl, e -CIPh NHCO- A r = 4-FPh, e -CIPh NHCO- A r = 2.4-diFPh, A r = 4-CIPh, e -N.

t oxalate A r = 4-FPh, e Nl R” A r = 2-F-4-CIPh, e -N.

-CIPh e 2-F-4-TfmPh CO- R1 oxalate ○ A r = 2.4-diFPh.

A r = 2.4-dicIPh, -CIPh -FPh 4-TfmPh 2-F-4-TfmPh Bu 2nd position NHCO- NHCO- NHCO- NHCO- NHCO- 3rd position potency Me 2,4-diFPh -NHCO-R"
R”Me 4-TfmPh -NHCO-R
"R"Me 4-TfmPh -NHC
O-RR-CI2- Me -CH2-Me -N3 R"S'-N3R"R" A r N4-CIPh, A r N4-BrPh, A r = 2.4-diclPh, -3O2CH3 10- -CIPh -CIPh -FPh 2.4-diFPh 4-TfmPh 4-TfmPh Bu NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- N3 A r = 2,4-diFPh, Me 4-CIPh Me 3-F Ph Me 4-FPh -NHCO-R” R” 5-Nl(CO-
R"It"5-NHCO-R' R
” 53-TfmPh 4-TfmPh 2-F-4-TfaPh -CNPh 4-TfmOPh Bu Me 5-C1-5-C 1-Thi4- tBuPh4- -MePh A r = 2-F-4-CIPh, 4-TfmPh -CIPh 2-F-4-TfmPh A r = 2-C1-4-FPh, A r N4-CIPh, 2-F-4-TfmPh NHCO- NHCO- -Nl(CO- NHCO- NHCO- NHCO- NHCO- NHCO- -NHCO-R” R” 4-Nf(CO-
R"R"5-NHCO-R"R'
5NHCO- NHCO- NHCO- N5 -N.

-N.

R’ A r N4-FPh, A r N4-BrPh, 2-TI(P N3 10- R”　　　R”　　4 R”　　　R”　　4 ゛Donko A　　　　2,4-diFPh.

A r = 2.4-dicIPh, Me 4-CIPh Me 3-FPh Me 4-FPh -NHCO-RtR" 5 -NHCO-R" R" 5 -NHCO~ R” R” 5 -FPh 2.4-diFPh 4-TfmPh 4-TfmPh NHCO- NHCO- NHCO- NHCO- 2-F-4-TfmPh -CNPh 4-TfmOPh aU NHCO- NHCO- NHCO- NHCO- 4-tBuPh 4-MeOPh -MePh -NHCO-R”　　　R”　4 -NHCO-R" R" 5 -NHCO-R" R" 5 A r = 2-C1-4-FPh, Me -CIPh 0CO- R" 5 Me N3 A　r　N4-CIPb, Me A r = 2-F-4-CIPh, 2-T) fP 2-F-4-TfmPh A r N4-FPh, -NHCO-R”　　R” -Nx　　　　　R”　　S” Me -CIPh NHCO- t N3 Me -5OzCH3 10- A r = 4-BrPh, + number Ni A r = 2.4-dicIPh, -CIPh e 2-F-4-TfmPh t 2.4-diFPh e -CIPh R” R” A r = 2.4-diFPh, -CIPh -FPh -FPh 2.4-diFPh 3, 4-diFPh 2.5-diFPh 3,5-diFPh 2.6-diFPh 2-TfmPh 3-TfmPh 4-TfmPh 2-F-4-TfmPh -CNPh 4-TfmOPh 4-TfmOPh Bu HC1z 5-CI-2-Thi 6-C1-3-Pyr -Pyr -Pyr NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- NHCO- -CIPh 4-tBuPh 4-MeOPh -MePh -CIPh 4-TfmPh 4-TfmPh NHCO- NHCO- NHCO- NHCO- 0CO- 0CO- 5CO- N3 N3 N5 -I’h ″N5 -N.

nitrate R”　R” R”　R” R”　R” R”　R1 R R”　S” R R”　R” R”　S” A r = 4-CIPh.

Et 2-THP Me 2-THP Me -5O2CH3 10- 10- R"R"5 R"R"5 R"R"5 A r = 4-FPh, A r = 2-F-4-CIPh, 4-TfmPh -CIPh 2-F-4-TfmPh -NHCO-R1R"5-NHCO-R"R' 5-NHCO-R
"R" 5A r =, 4-BrPh, Shingo A r = 2,4-dicIPh, Me 4-FPh -NHCO-R"
R"Me 4-TfmPh -NHCO-R"
R"Me -CH2-Me -N3 R"R" -N3H! Rz A r = 2.4-diFPh, A r = 4-CIPh, A r = 4-FPh, -CIPh NHCO- A r = 4-BrPh , e -THP -〇- A r = 2-F-4-CIPh, 4-TfmPh -CIPh 2-F-4-TfmPh -NHCO-R” R” 5-NHCO-R
"R"5-NIICO-R'R"
5 The compound of formula (I) is used as an agricultural fungicide and exhibits therapeutic and preventive effects against plant diseases without causing damage to parasitic plants.

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

In addition, when used as a soil treatment or seed treatment agent, it is particularly effective against seedling damping-off of various crops such as beets, cotton, and cucurbits caused by Rhizoctonia fungi, as well as white silk disease of eggplants, cucurbits, etc. Soil-borne diseases such as potato black bruise can be effectively controlled.

On the other hand, at practical dosages, crops such as rice, tomatoes, potatoes, cotton, eggplants, kirari, and kidney beans will not be harmed by the drug.

Furthermore, the compound having the formula (1) can be effectively used as a fungicide in orchards, non-agricultural lands, forests, etc.

The compound of the present invention can be mixed with a carrier and, if necessary, other adjuvants, to form a formulation commonly used as an agricultural fungicide, such as a powder, a coarse powder, a fine granule, a granule, a wettable powder, an emulsion. It is used after being prepared into aqueous solutions, aqueous solutions, oil suspensions, etc. The term "carrier" as used herein refers to a synthetic or synthetic compound that is mixed into an agricultural fungicide to help the active ingredient reach the area to be treated and to facilitate the storage, transportation, or handling of the active ingredient. means a natural inorganic or organic substance.

Suitable solid supports include kaolinite group, senmoli 0
Clays represented by Na48 group or attapulgite group, talc, mica, phyllite, pumice, perminichelite, gypsum, calcium carbonate, dolomite, diatomaceous earth, magnesium lime, apatite, zeolite, silicic anhydride, synthetic calcium silicate Inorganic substances such as soybean powder, tobacco powder, walnut powder, wheat flour, wood flour, starch, vegetable organic substances such as crystalline cellulose, coumaron resin, petroleum resin, alkyd resin, polyvinyl chloride, polyalkylene glycol, ketone resin,
Examples include synthetic or natural polymer compounds such as ester gum, copal gum, and dammar gum, wax necks such as carnauba wax and beeswax, and urea.

Suitable liquid carriers include paraffinic or naphthenic hydrocarbons such as kerosene, mineral oil, spindle oil, white oil, aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, cumene, methylnaphthalene, carbon tetrachloride, chloroform, etc. , chlorinated hydrocarbons such as trichloroethylene, monochlorobenzene, 0-chlorotoluene, ethers such as dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, diisobutyl ketone, cyclohexanone, acetophenone, isophorone, ethyl acetate, amyl acetate, Ethylene glycol acetate, diethylene glycol acetate,
Esters such as dibutyl maleate and diethyl succinate, alcohols such as methanol, n-hexanol, ethylene glycol, diethylene glycol, cyclohexanol, and benzyl alcohol, and ether alcohols such as ethylene glycol ethyl ether, diethylene glycol ethyl ether, and diethylene glycol butyl ether. , polar solvents such as dimethylformamide and dimethylsulfoxide, or water.

Surfactants used for the purposes of emulsification, dispersion, wetting, spreading, binding, disintegration control, stabilization of active ingredients, fluidity improvement, rust prevention, etc. are nonionic, anionic, and cationic. Both polar and zwitterionic compounds can be used, but nonionic and/or anionic compounds are usually used.

Suitable nonionic surfactants include, for example, those obtained by polymerizing and adding ethylene oxide to higher alcohols such as lauryl alcohol, stearyl alcohol, and oleyl alcohol; those obtained by polymerizing and adding ethylene oxide to alkylphenols such as isooctylphenol and nonylphenol; Products obtained by polymerizing and adding ethylene oxide to alkylnaphthols such as butylnaphthol and octylnaphthol; products obtained by polymerizing and adding ethylene oxide to higher fatty acids such as balmitic acid, stearic acid, and oleic acid; mono- or dialkylphosphoric acids such as stearic phosphoric acid and dilauryl phosphoric acid. ethylene oxide is polymerized and added to ethylene oxide, ethylene oxide is polymerized and added to amines such as dodecylamine and stearic acid amide, higher fatty acid esters of polyhydric alcohols such as sorbitan and ethylene oxide are polymerized and added to them, ethylene oxide and propylene Examples include those obtained by polymerizing and adding oxides. Suitable anionic surfactants include, for example:
Alkyl sulfate ester salts such as sodium laurine sulfate, oleyl alcohol sulfate amine salt, alkyl sulfonates such as sodium sulfosuccinate dioctyl ester, sodium 2-ethylhexene sulfonate, sodium isopropylnaphthalene sulfonate, sodium methylene bisnaphthalene sulfonate , arylsulfonates such as sodium ligninsulfonate and sodium dodecylbenzenesulfonate.

Furthermore, the agricultural fungicide of the present invention has improved formulation properties,
For the purpose of enhancing biological effects, polymeric compounds such as casein, gelatin, albumin, glue, sodium alginate, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, and other adjuvants can also be used in combination.

The above-mentioned carriers and various auxiliary agents are used individually or in combination as appropriate depending on the purpose, taking into consideration the dosage form of the preparation, the application situation, etc.

Powders, for example, usually contain 0.1 to 25% of the active ingredient compound.
The remaining part is a solid carrier.

Irrigation agents, for example, usually contain 1 to 80 parts by weight of the active ingredient compound, with the remainder being a solid carrier and a dispersing wetting agent, with protective colloid agents, thixotropic agents, antifoaming agents, etc. being added as necessary.

Granules, for example, usually contain 1 to 35 parts by weight of the active ingredient compound, with the remainder being mostly solid carrier.

Is the active ingredient compound homogeneously mixed with the solid carrier?
Alternatively, it is uniformly fixed or adsorbed on the surface of a solid carrier, and the particle diameter is about 0.2 to 1.5 mm.

An emulsion, for example, usually contains 1 to 50 parts by weight of the active ingredient compound, about 5 to 20 parts by weight of an emulsifier, and the remainder is a liquid carrier, and if necessary, a rust preventive agent may be added. It will be done.

The agricultural fungicides of the present invention prepared in various formulations in this way are sprayed on the leaves and leaves of crops, or sprayed on the soil or water surface, for example, in paddy fields or fields, before or after disease outbreaks. When applied to IOa
Diseases can be effectively controlled by administering 0.1 to 500 g, preferably 10 to 1000 g, of the active ingredient per dose. Further, when the agricultural fungicide of the present invention is used for seed treatment, for example, as a seed dressing, the active ingredient per weight of seeds is o, ooi% to
By applying powder coating at a concentration of 2%, preferably 0.2 to 0.5%, soil-borne or seed-borne diseases can be effectively controlled.

The agricultural fungicide of the present invention is preferably blended with other agricultural fungicides in order to broaden the bactericidal spectrum.
In some cases, synergistic effects can be expected.

The present invention will be explained in more detail below by giving Examples, Reference Examples, and Production Examples.

In the naming of the compounds below, the book indicates racemates.

That is, the expression (2R", 3R") is expressed as (2R, 3R").
) and (2s.

3S), which means a 1:1 mixture of isomers of (
2R8, 3R8) Indication and (2S8, 38x) Indication have the same meaning. Also, (2R", 3S
”) similarly represents (2R, 3S) and (2S,
3R) is meant a 1:1 mixture of isomers of (2R5,
3SR) and (2S”).

It has the same meaning as the expression 3R''').

(2R", 3R")-3-amino-(2,4-dichlorophenyl)-1-(IH-1,2,4-triazole-
1-yl)-2-butanol 68 mg (0,23 mm
ol) in 1 ml of pyridine, stirred at 0°C, and then 50 mg of 4-fluorobenzoyl chloride (0,3
2 mmol) was added. After 50 minutes, 0.2 ml of methanol was added at the same temperature, and the mixture was stirred for 10 minutes.

The solvent was distilled off from the reaction solution under reduced pressure, diluted sodium hydrogen carbonate water was added to the residue, and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated brine, dried, and the solvent was distilled off.

The obtained crystalline residue was recrystallized from ethyl acetate to obtain 59 mg of the target compound having a melting point of 217°C.

Infrared absorption spectrum ν, □ (KBr) c+n-1:3
440, 3280.1650.1503° NMR spectrum (CDC13) δppm: 0.95 (3H, d,
J = 7 Hz); 4.41 (LH, d, J = 15 H
z); 5.45 (2H, m); 5.64 (LH, d
.

J=15 Hz); 6.76 (IH, br, d);
7.11 (LH, dd, J=9,2 Hz); 7.1
7 (2H, t, J = 8.5 Hz); 7.36 (LH
, d, J=2 Hz); 7.56 (IH, d, J=9
Hz); 7.80 (IH, s); 7.84 (IH,
s); 7.91 (2H, dd, J=8.5, 6 Hz)
.

4-dilorophenyl-1-IH-124-razole(2R",3R")-3-amino-2-(2,4-dichlorophenyl)-1-(IH-1,2,4-triazole-1- yl)-2-butanol 197 mg (0,6
54n+mol) in 2.5 ml of pyridine, and
4-chlorobenzoyl chloride 16 while stirring at °C.
2 mg (0,925 mmol) was added. After 45 minutes, 0.5 ml of methanol was added at the same temperature and stirred for 10 minutes. The solvent was distilled off from the reaction solution under reduced pressure, dilute 1-lium hydrogen carbonate water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was distilled off. The obtained crystalline residue was recrystallized from a mixed solvent of ether:hexane=3=1 to obtain the target compound 221 rag having a melting point of 217-219°C.

Infrared absorption spectrum y, , (CHCh) cm-1:
3430, 1655.1585.1505° NMR spectrum (CDCb) δppm: 0.95 (3H, d,
J = 7 Hz); 4.40 (IH, d, J = 15 H
z); 5.46 (2H, m); 5.63 (IH, d
.

J=15 Hz); 6.88 (IH, br, d);
7.11 (IH, dd, J=9,2 Hz); 7.3
5 (IH, d, J = 2 Hz); 7.45 (2H, d
, J=8 Hz); 7.54 (IH, d, J=9 H
z); 7.78 (IH, s); 7.83 (2H, d
, J=8 Hz); 7.84 (IH, s).

203 mg of the synthesized amide compound was heated and dissolved in ethyl acetate, 46 mg of oxalic acid was added thereto, the mixture was cooled, and the precipitated crystals were collected by filtration. 225 mg of oxalate having a melting point of 178-182°C were obtained.

In the same manner as in Example 2, (2R,3R)-3-amino-
2-(2゜4-dichlorophenyl)-1-(IH-1,
From 230 mg of 2,4-)-riazol-1-yl)-2-butanol [(-) monoenantiomer], target compound 28
Obtained 3 mg as an oil.

Specific optical rotation [α] o”-104° (cm0.90, CHC
l3).

Melting point of oxalate: 121-123°C.

Actual flow rate A 2R"3R" -3-24-dichlorobenzol-amino-2-24-dichlorophenyl-1-IH-124-
F Azore 1- Sea 2-B Nore (2R", 3R")-3-7mi)-2-(2,4-di'
) 007r:Nil)-1-(1)! -1,2,4-triazol-1-yl)-2-butanol 56.5 m
g (0,188 mmol) was dissolved in 1 ml of pyridine, and while stirring at 0°C, 58 mg (0,28 mmol) of 2,4-dichlorobenzoyl chloride was added. After 50 minutes, 0.2 ml of methanol was added at lower temperature, and the mixture was stirred for 15 minutes. The solvent was distilled off from the reaction solution under reduced pressure, diluted sodium hydrogen carbonate water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was distilled off.

The residue was recrystallized from a mixed solvent of hexane-ethyl acetate to obtain 48 mg of the target compound having a melting point of 180-181°C.

Infrared absorption spectrum ν, aX (KBr) C! ll-1
:3360, 1570.1585.1530° NMR spectrum (CDC13) δPpm: 0.98 (3H,
d, J=7 Hz); 4.5 g (IH, d, J=15
Hz); 5.50 (2H, m); 5.68 (LH
,d.

J=15 Hz); 6.97 (IH, br, d);
7.15-7.8 (6H, m); 7.81 (H (, s)
; 7.85 (IH, s).

Actual product 1 (2R'', 3R-3-amino-2-(2,4-dichlorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2-butanol 126.5 mg (0,
42 mmol) was dissolved in 2 ml of pyridine, and 122.6 mg (0,588 mmol) of 4-(trifluoromethyl)benzoyl chloride was added while stirring at 0°C.

After 50 minutes, add 0.3 ml of methanol at incubation temperature.
Stir for a minute. The solvent was distilled off from the reaction solution under reduced pressure, and dilute aqueous sodium bicarbonate was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was distilled off. The obtained crystalline residue was recrystallized from a mixed solvent of ethyl acetate and a small amount of hexane to obtain the target compound 134 rng having a melting point of 186°C.

Infrared absorption spectrum ν, a, (KBr) cm-1:
3360, 1565.1530°NMR spectrum (CDC1y) δppm: 0.9
9 (3H, d, J=7 Hz); 4.40 (IH,
d, J-15Hz); 5.49 (2H, m);
5,68 (IH, d.

J=15 Hz); 6.84 (IH, br, d);
7.10 (IH, dd, J=9,2 Hz); 7.3
7 (LH, d, J = 2 Hz); 7.56 (IH, d
, J=9 Hz); 7.79 (2H, d, J=9 H
z); 7.83 (IH, s); 7.87 (LH, s
); 8.04 (2H, d, J=9 Hz).

In the same manner as in Example 5, (2R,3R)-3-amino-
2-(2゜4-dichlorophenyl)-1-(IH-1,
2,4-triazol-1-yl)-2-butanol [
(-) one enantiomer] 200 mg to target compound 221
mg was obtained.

Melting point: 88-91°C.

Specific optical rotation [(!] D25-114.5° (c=1.01
, CHCl3).

Azol-niyl-2-butanol (2R", 3R")-3-amino-2-(2,4-dichlorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2-butanol 200 mg (0,6
64 nmol) was dissolved in 10 ml of pyridine, and 247.9 mg (1,328 mmol) of 4-(methylthio)benzoyl chloride was added while stirring at 0°C. 3
After 0 minutes, the mixture was returned to room temperature and stirred for 30 minutes. The reaction solution was heated to 0°C.
Then, 0.6 ml of methanol was added and stirred for 10 minutes. The solvent was distilled off from the reaction solution under reduced pressure, diluted sodium hydrogen carbonate water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was distilled off.

The resulting residue was recrystallized from ethyl acetate, melting point 16.
121.7 mg of the target compound having a temperature of 7-168°C was obtained.

Infrared absorption spectrum ν,, aX(KBr) am-1:
3300, 1627.1596.1545.1508° NMR spectrum (CDC13) δppr11:
0.98 (3H, d, J=7 Hz); 2.51 (3
H, s); 4.42 (IH, d, J=I5 Hz);
5.47 (2H, m); 5,67 (IH, d, J=
15 Hz); 6.83 (IH, br, d); 7.
11 (IH.

dd, J = 9,2 Hz); 7.32 (2H, d, J
=8 Hz); 7.39 (IH, d.

J = 2 Hz); 7.58 (IH, d, J = 9 Hz
); 7.80 (IH, s); 7.82 (2H, cl
, J=8 Hz); 7.86 (IH,s).

Eggplant (2R", 3R")-3-amino-2-(2,4-difluorophenyl)-1-(LH-1,2,4-triazol-1-yl)-2-butanol 200 mgco ,
Dissolve 746 mmol) in 2 ml of pyridine and heat to 0°C.
4-fluorobenzoyl chloride 16 while stirring at
5.5 mg (1,044 mol+ol) was added. After 1 hour, 0.5 tml of methanol was added at the same temperature, and the mixture was stirred for 10 minutes. The solvent was distilled off from the reaction solution under reduced pressure, diluted sodium hydrogen carbonate water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was distilled off. The resulting residue was recrystallized from ethyl acetate to a melting point of 2.
258.5 mg of the target compound having a temperature of 05°C was obtained.

Infrared absorption spectrum v, a, (KBr) cm-1:3
280, 1634.1600.1530.1502°N
MR spectrum [CDCh-CDaOD (10:1)]
δppm: 1.04 (3H, d, J=7 Hz);
4.47 (LH, d, J=15 Hz); 4.96
(IH, m); 5.0 g (IH, d, J = 15 Hz
); 6-6-5-7-1 (2Ht; 7.1-7.9
(IH, m); 7.19 (21 (, t, J=9 Hz
); 7.78 (1/H, s); 7.97 (2H, dd
, J=9,6 Hz); 8.01 (IH, s).

(2R”, 3R”)-3-amino-2-(2,4-difluorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2-butanol 200 mg (0,
746 mmol) was dissolved in 2 nil pyridine and heated to 0°C.
4-chlorobenzoyl chloride 184 while stirring at
mg (1.05 mmol) was added. After 1 hour, 0.5 ml of methanol was added at the same temperature, and the mixture was stirred for 10 minutes.

The solvent was distilled off from the reaction solution under reduced pressure, diluted sodium hydrogen carbonate water was added to the residue, and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated brine, dried, and the solvent was distilled off.

The resulting crystalline residue was recrystallized from ethyl acetate to obtain 229 mg of the desired compound having a melting point of 221-222°C.

Infrared absorption spectrum ν,. (KBr)cm-1:33
10.1635, 1618, 1595.1536, 15
03°NMR spectrum [CDC13-CD30D(1
0: 1)] δppns: 1.02 (3H, d, J
= 7 Hz); 4.50 (IH, d, J = 15 Hz
); 4.95 (IH, m); 5.06 (IH, d,
J=15 Hz); 6.5-7.1 (2H, n+);
7.1-7.9 (LH, m); 7.50 (2H, d
, J=8 Hz); 7.77 (LH, s); 7.90
(2H, d, J=8 H2); 8.00 (IH, S)
.

(2R", 3R")-3-amino-2-(2,4-difluorophenyl)-1-(LH-1,2,4-triazol-1-yl)-2-butanol 200 mg (0,
746 mmol) was dissolved in 2 nil pyridine and heated to 0°C.
While stirring, 217.7 mg (1,044 mmol) of 4-(trifluoromethyl)benzoyl chloride was added. After 1 hour and a half, add 0.3 ml of methanol at the same temperature.
was added and stirred for 10 minutes. The solvent was distilled off from the reaction solution under reduced pressure, diluted sodium hydrogen carbonate water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was distilled off. The resulting crystalline residue was recrystallized from ethyl acetate to give crystals 2 having a melting point of 201-205°C.
54 mg was obtained.

Infrared absorption spectrum ν18, (KBr) cm-1:3
375, 1666, 1540.1502°NMR spectrum [CDCl3:CD30D (10:1)] δpp
m: 1.08 (3H, d, J near Hz); 4.5
0 (IH, d, J=15 Hz); 4.98 (IH,
m); 5.11 (LH, d, J=15 Hz); 6
．． 60-7.16 (2H, m); 7.20-7.90
(IH, n+); 7.77 (IH, s); 7.80
(2H, d, J=8 Hz); 8°10 (IH, s)
; 3.11 (2H, d, J=8 Hz).

(2R", 3R")-3-amino-2-(2,4-difluorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2-butanol 200 mg (0,
Dissolve 75 mmol) in 2.5 ml of pyridine and heat to 0°C.
While stirring, add pentafluorobenzoyl chloride 2
50 mg (1.09 mmol) was added. Example 10
The crude product obtained was recrystallized from a mixed solvent of ethyl acetate-benzene-hexane to obtain the target compound 282 rrr having a melting point of 111-116°C.
I got g.

Infrared absorption spectrum Sea JIX (CHCL3) c! m
-1:3425, 1680.1500° NMR spectrum (CDC13) δppm: 0.
98 (3H, d, J=7 Hz); 4.53 (IH,
d, J=14 Hz); 5.09 (IH, d, J=1
4 Hz); 5.1 (2H, m); 6.6-7.8 (
4H, m); 7.82 (IH, s); 7.85 (L
H,s).

The target compound 70 having a melting point of 254-255.5°C was obtained by reacting 90 rng of (ruamino)benzoyl chloride.
Got nag.

NMR spectrum [CDC11:CD30D (3:1)
]δppnt: 1.01 (3H, d, J=7 Hz)
; 2.16 (3H, s); 4.43 (IH, d, J
=15 Hz); 5.5 (IH, m); 5.61 (
IH, d, J = 15 Hz); 7.12 (IH, dd
.

J=8,2 Hz); 7.39(IH,d, J=2
Hz); 7.57 (IH, d, J=8Hz); 7.
67 (2H; d, J=9 Hz); 7.74 (LH,
s); 7.88 (2H.

d, J=9 Hz); 7.99 (IN, s).

In the same manner as in Example 1, (2R", 3R")-3-amino-2-(2°4-dichlorophenyl)-1-(IH
The following compounds were synthesized by reacting -1,2,4-triazol-1-yl)-2-butanol with various substituted benzoyl chlorides.

In the same manner as in Example 8, (2R", 3R")-3-
Amino-2-(2,4-difluorophenyl)-1-(
86 mg of IH-1,2,4-triazol-1-yl)-2-butanol and 4-(acet-1-yl-2-butanol Melting point: 246-248°C.

Not implemented H Melting point: 257-258.5°C.

Melting point: 129-130°C.

Melting point: 169-172°C.

(2R", 3R")-2-(2,4-dichlorophenyl)-3-([4-(methylthio)benzoylcoamino)
-1-(IH-1, 2,4-triazol-1-yl)
-2-Butanol 88 mg (0,195 mmol) was dissolved in methylene chloride 2 ml, and while stirring at 0°C,
m-chloroperbenzoic acid (85% purity) 35 mg (0,
19 mmol) was added. After 15 minutes, the mixture was diluted with ethyl acetate, washed successively with diluted sodium bicarbonate water and saturated brine, dried, and the solvent was distilled off. The resulting crystalline residue was recrystallized from ethyl acetate to obtain 68 mg of the target compound having a melting point of 206.5-207.5°C.

Infrared absorption spectrum ν+s @ w (KBr) cm
-1:3360(br,), 1664.1526°N
MR spectrum (CDCh) δppm: 1.00 (
3H, d, J=6.5Hz); 2.76 (3H, s)
; 4.45(I) f, d, J=15 Hz); 5.
5 (2H.

m); 5.67 (IH, d, J=15 Hz); 7
．． 03 (IH, br, d); 7.13 (LH, dd,
J = 9.2 Hz); 7.39 (LH, d, J = 2
Hz); 7.58 (LH.

d, J=9 Hz); 7.77(2H, d, J=8
Hz); 7.80 (IH, s); 7.86 (LH, s
); 8.08 (2H, d, J=8 Hz).

s); 8.05 (IH, s).

42 mg of this oxazolidine compound and 20 mg of oxalic acid
were mixed in ether, and the precipitated crystals were collected by filtration.

Oxalate 38 with melting point 155-161'C (decomposition)
mg was obtained.

1-(3-[N-(4-chlorophenyl)amino]-2
-(2,4-dichlorophenyl)-2-hydroxypropyl)-1H-1゜2.4-triazole 41 mg (
0,103 mmol) and paraformaldehyde 13.7
mg (0.45 mmol) were heated in toluene 4 n+1 at 90° C. for 3 hours. The oily substance obtained by distilling off the solvent under reduced pressure was subjected to column chromatography using 2 g of silica gel, and benzene-ethyl acetate (3:2-1:
4) to obtain the target compound 42 rrrg as an oil.

NMR spectrum (CDCh) δppm: 3.68 (
IH, d, J = 10Hz); 4.09 (IH, d, J
=10 Hz); 4.77 (2H, s); 4.78
(IH.

d, J=2.5 Hz); 5.05 (IH, d, J=
2.5 Hz); 6.42 (2H, d); 7.0-
7.5 (4H, m); 7.53 (IH, d, J=8
Hz); 7.77 (IH.

1-(3-[N-(4-(methylthio)phenyl)aminoco-2-(2,4-dichlorophenyl)-2-hydroxypropyl)-IH-1,2,4-triazole 23
4 mg (0,572 mmol) and 76 mg (2,53 nsmol) of paraformaldehyde in toluene at 90
Heated at ℃ for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography using 5 g of silica gel and eluted with benzene-ethyl acetate (3:2-1:4) to obtain 240 mg of the target compound as an oil. Ta.

Infrared absorption spectrum v,,, (CDCh) cm-
1:1600, 1500° NMR spectrum (CDC13) δppm: 2.40
(3H, s); 3.70 (IH, d, J=10 Hz
); 4.10 (LH, d, J40 Hz); 4.7
9 (2H.

s); 4.80 (IH, d, J=2.5 Hz);
5.09 (LH, d, J=2.5 Hz); 6.46
(2H, d); 7.1-7.5 (4H, m); 7.
53 (IH, d, J=8Hz); 7.76 (IH, s
); 8.06 (IH, s).

80 mg (0.19 mmo) of this oxazolidine compound
1) and 34 mg (0.38 mmol) of oxalic acid were mixed in ether, and the precipitated crystals were collected by filtration. Melting point 162-1
76 IIIg of oxalate having a temperature of 65°C was obtained.

5-(2,4-dichlorophenyl)-3-[4-(methylthio)phenyl]-5-[(IH-1,2,4-triazol-1-yl)methyl]oxazolidine 31.5
mg (0,075 mmol) of methylene chloride 0.8
ml of m-chloroperbenzoic acid under stirring at 0°C.
4.2 n+g (0,082 mmol) was added.

After 30 minutes, an aqueous sodium sulfite solution was added and extracted with chloroform. The crude product obtained by washing with diluted sodium bicarbonate water and saturated brine, drying, and distilling off the solvent was subjected to column chromatography using silica gel. 10
Elution was carried out with -30% ethanol-ethyl acetate to obtain 31 mg of the target compound. Crystallization from benzene-ethyl acetate gave one of the diastereomers as crystals (13 mg) with a melting point of 181-186°C.

NMR spectrum (CDC13) δppm: 2.68
(3H, s); 3.83 (LH, d, J=10 Hz
); 4.19 (LH, d, J-10Hz); 4.7
0(LH.

d, J=14 Hz); 4.92(IH, d, J=2
．． 5 Hz); 4.95 (LH, d.

J = 14 Hz); 5.14 (IH, d, J = 2.5
Hz); 6.60 (2H, d); 7.25 (IH,
dd, J = 9,2 Hz); 7.50 (IH, d, J
=2 Hz); 7.55 (2H, d); 7.58 (I
H, d, J = 9 Hz); 7.79 (18, s); 8
．． 09 (IH, s).

5-(2,4-dichlorophenyl)-3-[4-(methanesulfinyl)phenyl]-5-[(IH-1,2,
80 mg (0.18 mmol) of 4-triazol-1-yl)methyl]oxazolidine was dissolved in 2.5 methylene chloride.
ml of m-chloroperbenzoic acid under stirring under water cooling.
7.8 mg (0.22 mn+ol) was added.

After 1 hour, an aqueous sodium sulfite solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with diluted sodium bicarbonate water and saturated brine in that order, dried, and then the solvent was distilled off. The crystalline residue obtained was recrystallized from ethyl acetate and had a melting point of 1.
60 mg of the target compound having a temperature of 93-196°C was obtained.

NMR spectrum (CDCl2) δppm: 2.98
(3H, s); 3.88 (IH, d, J: 10 Hz
); 4.20 (LH, d, J=10 Hz); 4.
68 (IH.

d, J=15 Hz); 4.94(IH, d, J=2
．． 5 Hz); 4.95 (IH, d.

J = 15 Hz); 5.13 (IH, d, J = 2.5
Hz); 6.50 (2H, d); 7.23 (IH,
dd, J = 9,2 Hz); 7.49 (LH, d, J
= 2 Hz); 7.55 (IH, d, J = 9 Hz);
7.75 (2H, d); 7.77 (LH, s); 8
．． 05(IH,s) - Externalized 3-4-chlorobenzoyl-5-24-difluorophenyl-5-IH-124-r C-1-5-(2
,4-difluorophenyl)-5-[(IH-1,2,
140 mg (0.33 mmol) of 4-triazol-1-yl)methyl]oxazolidine was added to methylene chloride I n
Dissolved in il and cooled with water, add 53 mg of triethylamine (
0.53 mmol) and 4-chlorobenzoyl chloride 9
2 mg (0.53 mmol) was added and stirred for 30 minutes. Add 0.2 m+1 methanol and boil for 20 minutes under water cooling.
After stirring for a minute, the reaction solution was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The separated organic layer was washed with saturated brine, dried, and then the solvent was distilled off. Recrystallization from chloroform-hexane gave 106 mg of the target compound having a melting point of 152-155°C.

Elemental analysis value: Calculated value as Cl9H15CIF202N4: C, 56,38; H, 3,73; N, 13
．． 84° Actual measurement: C, 56,37; H, 3,68;
N, 13.40°NMR spectrum (CDC13)
δppm: 4.00 (IH, d, J=12Hz);
4.31 (IH, d, J = 12 Hz); 4.48 (
IH, d, J = 15 Hz); 4.68 (IH, d, J
=15 Hz); 5.0-5.3 (2H, m); 6
．． 5-7.5 (3H, m); 7.40 (4H, s);
7.82 (LH, s); 8.03 (IH, s).

Dissolve 108 mg of the above compound in ethyl acetate, add 2 oxalic acid
5 mg was added and concentrated to yield 107 rng of oxalate with a melting point of 150-155°C.

5-(2,4-difluorophenyl)-5-[(IH-
138 mg (0.52 mmol) of 1,2,4-triazol-1-yl)methyl]oxazolidine was dissolved in pyridine 2
ml, 150 mg (0.72 mmol) of 2,4-dichlorobenzoyl chloride was added under water cooling, and the mixture was stirred for 30 minutes under water cooling. After adding 1 ml of ethanol and stirring at room temperature for 10 minutes, the solvent was distilled off under reduced pressure, and the residue was distributed between an aqueous ethyl acetate-sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried, and the solvent was distilled off. The residue was subjected to preparative silica gel thin layer chromatography and developed with ethyl acetate to obtain 98 mg of the target compound as an oil.

NMR spectrum (CDC13) δppm: 3.7
6(2X O,5H,s) ;3.9-4.4(2X0
．． 5H, n+); 4.5-4.7 (2H, m); 4
．． 82 (2XO, 5H, s); 5.31 (2X0.5
H, s); 6.6-7.6 (6H, m); 7.86 (
IH, s); 8.04 (0,5H, s); 8.09
(0,5H,s).

Dissolve this compound 98 rag in ethyl acetate and add oxalic acid 2
3 mg was added, the solvent was distilled off, and foamy oxalate (96 m
g) was obtained.

Fruit No. 11 is (4R", 5R")-5-(2,4-dichlorophenyl)-4-methyl-5-[(IH-1,2,4-triazol-1-yl)methyl]oxazolidine 420 mg
(1,34 mmol) was dissolved in 10 ml of pyridine, and 350 mg of 4-chlorobenzoyl chloride was added under stirring while cooling with water.
(2,00 mmol) is added. 1 hour later methanol 0
．． 8 ml was added and stirred for 10 minutes. Dilute aqueous sodium hydrogen carbonate was added to the residue obtained by distilling off pyridine under reduced pressure, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off, and the resulting crude product was subjected to column chromatography using silica gel, and benzene-ethyl acetate (6:1-
A crystalline target compound was obtained by elution with a 1:1) mixed solvent. Recrystallized from ethyl acetate-hexane, melting point 166
360 mg of pure product having a temperature of -167°C was obtained.

Infrared absorption spectrum v, aX (CHCl3) am-1
: 1640° NMR spectrum (CDC13) δpp
m: 1.03 (3H, d, J=6.5Hz); 4.
50 (IH, d, J=16 Hz); 4.95 (IH
, d, J=16 Hz); 5.25 (3H, br, s)
; 7.0-7.7 (9H, m).

After dissolving 150 mg of this amide compound and 35 mg of oxalic acid in ethyl acetate, it was concentrated and crystallized to give a melting point of 138.
157 mg of oxalate having a temperature of -140°C was obtained.

In the same manner as in Example 24, (4R,5R)-5-(2,
4-dichlorophenyl)-4-methyl-5-[(IH-
420 mg of 1,2,4-triazol-1-yl)methyl]oxazolidine [(-) monoisomer] and 350 mg of 4-chlorobenzoyl chloride were reacted to obtain 370 mg of the target compound as an oil.

Specific optical rotation [cz]n” +5.42 (c=1.07, C
HCl3) 205 mg of the optically active amide compound described above was mixed with 41 mg of oxalic acid in ethyl acetate to give a melting point of 122-
150 mg of oxalate having a temperature of 126°C were obtained.

I copied it from the actual story. Oxalate 158 m with melting point 161-164 °C
I got g.

(4R", 5R")-5-(2,4-difluorophenyl)-4-methyl-5-[(IH-1,2,4-triazol-1-yl)methyl]oxazolidine 155 m
Dissolve g (0.55 mmol) in 2 ml of pyridine, stir at 0°C, and add 1 ml of 4-chlorobenzoyl chloride.
44 mg (0.82 mmol) was added. Example 24
Post-treatment was carried out in the same manner as above, and the obtained crude product was purified by column chromatography using silica gel. Elution was performed with a hexane-ethyl acetate (1:3) mixed solvent to obtain 204 mg of the target compound as an oil.

Infrared absorption spectrum v ,, aX (CDC13) am
-1:1638゜NMRX Pect 7L/ (CDC13) δppm: 1
．． 01 (31-1, d, J=7 Hz); 4.55 (
2H,s); 4.8-5.5(3)(,m); 6.
6-8.0 (9H, m).

Dissolve 150 mg of this amide compound in ethyl acetate,
Add 40 mg of oxalic acid, cool, and collect the precipitated crystals by filtration (
4R”, 5Ra-5-(2,4-difluorophenyl)
-4-Methyl-5-[(LH-1,2,4-triazol-1-yl)methyl]oxazolidine 200 mg (
Dissolve 0.71 mmol) in 2.5 ml of pyridine,
Pentafluorobenzoyl chloride 2 with stirring at °C.
45 mg (1.06 mmol) was added.

After 1 hour, 0.5 ml of methanol was added and stirred for 10 minutes. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in ethyl acetate. After washing with saturated brine and drying, the solvent was distilled off. The obtained crude product was subjected to column chromatography using silica gel and eluted with a benzene-ethyl acetate (3:1) mixed solvent, yielding 291 mg of the target compound.
was obtained as an oil.

NMR spectrum (CDC13) δppu+: 0.9
2 (1,5H,d, J=7Hz); 1.11 (1,5
H, d, J=7 Hz); 4.2 (0,5 H, m);
4.60 (2H, s); 5.0 (0.5H, m);
5.14 (IH, s); 5.45 (0°5H, d, J
=6 Hz); 5,75 (0,5H,d, J=6H
z); 6.6-7.5 (3H, m); 7.62 (0
,5H,s); 7.68 (0,5H,s); 7.7
1 (0,5H,s); 7.77 (0,5H,s).

200 mg of this amide compound was dissolved in ethyl acetate,
After adding 50 mg of oxalic acid and cooling, the precipitated crystals were collected by filtration. 225 mg of oxalate with a melting point of 140°C (decomposition)
I got it.

206 mg (0,9
9 mmol) was added. Post-treatment was carried out in the same manner as in Example 27, and the obtained crude product was purified by column chromatography using silica gel. Benzene-ethyl acetate (
Elution with a 3:1) mixed solvent gave 245 mg of the target compound as an oil.

Infrared absorption spectrum v-a-(CHCL3) cm-1
: 1645°NMR spectrum (CDC13) δpp
m: 1.01 (3H, d, J=6 Hz); 4.5
5 (2H, s); 4.9-5.5 (3H, m); 6
．． 6-7.6 (3H,!+1); 7.6-7.9 (6H
, m).

220 mg of this amide compound was dissolved in ethyl acetate,
After adding 50 mg of oxalic acid and cooling, the precipitated crystals were collected by filtration. Oxalate 242 m with melting point 176-179℃
I got g.

(4R”, 5Ra-5-(2,4-difluorophenyl)-4-methyl-5-[(IH-1,2,4-triazol-1-yl)methyl]oxazolidine 185 rn
g (0.66 mmol) was dissolved in 2.5 ml of pyridine and stirred at 0°C.
t)-2-(2,4-dichlorophenyl)-1-(IH
-1.

2.4-triazol-1-yl)-2,3-butanediol [Synthesized by the method described in the 8th Medicinal Chemistry Symposium Abstracts (1986), page 9] 164 mg (0.54 mmol) was suspended in 4 ml of pyridine, and 118 mg (0.67 mmol) of 4-chlorobenzoyl chloride was added under water cooling.
The mixture was removed from the water bath and stirred at room temperature for 40 minutes. During this time, the raw materials reacted and melted.

After evaporating the solvent under reduced pressure, the residue was distributed between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried, and the solvent was distilled off. The residue was recrystallized from a mixed solvent of ethyl #acid and hexane to obtain 207 mg of the target compound having a melting point of 214-215°C.

Infrared absorption spectrum v ,, (CHCL3) cm
-1:3400, 1715.1502.1502.12
70°NMR spectrum (CDC13) δppm:
1.13 (3H, d, J=7 Hz); 4.54 (I
H, d, J-15Hz); 5.51 (IH, d, J=
15 Hz); 6.27 (LH, q, J=7 Hz);
7.0-8.2 (9H, m)-Daishunso 2R"3R" -2-24-dichlorophenyl-1-
IH-124, rAzole-1-3-4-rFluoro As described in Reference Example 14, unpurified (2R1,3R8
)-z・-(z,4-dichlorophenyl)-3-mercapto-1-(If(-1,2,4-triazole-1-
2.67 g (5, Ommo
1) was dissolved in 26 ml of pyridine and stirred under water cooling.
4-(trifluoromethyl)benzoyl chloride 1.4
0 g (6.7 mmol) was added. After stirring at the same temperature for 30 minutes and then at room temperature for 50 minutes, the reaction solution was cooled on ice again, 2.5 ml of methanol was added, and the mixture was stirred for 10 minutes.

The solvent was distilled off from the reaction solution under reduced pressure, diluted sodium hydrogen carbonate water was added to the residue, and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated brine, dried, and the solvent was distilled off.

The crystalline residue obtained was recrystallized from methanol to give 0.85 g of crystals with a melting point of 161-164°C.

Infrared absorption spectrum v,, a*(CHCL3) c+n
-1:3350, 1650° NMR spectrum (CDC13) δppm: 1.18
(3H, d; J=7 Hz); 4.67 (IH, d,
J = 14 Hz); 5.15 (IH, q, J = 7 H
z); 5.4 (LH, br, ); 5.60 (IH, d
, J=14 Hz); 7.12 (IH, dd.

J=8.2 Hz); 7.40(IH, d, J=2
Hz); 7.58 (IH, d.

J=8 Hz); 7.78(2H,d, J=8H
z); 7,87 (2H, s); 8.2 (2H, d,
J4 Hz).

Unpurified (2R", 3R")-2 described in Reference Example 17
-(2,4-difluorophenyl)-3-mercapto-
1-(IH-1,2゜4-triazol-1-yl)-
180 mg (0.37 m
mol) was dissolved in 2 ml of pyridine, and while stirring under water cooling, 91 mg' of 4-chlorobenzoyl chloride (0
, 52 mmol) was added. After stirring at the same temperature for 30 minutes and then at room temperature for 30 minutes, it was cooled with water again, and methanol was added.
．． 2 ml was added and stirred for 10 minutes. The solvent was distilled off from the reaction solution under reduced pressure, diluted sodium hydrogen carbonate water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was distilled off.

The resulting crystalline residue was dissolved in ether-hexane (1:1).
Recrystallization from a mixed solvent gave 79 mg of the target compound as crystals having a melting point of 139-140°C.

Infrared absorption spectrum 'l' mhx (KBr) cm
-1:3400, 1567°NMR spectrum (CDC13) δppm: 1.19
(3H, d, J=7 Hz); 4.60 (IH, br
, q, J=7 Hz); 4.69(IH, d, J=1
5 Hz); 5.04 (LH, d, J=15 Hz);
5.20 (IH, d, J=1.5 Hz); 6.6
-7.1 (2H, m); 7,2-7.7 (LH, m)
; 7.47 (2H, d, J=9Hz); 7.80
(2H, s); 8.01 (2H, d, J=9 H
z).

In the same manner as in Example 32, (2R", 3R")-2-(
2,4-difluorophenyl)-3-mercapto-1-
(IH-1,2,4-triazol-1-yl)-2-
The following compounds were synthesized by reacting butanol with various substituted benzoyl chlorides or substituted cinnamoyl chlorides.

However, ■ 2R'3R" -2-24-Sif Olof Nil-1
-LH-14-T C-1-i fluoro Melting point: 118.5-120°C.

Lunaau 2-bunor Melting point: 143-144°C.

Melting point: 110-113°C.

! Fluoromethylbenzo luna-2-butonol Melting point: 113-114.5°C.

24-I Azole-1-ru-3-4-chlorocinnamo(2R",3R")-3-amino-2-(2,4-difluorophenyl)-1-(LH-1,2,4-triazole-1 -yl)-2-butanol 200 mg (0,
75 mmol) was suspended in 2 ml of pyridine, and 4-(
trifluoromethyl) cinnamoyl chloride 242 m
g (1.12 mmol) was added thereto, and the mixture was heated under reflux for 30 minutes. After cooling, 0.2 ml of methanol was added, and the mixture was stirred for 15 minutes. The solvent was distilled off from the reaction solution under reduced pressure, diluted sodium bicarbonate water was added, and the mixture was extracted with ethyl acetate.

The residue obtained by distilling off the solvent was subjected to column chromatography using silica gel, and the crystalline product obtained by eluting with a mixed solvent of ethyl acetate and hexane (5:1) was purified using ethyl acetate. - Recrystallization from hexane gave 260 mg of the target compound having a melting point of 166-167°C.

Infrared absorption spectrum v,,ax(KBr) cm-1
:3300, 1760.1617°NMR spectrum (CDC13) δppm: 1.00
(3H, d, J=7 Hz); 4.51 (LH, d,
J=14 Hz); 5.0 (IH, m); 5.08
(IH, d, J=14 Hz); 5.39 (IH
, br, s); 6.64 (LH, d, J=16
Hz); 6.4-7.1 (3H, m); 7.2-7.
4 (IH, m); 7.65 (4H, s); 7°77
(LH, d, J-16Hz); 7.84 (2H, s)
.

Similar to Example 36, (2R", 3R")-3-
7mi/-2-(2,4-difluorophenyl)-1-
(IH-1,2,4-)-riazol-1-yl)-2
The following compound was synthesized by reacting -butanol with 3-(trifluoromethyl)cinnamoyl chloride or 4-chlorocinnamoyl chloride.

LH-124-triazol-1-yl-2-butanol Melting point: 171°C.

Melting point: 204-206℃.

(2R”, 3R”)-2-(2,4
-difluorophenyl)-3-(methylamino)-1-
(I)(-1,2,4-triazol-1-yl)-2
- Dissolve 428 mg (1,50 mmol) of butanol in 8 ml of pyridine, and dissolve 450 mg (2,16 mmol) of 4-(1-trifluoromethyl)benzoyl chloride.
) and stirred at room temperature for 20 hours. Cool the reaction solution on ice,
0.5 ml of methanol was added and stirred for 15 minutes. The solvent was distilled off from the reaction solution under reduced pressure, and dilute aqueous sodium hydrogen carbonate was added to the residue, followed by extraction with ethyl acetate. After drying the organic layer, the solvent was distilled off, and the resulting residue was recrystallized from ether to obtain the target compound 380 having a melting point of 144-146°C.
mg was obtained.

Infrared absorption spectrum v,, a, (KBr) cm-1:
3110, 1638.1610° In the same manner as in Example 39, (2R', 3R''')-4-
(Methylamino)-2-(2,4-difluorophenyl)-1-(LH-1,2゜4-triazol-1-yl)-2-butanol and 2-fluoro-4-(trifluoromethyl)benzoyl The following compound was synthesized by reacting with chloride or 4-chlorocinnamoyl chloride.

Melting point: 157-159°C.

In the same manner as in Example 36, (2R", 3R")-3
-Amino-2-(2,4-difluorophenyl)-1-
(IH-1,2,4-triazol-1-yl)-2-
Butanol, or (2R'', 3R'')-3-amino-2-(4-chlorophenyl)-1-(LH-1,Z,
The compounds shown below were synthesized by reacting 4-triazol-1-yl)-2-butanol with various substituted benzoyl chlorides or 5-chloro-2-thenoyl chloride.

E-Sho Fk's Mata Sunie Fluoro 4-t 1 Fluoromethylbenzoylamine Melting point: 191-193°C.

Knoll Melting point: 176-177°C.

Melting point: 204-207°C.

Example 44 Melting point: 260°C.

Melting point: 219-220°C.

1-yl-2-butanol (4R", SR")-5-(2,4-difluorophenyl)-4-methyl-5-[(IH-1,2,4-triazol-1-yl)methyl ]Oxazolidine 197 m
Dissolve g (0.70 mmol) in 2 ml of pyridine,
4-chlorocinnamoyl chloride 202 mg (1,06
mmol) was added. After stirring at room temperature for 1 hour, 0.5 ml of methanol was added and stirred for 10 minutes.

Pyridine was distilled off under reduced pressure, dilute aqueous sodium bicarbonate was added to the resulting residue, and the mixture was extracted with ethyl acetate. The crude product was subjected to chromatography using silica gel and eluted with a mixed solvent of ethyl acetate and hexane (5:1) to obtain 250 mg of the target compound as an oil.

Infrared absorption spectrum ν,. (CHCla) cm-1:
1645.1615°NMR spectrum (CDC13) δppm: 1,01
(3H, d, J=7 Hz); 4.55 (2H, s)
; 4.75 (IH, br, ); 5.33 (LH, b
r, d, J=5Hz); 5.56 (IH, d, J=5
Hz); 6.2-8.1 (IIH, m).

After 250 mg of this amide compound and 51 mg of oxalic acid were dissolved in ethyl acetate, hexane was added for crystallization to obtain 238 mg of oxalate having a melting point of 161-165°C.

(4R", 5R")-5-(2,4-difluorophenyl)-4-methyl-5-[(IH-1,2,4-triazol-1-yl)methyl]oxazolidine 207 m
Dissolve g (0.74 mmol) in 2 ml of pyridine and add 0.
While stirring at °C, 260 mg (1.11 mmol) of 4-(trifluoromethyl)cinnamoyl chloride was added. Post-treatment was carried out in the same manner as in Example 48, and the obtained crude product was purified by column chromatography using silica gel. Elution was performed with a mixed solvent of ethyl acetate and benzene (5:1), and the obtained crystalline product was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 206 mg of the target compound having a melting point of 168-169°C.

Infrared absorption spectrum v t-ax (CHCL3) c
m-1: 1655.1618° NMR spectrum (CDC13) δppm: 1.03
(3H, d, J=7 Hz); 4.59 (2H, s)
; 4.8 (IH, br, ); 5.34 (IH, br
, d, J=5Hz); 5.58(IH, d, J=5
Hz); 6.3-8.0 (IIH, m).

Example 2 Same as Example 48, (4R", 5R")-5-(
2,4-difluorophenyl)-4-methyl-5-[(
IH-1,2,4-triazol-1-yl)methyl]
Oxazolidine 119 mg (0.43 mmol) and 3
-(trifluoromethyl)cinnamoyl chloride 150
By reaction with mg (0.64 mmol), melting point 16
100 mg of the target compound having a temperature of 0-162°C was obtained.

Infrared absorption spectrum v ,, (CHCL3) cm
-1:1555.1616°NMR spectrum (CDC1a) δppm: 1.04
(3H, d, J=7 Hz); 4.61 (2H, s)
; 4.8 (IH, br, ); 5.36 (IH, br
, d, J=5Hz); 5.60(IH, d, J=5
Hz); 6. '3-8.0 (IIH, m).

Ward 2 (4R", 5R")-5-(4-chlorophenyl)-4
-Methyl-5-[(IH-1,2,4-triazole-
1-yl)methyl]oxazolidine 321 mg (1,
21 mmol) was dissolved in 3 ml of pyridine, and while stirring at 0°C, 427 mg (1.82 mmol) of 4-(trifluoromethyl)cinnamoyl chloride was added. After stirring at room temperature for 1 hour, 0.5 ml of methanol was added, and 1
Stirred for 0 minutes. Dilute aqueous sodium hydrogen carbonate was added to the residue obtained by distilling off pyridine under reduced pressure, and the mixture was extracted with ethyl acetate. The crude product was subjected to chromatography using silica gel and eluted with a mixed solvent of ethyl acetate-hexane (4:1) to obtain a crystalline product. Recrystallization was performed from a mixed solvent of ethyl acetate and hexane to obtain 310 mg of the target compound having a melting point of 180-181°C.

Infrared absorption spectrum y, , (C) fc13) cn
i-1:165], 1611° NMR spectrum (CDC13) δppm: 0.91
(3H, d, J=6.5Hz); 4.53 (2H, s
); 4.88 (IH, q, J=6.5 Hz); 5
．． 37 (18, br, d, J=5 Hz); 5.57
(IH, d, J=5 Hz); 6.6-8.0 (12
H, m).

After 230 mg of this amide compound and 45 mg of oxalic acid were dissolved in ethyl acetate, hexane was added for crystallization to obtain 237 mg of oxalate having a melting point of 175-177°C.

Similar to Example 48, (4R”, 5Rx)-5-(
4-ri.

lophenyl)-4-methyl-5-[(IH-1,2,4
-triazol-1-yl)methyl]oxazolidine 4
30 mg (1,61 mmol) and 2-fluoro-4-
(Trifluoromethyl)benzoyl chloride 547 m
By reaction with g (2.42 mmol), the target compound 2
Obtained 33 mg as an oil.

NMR spectrum (CDC13) δppm: 0.7
6.1.00 (2:3,3H.

d, J=7 Hz); 4.3 (IH, m); 4.5
9 (2H, s); 4.8-5.9 (2H.

m); 6.8-7.9 (9H, m).

In the same manner as in Example 48, (4R", 5R")-5-(
2,4-difluorophenyl)-4-methyl-5-[(
LH-1,2,4-triazol-1-yl)methyl]
By reacting 200 mg (0,714 mmol) of oxazolidine with 242 mg (1,07 mmol) of 2-fluoro-4-(trifluoromethyl)benzoyl chloride, 193 mg of the target compound was obtained as an oil.

Infrared absorption spectrum v ,,, (CHCL3) c
m-1: 1650.1620° NMR spectrum (CDC1i) δppm: 0.8
4,1.10 (2:3,3H.

d, J=7 Hz); 4,3(LH,m); 4.6
1,4.67(3:2,2H,s);4.9-5.9(
2H, m); 6.6-7.9 (8H, m).

After 193 mg of this amide compound and 37 mg of oxalic acid were dissolved in ethyl acetate, hexane was added to crystallize the solution to obtain 188 mg of oxalate having a melting point of 167-168°C.

2R”, 3R-2-(2,4-dichlorophenyl)
-1-(IH-1゜2.4-triazol-1-yl)
-3-(methanesulfonyloxy)-2-butanol 1
Dissolve 1.0 g (29 mn5 ol) in 160 ml of dimethylformamide and add 9.69 g of sodium azide.
(149 timol) and ammonium chloride 1.55 g
(29 mmol) was added, and the mixture was heated and stirred at 115° C. for 15 hours.

The solvent was distilled off from the reaction solution under reduced pressure, and 70% of benzene was added to the residue.
0 ml was added and washed with water. After drying, the solvent was distilled off and the resulting crystalline residue was recrystallized from ethyl ether to obtain the target compound 6.42 having a melting point of 113-114°C.

In the same manner as in Example 54, (2R,3R)-2-(2,
4-dichlorophenyl)-1-(IH-1,2,4-triazol-1-yl)-3-(methanesulfonyloxy)-2-butanol [(-) monoisomer] 2.36 g
1.42 g of the target compound was obtained.

Melting point: 154-6°C.

Specific optical rotation [α] o25-I00' (c=0.89, C
HCl3) (2R", 3R)-2-(4-chlorophenyl)-1-(IH-1,2,4-triazol-1-yl)-3-(methanesulfonyloxy)-2-butanol 2.05 g (5.94 mmol) was dissolved in 30 ml of dimethylformazide, and 1.95 ml of sodium azide was added.
g (30 mn+ol) and ammonium chloride 380 m
g (7.13 mmol) was added thereto, and the mixture was heated and stirred at 100° C. for 2 hours.

The solvent was distilled off from the reaction solution under reduced pressure, and benzene was added to the residue, which was then washed with water. After drying, the solvent was distilled off and the resulting residue was subjected to column chromatography using silica gel and eluted with a mixed solvent of ethyl acetate and hexane (3:1) to obtain 1.52 g of the target compound as an oil. Ta. This was recrystallized from a mixed solvent of benzene and hexane and had a melting point of 103.
A pure product with a temperature of 5-104°C was obtained.

NMR spectrum (CDC13) δppm: 1.1
1 (3H, d, J=7 Hz); 3.6 & (IH, q
, J=7 Hz); 4.50 (IH, d, J=14
Hz); 4.71 (IH, d, J=14 Hz); 5
．． 10 (IH, s); 7-35 (4Hys); 7.7
2 (IH, s); 7.74 (IH, s).

Dissolve this azide alcohol in ethyl acetate and add 1 oxalic acid.
Oxalate crystals were obtained by adding molar equivalents.

Melting point: 153-155°C.

(2R”,3S”)-2-(2,4-difluoro:phenyl)-5-(methanesulfonyloxy)-3-methyl-1-(1)i-1,2,4-triazole-1- yl)-2-pentanol 38 mg (0,101 mmol
e) was dissolved in 1 ml of dimethylformamide, 33 mg (0.51 mmole) of sodium azide was added, and the mixture was stirred at 100°C for 2 hours. Ethyl acetate was added cold, and the mixture was washed with saturated brine. The oil obtained by distilling off the solvent was subjected to column chromatography using silica gel,
Elution was performed with a mixed solvent of ethyl acetate-hexane (7:1) to obtain the target compound 13 tag as an oil.

Infrared absorption spectrum v, a, (CHCh) am-1:
3420, 2100° NMR spectrum (CDC13) δppm: 0,77
(3H, dd, J=6.5°0.5 Hz); 1.5
-2.5 (3H, m); 3.2-3.7 (2H, m)
; 4.53 (IH, d, J=14 Hz); 4.8
5 (1, H, s); 4.97 (IH, dd, J=14
゜I Hz); 6.5-7.0 (2H, m); 7.
2-7.7 (IH, fl); 7.79 (IH.

s); 7.87 (IH, s) - 13 mg of this azide alcohol was dissolved in ethyl acetate, 4 mg of oxalic acid was added, and then hexane was added to precipitate crystals. Oxalate 13 with melting point 140-144℃
I got it.

2R"3S"-4-azido-2-24-difluorophenyl-3--1-IH-124-1C-2-P(2R",3S")-2-(2,4 -difluorophenyl)-4-(methanesulfonyloxy)-3-methyl-
Dissolve 168 mg (0.45 mmole) of 1-(IH-1,2,4-triazole)-2-pentanol in 5 ml of dimethylformamide, and dissolve 11 ml of sodium azide.
6 mg (1,79 nuoole) was added and stirred at 100°C for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with saturated brine. After drying, ethyl acetate was distilled off, and the resulting oil was subjected to column chromatography using silica gel.
Elution was carried out with a hexane (2:1) mixed solvent, and one of the target compounds, isomer 1 (135 mg), was converted into crystals (washed with hexane, melting point 99-100°C), and the other isomer 2 (70!E1 g) ) (further purified by preparative thin layer chromatography [developing solvent: #acid-ethylhexane (1:1)]) was obtained as an oil.

[Isomer l] Infrared absorption spectrum ν,, 1X (CHCL3) cm-
1:3420, 2100° NMR spectrum (CDC13) δppm: 0,
72 (3H, dd, J=7.IHz); 1.34 (3
H, d, J = 6.5 Hz); 2.24 (IH, br
, quint.

J=7 Hz); 3.98(LH, quint, J=
6.5 Hz); 4.69 (IH, d.

J = 14 Hz); 4.97 (IH, d, J = 1.5
Hz); 5.00 (LH, dd, J=14, IH
z); 6.5-7.0 (2H, m); 7.32 (I
H, td, J = 9.7 Hz); 7.77 (IH, s
); 7.81 (IH, s).

[Isomer 2] Infrared absorption spectrum v,, (CHC1'3) c! !
1-1: 3420, 2100° NMR spectrum (CDC13) δppm: 0.84
(3H, dd, J=6.5, 0.5 Hz); 1.3
7 (3H, d, J = 6.5 Hz); 2.23 (IH
.

qd, J=6.5.2 Hz); 4.13(LH, q
d, J = 6.5, 2 Hz); , 4.53 (IH, d
, J=14 Hz); 4.73 (IH, s); 5.
00 (IH, dd, J=14°I Hz); 6.5-
7.0 (2H, m); 7.2-7.7 (IH, m);
7.71 (IH.

s); 8.01 (IH, s).

Dissolve 62 mg of this isomer in ethyl acetate and add 17 m of oxalic acid.
After adding 50 g, hexane was added to precipitate crystals, which were collected by filtration to obtain 46 mg of oxalate having a melting point of 130°C.

(2R", 3R")-2-(2,4-difluorophenyl)-3-methyl-1-(IH-1,2,4-triazol-1-yl)-2,4-bentanediol (melting point 1
45-146°C single product) 56 mg (0,19 mmo
le) was dissolved in 1 ml of methylene chloride.

Under water-cooling and stirring, add 25 mg of triethylamine (0.25 m
! 1Iole) and methanesulfonyl chloride 27 mg
(0.24 mmole) was added. After 15 minutes, aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate.

After washing with saturated saline, the solvent was distilled off, and 711 II g of the obtained oil was dissolved in 2 ml of dimethylformamide, and 49 ngg (0.76 mmol) of sodium azide was dissolved.
e) was added and stirred at 100°C for 1 hour. Ethyl acetate was added to the reaction mixture cold, and the mixture was washed with saturated brine. The oily substance obtained by distilling off the solvent was subjected to column chromatography using silica gel, and ethyl acetate-hexane (2:1) was added.
Elution was performed with a mixed solvent to obtain 25 mg of the crystalline target compound. Recrystallize from a benzene-hexane mixed solvent,
A pure product with dual melting points (82-84°C and 91-92°C) was obtained.

Infrared absorption spectrum v,,, (CHCL3) cn+
-1:3425, 2110°N? fR spectrum (CDCb) δPPM: 1.16
(3H, d, J=6.5Hz); 1.20 (3H, d
d, J: 6.5, 0.5 Hz); 2.4 (IH, m
); 3.27 (IH, qd, J=6.5, 3 Hz);
4.49 (18, d, J=14 Hz); 4.81 (
IH, dd, J=14. I Hz); 4.81 (LH
, d, J=2 Hz); 6.5-7.0 (2H, m);
7.1-7.6 (IH, DI); 7.74 (2H,
s).

(2R", 3S")-2-(2,4-dichlorophenyl)-4-(methanesulfonyloxy)-3-methyl-1
-(IH-1,2,4-triazol-1-yl)-2
- 180 mg (0.46 mmole) of butanol,
Dissolve in 3 ml of dimethylformamide.

119 mg (1,82 mm) of sodium azide was added and heated at 100° C. for 3 hours. The mixture was cooled down, ethyl acetate was added, and the mixture was washed with saturated brine. The oil obtained by distilling off the solvent was subjected to column chromatography using silica gel and eluted with a mixed solvent of ethyl acetate and hexane (2:I) to obtain crystalline target compound 108 rag.

Recrystallization was performed from a benzene-hexane mixed solvent to obtain a pure product having a melting point of 116-117°C.

Infrared absorption spectrum v m a X (CHCL3)
cm-1: 3430, 2100° NMR spectrum (CDC13) δppm: 0.71
(3H, d, J=7 Hz); 2.6-3.2 (IH
, El); 3.2-4.1 (2H, m); 4.59
(If (, d, J = 14 Hz); 5.00 (IH,
s); 5.50 (IH, d, J=14 Hz); 7
．． 05 (IH2dd, J=8,2 Hz); 7-28
(IH2dpJ=2 Hz); 7-43 (IH2d,
J=8 Hz); 7.74 (IH, s); 7.80
(IH, s).

1-IH-124-triazol-1-yl-4-4
-Trifluorevezo 2-buton (2R”, 3S”)-4-amino-2-(2,4-dichlorophenyl)-3-methyl-1-(IH-1,2,4
-triazol-1-yl)-2-butanol 46 m
g (0,146 mmole) was dissolved in 1 ml of pyridine, and while stirring at 0°C, 4-(trifluoromethyl)
Benzoyl chloride 37 mg (0,176 mmole
) was added. After 30 minutes, cooled sodium hydrogen oxide solution was added, and the mixture was extracted with ethyl acetate. After drying the extract, the solvent was distilled off and the obtained oil was subjected to column chromatography using silica gel, and ethyl acetate-hexane (2:1
) Elution with a mixed solvent gave 53 mg of the target compound as an oil.

Infrared absorption spectrum y saw (CHCL3) cm
-1: .

3350, 1665.1525°NMR spectrum (CDC13) δppm: 0.78
(3H, d, J=7 Hz); 2.7-3.2 (LH
, m); 3.3-4.4 (2H, m); 4.69 (
LH, d, J = 14 Hz); 5.64 (lLd, J
= 14 Hz); 7.11 (IH, dd, J = 8.2
Hz); 7.31 (IH, d, J=2 Hz); 7
．． 53 (IH, d, J = 8 Hz); 7.79 (LH,
s); 7.92 (IH, s); 7.6-8.1 (4
H, m).

After dissolving 53 mg of this amide compound in ethyl acetate and adding 10 mg of oxalic acid, hexane was added to precipitate it.
58 mg of oxalate having a melting point of 81° C. (decomposed) was obtained.

In the same manner as in Example 61, (2R'',3S'')-4-amino-2-(2,4-dichlorophenyl)-3-methyl-1-(IH-1,2,4-triazole-nyyl)
-2-Butanol 46 mg (0,146 mmole)
and 30 mg of 4-chlorocinnamoyl chloride (0,1
61 mmole) was reacted in pyridine to obtain 33 mg of the target compound as an oil.

33 mg of this amide compound was dissolved in ethyl acetate, 6 mg of oxalic acid was added thereto, hexane was added, and the precipitated crystals were collected by filtration to obtain 33 mg of oxalate having a melting point of 190-191°C.

Calcium (2R,3S)-2-(2,4-difluorophenyl)
-3-methyl-2-((IH-1,2,4-triazol-1-yl)methyl]oxirane 30 g (119 m
mole) in 400 nil of dimethylformamide, and 23.5 g of sodium azide (360 mn+o
le) and 10.6 g (195 mmo
le) was added thereto, and the mixture was stirred at 105°C for 4 hours. After cooling, benzene was added to the reaction mixture, which was then washed with water and saturated brine, dried, and then the solvent was distilled off. 32.7 g of crystalline residue obtained
was recrystallized from benzene-hexane to give a melting point of 139.
-140°C 25.8 g of target compound (yield '7
3%).

Specific optical rotation [α] D25-33° (C=1.12, CHC
l3).

Infrared absorption spectrum y,,, (KBr) CEI-1
:3195(br,), 2120.2090°NMR
Spectrum (CDC13) δppm: 1.16 (3H
, d, J=6.5Hz); 3.7 & (LH, q, J=
6.5 Hz); 4.78 (2H, s); 4.95
(IH, s); 6.5-7.0 (2H, m); 7.
2-7.6 (IH, !l); 7.76 (IH, s);
7.82 (IH, s).

(2R,3R)-3-Amino-2-(2,4-difluorophenyl)-1-(II(-1,2,4-triazol-1-yl)-2-butanol 1.20 g (4, 4
7 mmole) in 13 ml of pyridine and heated to 0°C.
4-cyanobenzoyl chloride 890 while stirring at
mg (5.37 mmole) was added. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure, aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was distilled off. The resulting oil was subjected to column chromatography using silica gel and eluted with 35-45% ethyl acetate-benzene to obtain 1.70 g of crystalline material. Recrystallization from a mixed solvent of ethyl acetate and hexane resulted in a melting point of 156-157°C.
1.33 g of the target compound with a yield of 78% was obtained.

Specific optical rotation [α] o25-122° (C=1.01, CH
Cl3).

Infrared absorption spectrum y,, 1x (KBr) cm-1
:3450, 2230.1659°NMR spectrum (CDC13) δPPm: 1.0
2 (3H, d, J=6.5Hz); 4.45 (LH,
d, J44 Hz); 5,08 (IH, d, J=14
Hz); 5.40 (IH, d, J = 1.5 Hz);
6.6-7.13 (2H, am); 7.18-7.
6 (2H, m); 7.78 (2H, d, J-8Hz)
; 7.83 (LH, s); 7.87 (LH, s);
8.02 (2H, d, J=8 Hz), (2R, 3S)
-2-(4-chlorophenyl)-3-methyl-2-[(
LH-I, 4.56 g (19, Oau++ol
e) in 50 ml of dimethylformamide, 3.71 g (57.1 mmole) of sodium azide and 1.52 g (28.4 n+mole) of ammonium chloride.
was added, and the mixture was heated and stirred at 110°C for 2 hours. Cool down, add benzene to the reaction solution, and wash sequentially with water and saturated saline.

After drying, the solvent was distilled off. The residue was subjected to column chromatography using silica gel and eluted with a mixed solvent of ethyl acetate and hexane (3:1) to obtain 4.0 g of a crystalline product. Recrystallization was performed from a benzene-hexane mixed solvent to obtain 3.27 g (yield: 59%) of a prismatic target compound having a melting point of 121-122.5°C.

Specific optical rotation [α]D”-71.3° (C=0.80, CH
Cl, 3).

Infrared absorption spectrum -y+-ax (KBr) cm-
1:3200(br,), 2120.2080゜NM
R spectrum (CDC13) δppm: 1.15 (
3 skins d, J = 6.5Hz); 3.65 (1 skin q, J =
6.5 Hz); 4.48 (IH, d, J=i5H
z); 4.6 (IH, br, ); 4.74 (IH,
d, J45 Hz); 7.23 (41(,s); 7
．． 68 (LH, s); 7.80 (LH, s).

(2R,3R)-3-amino-2-(4-chlorophecol)-1-(LH-1,2,4-triazole-1
-2-butanol 1.07 g (4,01 mm
ole) was dissolved in pyridine 12n+1, and 1.00 g (4,8I n+mole) of 4-(trifluoromethyl)benzoyl chloride was added while stirring at 0°C.

After stirring at the same temperature for 30 minutes, the reaction solution was mixed with 0.00 methanol.
5 ml was added and stirred for 10 minutes. The solvent was distilled off under reduced pressure, and cooled sodium hydrogen oxide solution was added to the residue.

Extracted with ethyl acetate. Wash the organic layer with saturated saline,
After drying, the solvent was distilled off. The obtained crystalline residue was recrystallized from a benzene-hexane mixed solvent to reduce the melting point to Zoo-
1.40 g of crystals (yield 79%) with a temperature of 201°C were obtained.

Specific optical rotation [α]n” (39° (C=0.49, CHC
l3).

Infrared absorption spectrum y,, aX(KBr) cm-1
:3370, 1647.1528°NMR spectrum (CDC, b) δppm: 1.0
4 (3H, d, J=6.5Hz); 4.47 (IH,
d, J=14 Hz); 4.72(IH, d, J=1
4 Hz); 4.6 (IH, m); 5.30 (LH
, br, s); 6.86 (IH, br, d, J=9
Hz); 7.30 (4H, s); 7.69 (IH
, s); 7.85 (IH, s); 7.75 (2H, b
r, d); 8.02 (2H, br, d).

In the same manner as in Example 64, (2R,3R)-3-amino-2-(4-chlorophenyl)-1-(IH-1,2,
4-triazol-1-yl)-2-butanol 1.1
8 g (4,42 mmole) and 2-fluoro-4-(
1.20 g of trifluoromethyl)benzoyl chloride
(5.31 mmole) was reacted in pyridine.

The obtained oily crude product was purified by silica gel column chromatography to obtain the target compound 1.76 g (yield 87.
%) was obtained as an oil.

Specific optical rotation [α] o25-107° (cm0.54, CH
Cl3).

Infrared absorption spectrum y, JIX(CH(,13) cn
-1:3440, 1660° NMR spectrum (CDCh) δPPm: 1.03 (
3H, d, J = 6.5Hz); 4.5-5.5 (4H
, m); 7.30 (4H, s); 7.0-7.8 (
3H, m); 7.69 (IH, s); 7.84 (I
H, s); 8.25 (IH, br, t, J=8Hz)
.

Dissolve 1.30 g of this amide compound in ethyl acetate,
Hydrochloride 1 having a melting point of 157-160°C was crystallized by adding 0.7 n+1 of 4N hydrogen chloride-dioxane solution.
．． 16 g was obtained.

Elemental analysis value: Calculated value as C2oH17N402CIF4・HCl: C, 48,70; H, 3,68; N
, 11.36° Actual value: C, 49,07; H, 3,
97; N, 11.56° specific optical rotation [α] o25-79
°(C=0.62, CH30H).

The mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. After drying,
The crystalline residue obtained by distilling off the solvent was recrystallized from ethyl acetate to obtain 270 mg of the target compound having a melting point of 204-205°C.

Infrared absorption spectrum ν, a, (KBr) CDl-1
:3450, 3300.1655.1620°NMR spectrum (CD30D) δppm=1.06 (3H
, d, J=6.5Hz); 4.4-5.3(5H, m
); 6.6-7.8 (8H, o+); 8.1 (IH
,br.

).

55% sodium hydride 130 mg (2,99 mmo
After washing le) with hexane, it was suspended in 8 ml of dimethyl sulfoxide, and (2R", 3R") was added under ice cooling.
-3-7mi/-2-(2゜4-difluorophenyl)-
1-(IH-1,2,4-triazol-1-yl)-
400 mg (1,49 mmole) of 2-butanol was added and stirred for 15 minutes. Phthalide 600 nag (
4.48 mmoie) was added thereto, and the mixture was stirred at 60°C for 1 hour. Reaction solution (2R", 3R")-3-[2-(hydroxymethyl)benzoylamino]-2-(2,4-difluorophenyl)-1-(IH-1゜2.4-triazol-1-yl )-2-butanol 30 mg (0,07
5 mmole) in methylene chloride 1 n+1,
While stirring at room temperature, 0.5 ml of pyridine, 11 mg (0.11 mmole) of triethylamine, 1.2 mg (0.11 auaole) of acetic anhydride and 1 nag of 4-(dimethylamino)pyridine were added. After 30 minutes, the reaction solution was diluted with ethyl acetate and washed with saturated saline,
The solvent was distilled off to obtain a crystalline residue. Recrystallization was performed from ethyl acetate-hexane to obtain 25 mg of the target compound having a melting point of 162-163°C.

NMR spectrum (CDC13) δppm21.0
4 (3H, d, J=6.5Hz); 2.07 (3H,
s); 4.56 (IH, d, J=14.5 Hz);
5.11 (IH, d, J=14.5 Hz); 5.
34 (2H, s); 4.7-5.5 (2H, m); 6
．． 5-7.7 (8H, m); -7,78 (IH, s);
7.84 (IH, s).

(2R”, 3R”)-3-7mi/-2-(2,4-
Schiff/L/O07 x Nil)-1-(IH-1,2,
4-triazol-1-yl)-2-butanol 150
mg (0.56 mmole), 124 mg (0.68 Illmole) of 4-chlorophthalic anhydride, and 5 vag (0.05 tnmole) of triethylamine were dissolved in 4 ml of toluene and packed with molecular sieve 4A while heating under reflux for 3 hours. The water distilled out in the Digi-Stark tube was removed.

After the reaction was completed, the reaction solution was partitioned between ethyl acetate and cooled aqueous sodium hydrogen oxide, the organic layer was dried, and the solvent was distilled off. The residue was subjected to preparative silica gel thin layer chromatography.
Development with ethyl acetate gave the target compound 238 rrrg as a colorless foam.

Infrared absorption spectrum ν,, aX(CHCla) cm-
1:3480, 1770.1705.1615.150
0.1350.1270°1130, 1040.960
．． 850°NMR spectrum (CDC13) δpp
m: 1.35 (3H, d, J=7 Hz); 4.
40 (IH, d, J2 15 Hz); 4.90 (
IH, d, J45 Hz); 5.16 (IH, q, J
=7 Hz); 5.3(LH,br,); 6.6-
7.1 (2H, El); 7.54 (IH, s); 7
．． 4-8.1 (4H, m); 8.13 (IH, s).

127 mg of this compound was dissolved in ether and about 20 mg of fuming nitric acid was added to obtain 108 hag of nitrate having a melting point of 143-150°C.

2R"3R" -2-24-Sif Olof Ni -3
-1-(2R", 3R")-3-[2-(hydroxymethyl)benzoylamino]-2-(2,4-difluorophenyl)-1-(IH-1゜2.4-triazole-1- yl)-2-butanol 140 mg (0,35 m
mole) was dissolved in 3 ml of tetrahydrofuran, and 182 rng (0
, 70 mmole) and 121 mg (0.70 tonmole) of azodicarboxylic acid diethyl ester were added.

After 10 minutes, water was added and extracted with ethyl acetate. After drying, the solvent was distilled off and the resulting oil was subjected to column chromatography using silica gel, eluting with a benzene-ethyl acetate (1:3) mixed solvent to obtain 200 mg of crude product.
I got it. Preparative thin layer chromatography of silica gel [
Developing solvent: chloroform: ethyl acetate: ethanol = 1
The crude crystals obtained by repeating [0:10:1] twice were recrystallized from ethyl acetate-hexane, and the melting point was 171-173.
The target compound 62.degree. C. was obtained.

Infrared absorption spectrum ν,,y(CHCL3) cm
-1:3400, 1673° NMR spectrum (CDC13) δppm: 1.18
(3H, d, J=6.5Hz); 4.27 (IH, d
, J=14.5 Hz); 4.56 (IH, d, J=
18 Hz); 4.99 (LH, q, J=18 Hz
); 5.04 (IH, q, J = 6.5 Hz); 5.
17 (IH, dd, J=14.5, 0.5 Hz);
5.7 (IH, br, ); 6,6-7.0 (2H, m
); 7.2-8.0 (5H, m); 7,68 (IH
, s); 7.90 (IH, s).

Examples 72-154 below were synthesized in the same manner as in the previous examples. The compound numbers are the same as those listed in Tables 1 and 2 above.

As for physical properties, the melting point is described, and when the compound is an oil, the Rf value [when using Art 5717 thin layer chromatography manufactured by Merck & Co., Ltd.] is described.

2R", 3R"2R",3R"2R",3R"2R',3R"150-151"Cl78℃ 224-225℃ 184-186℃ 81 1-142 2R", 3R" 166-
167℃82 1-143 2R", 3R"
219-223℃ 211", 3R" 175-177℃ 2R", 3S'2R',3R'2R",3R"2R",3R"2R",3R"190-191'C 164-166℃ 173-174 ℃ 186-188℃ 222-223℃ 123 1-26 2R, 3R 153-157℃
124 1-27 2R", 3R" 174-
177℃125 1-27 2R", 3S'
138-148℃135 1-225 2R",
3R" 157-159℃136 1-227
2R", 3R' 218-220℃137 1-
66 2R, 3R230-232℃Reference person (2R", 3R")-2-(2,4-di') 007
x -:/L/)-1-(LH-1゜2.4-triazol-1-yl)-2,3-butanediol [Collection of Abstracts of the 8th Medicinal Chemistry Symposium (1)
110 synthesized by the method described in 986), page 9.
．． Dissolve 0 g (33 mmol) in 400 ml of pyridine, and add 4.8 g of methanesulfonyl chloride with stirring while cooling with water.
(42 mmol) was added. After returning to room temperature and stirring for 2 hours, pyridine was distilled off under reduced pressure, and to the resulting residue was added cooled aqueous sodium hydrogen oxide, and the mixture was extracted twice with ether. The organic layers were combined, washed with saturated brine, and the ether was distilled off. The obtained crystalline residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 11.9 g of the target compound having a melting point of 157-159°C.

Reference layer formation (2R"3R"-3-7mi/-2-24-shi')
OOpheni) L/-1-IH-124-Ding Sol-
1--2-butanol (2R", 3R")-3-azido-2-(2,4-dichlorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2-butanol 6.42 g (19,
Dissolve 6 mmol) in 128 ml of ethanol and add 10
% palladium-carbon was added thereto, and the mixture was stirred for 1 hour under a hydrogen gas atmosphere at normal pressure. After the reaction was completed, the reaction solution was filtered using Celite. The crystalline residue obtained by concentrating the filtrate was recrystallized from ethyl ether, melting point 104-10.
4.90 g of the target compound having a temperature of 5°C was obtained.

(2R”, 3Ra-2-(2,4-dichlorophenyl)
-1-(IH-1.

2.4-triazol-1-yl)-2,3-butanediol (racemic form) [Synthesized according to the method described in the 8th Medicinal Chemistry Symposium Abstracts (1986), page 9] 4 .39 g (14,5 mmo
1) in 100 ml of methanol and dissolve it, 1-
Camphorsulfonic acid 3.54 g (15.2 mmol
) was added. 330 ml of ethyl ether was added and 3.4 g of crystals precipitated were collected by filtration.

Specific optical rotation [α]D25-92° (c=0.90, methanol).

These crystals were heated and dissolved in 50 ml of methanol, and 150 ml of ethyl ether was added to recrystallize them to obtain 1.95 g of l-camphorsulfonic acid salt of the target compound having a melting point of 209-212°C. obtained as.

Specific optical rotation [α] n25-99° (c=1.00, methanol).

1.90 g of this optically active camphorsulfonate was added to 70 ml of ethyl acetate and 35 ml of cooled sodium hydrogen oxide water and stirred, and the ethyl acetate layer was separated and washed with water and saturated brine. After drying, the solvent was distilled off to obtain 1.05 g of the crystalline target compound. Recrystallization was performed from a mixed solvent of ethyl acetate and hexane to obtain a pure product with a melting point of 110°C.

Specific optical rotation [a] o25-111° (c=0.74, methanol).

Reference amount 1 2R3R-2-24-dichlorophenyl-1-IH-1
24i ゝ--1- -3- ゝ, d (2R,3R)-2-(2,4
-dichlorophenyl)-1-(LH-1,2,4-triazol-1-yl)-2,3-butanediol [(-
)・one enantiomer] 2.1 g to 2.37 g of the target compound
I got it.

Melting point: 140-143°C.

Specific optical rotation [cz] o25-138° (c=1.02, C
HCl3).

In the same manner as in Reference Example 2, (2R,3R)-3-azido-
2-(2゜4-dichlorophenyl)-1-(LH-1,
2,4-triazol-1-yl)-2-butanol [
(-) monoenantiomer] from 1.20 g, target compound 0.7
5 g was obtained.

Melting point: 238-242°C (decomposed).

Specific optical rotation [a In''-74° (c=0.50, methanol).

1-3-N-4-Rolofnylamino-2-24-di1-[2-(2,4-dichlorophenyl)-2,3-epoxypropyl]-18-1,2,4-triazole[
A mixture of 1140 mg (0.52 mmol), 133 mg (1.04 mmol) of p-chloroaniline, and 0.2 ml of xylene synthesized by the method described in JP-A-58-128383 was heated at 150°C for 50 minutes under a nitrogen atmosphere.
heated for an hour. After the reaction was completed, the crude product was subjected to column chromatography using silica gel and eluted with a benzene-ethyl acetate (3:2-2:3) mixed solvent to obtain crude crystals. Recrystallized from benzene-hexane, melting point 1
52 mg of the target compound having a temperature of 69-170°C was obtained.

NMR spectrum [CDC13-CD30D (2:1)
] δppm: 3.78 (2H, s); 4.70 (I
H, d, J = 14 Hz); 5.19 (LH, d, J
=14Hz); 6.54(2H,d); 7.08(
2H, d); 7.15 (IH, dd, J=9.2 H
z); 7.38 (IH, d, J=2 Hz); 7.
62 (IH, d, J=9 Hz); 7.79 (LH,
s); 8.04 (IH, s).

Reference bile-depleting reference amount
250 mg (0.93 mmol), 260 mg (1.87 mmol) of 4-(methylthio)aniline (synthesized by the method described in JP-A-58-128383)
, xylene (0.3 ml) under nitrogen atmosphere,
Heated at 40°C for 5 hours. After the reaction is complete.

The crude product was subjected to column chromatography using silica gel and eluted with a mixed solvent of benzene-ethyl acetate (3:2-2:3) to obtain 87 mg of the target compound as an oil.

NMR spectrum (CDC13) δppm: 2.4
0(3H,s); 3.5-4.2(3)[,m);
4.70 (IH, d, J=14 Hz); 5.
09 (IH, s); 5.23 (IH, d, J = 14 H
z); 6.56 (2H, d); 7.15 (II-1
, dd.

J=9,2 Hz); 7.17 (2H, d); 7.
35 (IH, d, J = 2 Hz); 7.65 (IH, d
, J=9 Hz); 7.82 (IH, s); 7.9
3(LH,s).

1-amino-2-(2,4-difluorophenyl)-3
-(LH-1,2,4-triazol-1-yl)-2
- Propatool [synthesized according to the method described in JP-A-59-62574] 400 mg (1,57 mmo
l) and paraformaldehyde 78 mg (2,6 mmo
1) was dissolved in 15 ml of toluene and stirred at 80°C for 2 hours. After cooling, unreacted paraformaldehyde was removed by filtration, and the solvent was distilled off from the filtrate to obtain the target compound 420.
Obtained mg as an oil.

(2R", 3R")-3-amino-2-(2,4-dichlorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2-butanol 4.00 g (13,
3 mmol) and paraformaldehyde 400 mg (13
, 3 mmol) was heated under reflux for 3 hours in 400 ml of benzene. Benzene was distilled off to obtain the target compound 4.1.
6 g were obtained as an oil.

By reaction with 0.13 g of maldehyde, 1.10 g of the target compound was obtained as an oil.

In the same manner as Reference Example 9, (2R,3R)-3-amino-
2-(2゜4-dichlorophenyl)-1-(LH-1,
2,4-triazol-1-yl)-2-butanol [
(-) One pair of palms suspended 00 mg and paraformaldehyde 4
By reaction with 0 mg, 420 mg of the target compound was obtained as an oil.

In the same manner as in Reference Example 9, (2R''', 3R'')-3-amino-2-(2,4-difluorophenyl)-1-(I
1.00 g of H-1,2,4-triazol-1-yl)-2-butanol and 535 mg of baraforsilane 55% sodium hydride (12,3 mmo
1) was washed with dry hexane, suspended in 6 ml of dimethylformamide, stirred with water cooling, and added (2R",
3R”)-2-(2,4-dichlorophenyl)-3-(
methanesulfonyloxy)-1-(LH-1,2,4-
Triazol-1-yl)-2-butanol 4.77
g (12.5 mmol) in dimethylformamide 48 m
1 solution was slowly added. After stirring at the same temperature for 30 minutes, the reaction solution was poured into 300 ml of ice water and extracted with benzene. After washing the organic layer with water and then with saturated saline, the solvent was distilled off to give 3.50 g of the target compound as an oil.
Obtained.

NMR spectrum (CDC13) δppm: 1.63
(3H, d, J=6 Hz); 3.18 (LH, q,
J = 6 Hz); 4.37 (IH, d, J = 15 H
z); 4.99 (LH, d, J2 15 Hz);
6.90 (IH, d, J=8 Hz); 7.11
(LH, dd, J=8,2 Hz); 7.38 (IH
, d, J=2 Hz); 7.83 (LH.

s); 7.99 (LH, s).

After washing 1.09 g of 55% sodium hydride with hexane, it was suspended in 31 ml of dimethylformamide, cooled with water and stirred, and then dissolved in 4-methoxy-α-toluenethiol 4.
．． 86 g (31.5 mmol) were added. 7 under water cooling
After stirring for a minute, the solution was further stirred for 20 minutes at room temperature (
2R”.

3S')-2-(2,4-dichlorophenyl)-3-methyl-2-[(LH-1,2,4-triazole-I-
yl)methyl]-oxirane 3.58 g (12.6 m
mol) dissolved in 26 ml of dimethylformamide was added. After heating to 60°C and stirring for 45 minutes, the reaction solution was returned to room temperature, poured into 340 ml of ice water, and extracted with benzene. The organic layer was washed with water and then with saturated brine, dried, and the solvent was distilled off.

The obtained crude product was subjected to column chromatography using 75 g of silica gel, and ethyl acetate-hexane (3
Near-1:l) was eluted with a mixed solvent to give the target compound 4 as an oil.
．． 10 g was obtained.

Infrared absorption spectrum ν1.8 (liquid film) cm-1:34
00, 1615.1586.1517° NMR spectrum (CDC13) δppm: 1.03 (3H, d
, J=7 Hz); 3.64(LH,q, J=7 H
z); 3.82 (5H, s); 4.85 (LH, s
); 4.94 (2H, s); 6.90 (2H, d, J
=9 Hz); 7.05 (LH, dd.

J=9,2 Hz); 7.23(IH,d, J=2
Hz); 7.33 (2H, d, J-9Hz); 7.
49 (IH, d, J=9 Hz); 7.72 (2H,
s).

nor(2Rゞ,3R'')-2-(2,4-dichlorophenyl)-3-[4-(methoxy)benzylthio]-1-(L
2.19 g (5,00 mmol) of H-1,2,4-triazol-1-yl)-2-butanol, 5.4 g of anisole, 28.5 g of trifluoroacetic acid, and 1.65 g of trifluoromethanesulfonic acid. and stirred at room temperature for 17 minutes. The reaction solution was concentrated under reduced pressure, and cooled aqueous sodium hydrogen oxide was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was distilled off to obtain 2.67 g of an oil containing the target compound.

was added and extracted with ether. After drying the extract, the solvent was distilled off to obtain the target compound 18 having a melting point of 122-125°C.
．． 0 g was obtained.

Infrared absorption spectrum v +aaX (CHCL3) c
m-1: 3400, 1620.1500° NMR spectrum (CDC13) δppm: 1.27
(3H, d, J-6, 5Hz); 3.09 (3H, s
); 4.70 (IH, d, J44 Hz); 5.0
3(LH.

br, d, J=14 Hz); 5.35 (IH, q,
J=6.5 Hz); 6.5-7.6 (3H, m);
7.80'CIH,s), 7.96(LH,s).

(2R”, 3R”)-2-(2,4-difluorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2,3-butanediol [8th Medicinal Chemistry Synthesized according to the method described in Symposium Abstracts (1986), page 9] 15.0 g
, 7 mmol) in 350 ml of pyridine, and
Methanesulfonyl chloride 8.0° C. with stirring
g (70 mmol) was added over about 3 minutes.

After stirring at the same temperature for 1.5 hours, pyridine was distilled off at 30°C under reduced pressure. To the residue, add 985 mg (22.6 mu + ol) of chilled sodium hydroxide solution 5 and brocade sodium hydride,
After washing with hexane, it was suspended in 20 ml of dimethylformamide, and 2.72 g (17.6a+mol) of 4-methoxy-α-toluenethiol was added under water cooling. After stirring at the same temperature for 5 minutes and then at room temperature for 15 minutes,
3R”)-2-(2゜4-difluorophenyl)-3-
(methanesulfonyloxy)-1-(LH-1,2,4
-)-Riazol-1-yl)-2-butanol 2.4
5 g (7.05 mmol) in dimethylformamide 2
A solution of 5ml was added. After stirring for 1 hour at room temperature,
The reaction solution was poured into 200 ml of ice water and extracted with benzene. The organic layer was washed with ice and saturated brine in that order, dried, and then the solvent was distilled off. The obtained oil was subjected to column chromatography using 40 g of silica gel and eluted with a mixed solvent of ethyl acetate and hexane (2:3).
g was obtained as an oil.

Infrared absorption spectrum v may (CHCli) c
m-1: 3420, 1612.1510.1500°N
MR spectrum (CDC13) δppm: 1.12 (
3H, d, J = 7 Hz); 3.18 (IH, q, J
-7Hz); 3.79 (5H, s); 4.37 (I
H,d.

J=14 Hz); 4.98(LH,d, J=14
Hz); 6.5-7.6 (3H, m); 7.75 (2
H,s).

(2R", 3R")-2-(2,4-difluorophenyl)-3-[4-(methoxy)benzylthio]-1-(
A mixed solution of 300 mg (0 = 74 mmol) of IH-1,2,4-triazol-1-yl)-2-butanol, 0.8 g of anisole, 4.2 g of trifluoroacetic acid, and 244 mg of trifluoromethanesulfonic acid, Water cooling 2
Stir for 5 minutes. After the reaction was completed, the mixture was concentrated under reduced pressure, diluted sodium bicarbonate water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and after drying, the solvent was removed.
337 mg of an oil containing the target compound was obtained.

NMR spectrum (CDC13) δppm: 1.1
8 (3H, d, J=7 Hz); 1.94 (LH, d
d, J-10,1,5Hz); 3.46(LH, dq
, J=10.7Hz); 4.79(LH,d, J=1
4 Hz); 4.8 (IH, br, ); 5,02 (
LH, d, J = 14 Hz); 6.5-7.0 (2H
, m); 7.1-7.6 (IH, m); 7,78 (
LH, s); 7.80 (LH, s).

Kunoto Shishi Monobutanol Lithium aluminum hydride 127 mg (3,36m
(4R", 5R")-5-(2,
4-difluorophenyl)-4-methyl-5-[(LH
A solution of 941 mg (3.36 mmol) of -1,2,4-triazol-1-yl)methyl]oxazolidine dissolved in 16.8 ml of tetrahydrofuran was added dropwise. After stirring at the same temperature for 30 minutes, 0.51 ml of 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite, and the solvent was distilled off from the filtrate to obtain the target compound 868. Recrystallization from a mixed solvent of ethyl acetate and hexane resulted in a melting point of 141-
A pure product was obtained at 145°C.

Infrared absorption spectrum v,,x(KBr) cm-1:
3210, 1610.1580.1499° NMR spectrum (CDC13) δppm 20, 90 (3H,
dd, J=7.2Hz); 2.48 (3H, s);
2.96 (IH, qd, J=7.2 Hz); 4.
80 (2H, s); 6.55-7.1 (2H, m);
7. i-7,7(IH,m); 7,77(LH,s
) ; 7.96 (IH, s).

Elephant doctor 2R"3R" -2-4-Roloff Nil-1-IH-
124-(2R", 3R")-2-(4-chlorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2,3-butanediol [8th Medicinal Chemistry Symposium Synthesized according to the method described in Lecture Abstracts (1986), page 9] 2.00 g (7,
49 mmol) was dissolved in 45 ml of pyridine, and while cooling with water and stirring, 1.11 g of methanesulfonyl chloride (
9.73 mmol) was added. After returning to room temperature and stirring for 1 hour, pyridine was distilled off under reduced pressure, dilute aqueous sodium bicarbonate was added to the resulting residue, and the mixture was extracted twice with ether. The organic layers were combined, washed with saturated brine, and the ether was distilled off.

The obtained crude product was purified by silica gel chromatography [eluted with a mixed solvent of ethyl acetate and hexane (2:1)] to obtain 2.05 g of the target compound as an oil.

NMR spectrum (CDC13) δppm: 1.27
(3H, d, J=7 Hz); 3.03 (3H, s)
; 4.70 (2H2s); 5.11 (LH, q, J
=7 Hz);5.6(LH,br,);7.29(
4H,s); 7,76(LH,s); 7.84(I
H,s).

Dissolve 1.52 g of (2R", 3R")-3-azido-2-(4-chlorophenyl)-1-(LH-1,2,4-triazol-1-yl)-2-butanol in 45 ml of ethanol. , 10% palladium on carbon 430 m
g was added thereto, and the mixture was stirred for 1 hour under a hydrogen gas atmosphere at normal pressure. After the reaction was completed, the reaction solution was filtered using Celite, and the solvent was distilled off from the filtrate to obtain 1.26 g of the target compound as an oil.

NMR spectrum (CDC13) δppm: 0.88
(3H, d, J=7 Hz); 2.8-3.6 (4H
,br,); 4.56(2H,s); 7.26(4
H, s); 7.80 (LH, s); 7.94 (IH,
s).

(2R", 3R")-3-amino-2-(4-chlorophenyl)-1-(LH-1,2,4-triazole-1
-yl)-2-butanol 592 mg (2,22 mm
ol) and paraformaldehyde 81 mg (2,67 m
mol) was heated under reflux for 2 hours in 50 ml of benzene. After the reaction, benzene is distilled off to obtain the target compound 650
Obtained mg as an oil.

Shujin - Santaka] Reference (2R", 3S") -2-(2,4-difluoro07 x
2#)-3-methyl-1-(LH-1,2,4-triazol-1-yl)-4-penten-2-ol [synthesized according to the method described in JP-A-60-36468 ]200 mg (0.72n+mole) was dissolved in 5 ml of tetrahydrofuran, and a 2M borane-dimethylsulfide complex tetrahydrofuran solution was added under stirring while cooling with water.
2 ml (4,4 mmole) was added. The mixture was returned to room temperature and stirred for 15 minutes, then at 50°C for 20 minutes. The reaction solution was ice-cooled again, and 1 ml of 15% aqueous sodium hydroxide solution and 1 ml of 30% 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 brine. After drying, the solvent was distilled off and the obtained oil was subjected to column chromatography using silica gel, and ethyl acetate-hexane (5:1-1
0:1) Elute with a mixed solvent to obtain the target compound (latter) 30
nxg was obtained as an oil. This material was an approximately 1:1 mixture of C-4 isomers A and B, as determined by NMR spectral analysis.

[Main peak NMR spectrum of isomer A (CDC13) δppm: 0.80
(3H, dd, J=7.3.5 Hz); 1.18(
3H, d, J=6 Hz); 4.90 (2H, s);
5.97 (IH, s); 7.79 (IH, s); 8
．． 05 (IH, s).

Main peak NMR spectrum of [isomer B] (CDC13) δppm: 0.7
6 (3H, dd, J=7.1.5 Hz); 1.27
(3H, d, J-6Hz); 5.47 (1/H, s)
; 7.70 (LH, s); 7.93 (IH, s).

Furthermore, 139 rtxg of the target compound (former) was obtained by sequential elution with ethyl acetate and 1% methanol-ethyl acetate.
Recrystallization was performed from a mixed solvent of ethyl acetate and hexane to obtain a pure product having a melting point of 121-122°C.

NMR spectrum (CDC13) δppm: 0.78
(3H, dd, J=7.IHz); 1.6-2.0(
2H, m); 2.4 (IH, m); 3.3-4.0
(3H.

m); 4.62 (IH, d, J=14 Hz); 4
．． 93 (LH, dd, J=14.I Hz); 5.5
2 (IH, br,); 6.5-7.0 (2H, m);
7.43 (IH, td, J=9.7 Hz); 7,
73 (IH, s); 7.97 (IH, s).

1Hz); L, 6-2.6 (3H, m); 3.03
(3H, s); 4.0-4.7 (2H.

m); 4.59 (IH, d, J=14 Hz); 4
．． 70 (IH, s); 5.00 (IH.

d, J=14 Hz); 6.5-7.0 (2H, m)
; 7.2-7.7 (IH, m); 7.83 (IH, s
); 8.17 (IH, s).

(3S",4R")-4-(2,4-difluorophenyl)-3-methyl-5-(IH-1,2,4-triazol-1-yl)-1,4-bentanediol 30 m
g (0.1 mmole) was dissolved in 1 ml of methylene chloride, and 25 g of triethylamine was added with stirring at -15°C.
mg (0.25 mmole) and methanesulfonyltalolide 25 mg (0.22 mmole) were added. After 15 minutes, dilute aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. After drying, the solvent was distilled off to obtain the target compound 38 rag as an oil.

NMR spectrum (CDC13) δppm: 0.82
(3H, dd, J=6.5゜(2R", 33ズ-2-(
2,4-difluorophenyl)-3-methyl-1-(I
H-1,2,4-triazol-1-yl)-2,4-
213 mg (0.72 m@ole) of bentanediol (approximately 2=1 mixture of C-4 isomers) was dissolved in pyridine 4
ml of methanesulfonyl chloride at 0°C.
mg (1.22 mmole) was added and stirred for 2.5 hours. After the reaction was completed, pyridine was distilled off under reduced pressure, dilute aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. After drying, the solvent was distilled off to obtain 270 mg of the target compound as an oil.

The material was an approximately 2:1 mixture of two stereoisomers for the C-4 position.

[Main component] NMR spectrum (CDC1g) δpp
m: 0.76 (3H, dd, J=6.5, 0.5H
z); 1.46 (3H, d, J=6.5 Hz); 2
．． 5 (LH, m); 3.05 (3H, s); 4.6
5(IH, d, J=14)1z); 5.05(IH,
dd, J=14. I Hz); 5.35 (II-f,
m); 6.5-7.0 (2H, m); 7.1-7.
6 (LH, m); 7.77 (IH, s); 7.85
(LH,s) [Main subcomponents] NMR spectrum (C
DC13) δPP! l: 0.37 (3H, dd, J=6
．． 5,0.5 Hz); 1.57 (3H, d, J=6
．． 51(z); 3.02(3H,s); 4.71(
IH, d, J44 Hz); 5,05 (IH, dd.

J=14,0.5. Hz); 7,77 (IH, s);
7,89 (LH, s).

(2R", 3R")-2-(2,4-difluorophenyl)-3-methyl-1-(IH-1,2,4-triazol-1-yl)-4-penten-2-ol [Special Synthesized according to the method described in JP-A No. 60-36468]
514 mg (1.84 mmole) was dissolved in 15 ml of methylene chloride and m-chloroperbenzoic acid (85 mmole) was dissolved at 0°C.
'I, purity) 635 mg (3.13 mn+ole) was added. 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 successively with an aqueous sodium sulfite solution, an aqueous sodium bicarbonate solution, and a saturated saline solution. After drying,
The solvent was distilled off, the residue was subjected to column chromatography using silica gel, and ethyl acetate-hexane (2:1
) Elution with a mixed solvent gave 472 mg of the target compound as a solid.

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

Recrystallization was performed from a mixed solvent of ethyl acetate and hexane to separate the main component isomer (melting point 106-109°C).

NMR spectrum (CDC13) δppm: 1.30
(3H, d, J=6 Hz); 1.90 (IH, br
, quint); 2.00 (IH, dd, J=4.3
Hz); 2.35 (IH, t, J=4 Hz); 2
．． 85 (IH, m); 4.53 (IH, d, J=14
Hz); 4.89 (IH, dd, J=14, 1.5
1 (z); 4.9 (IH, br, ); 5.5-7.
0 (2H, m); 7.3-7.7 (IH, m); 7
．． 79 (IHps); 7.91 (LH, s).

(2R", 3R")-2-(2,4-difluorophenyl)-4,5-epoxy-3-methyl-1-(IH-I
, 2,4-triazol-1-yl)-2-pentanol (approx. 3:1 mixture of C-4 isomers) 207 mg (
0.70 mmole) in 4 ml of ether,
Under a nitrogen atmosphere, 53 mg (1.40 mmole) of lithium aluminum hydride was added while cooling with water and stirring.

After 10 minutes, the reaction solution was refluxed for 1 hour. Cool, 1 ml of water
was slowly added and stirred for 10 minutes. 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 resulting oil was subjected to column chromatography using silica gel.
Elution was performed with a mixed solvent of chloroform-hexane (5:5:1) to obtain 160 mg of the target compound.

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

Recrystallization was performed from a benzene-hexane mixed solvent to separate the main component isomer (melting point 145-146°C).

NMR spectrum (CDCb) δppm: 1.05 (
3H, d, J = 6.5 Hz), 1.25 (3H, d, J
=6.5 Hz); 2.20 (IH, qd, J=6.
5゜I Hz); 3.03 (LH, br, s); 3
．． 74 (IH, br, q, J=6.5 Hz); 4.
51 (IH, d, J = 14 Hz); 4.77 (LH
, dd, J=14. I Hz); 5.33 (IH, s)
; 6.5-7.0 (2H, be); 7.1-7.6
(IH, m); 7.65 (IH, s); 7.89 (I
H,s).

(2R", 3S")-4-(2,4-dichlorophenyl)-3-methyl-1-(IH-1,2,4-triazol-1-yl)-4-pentyn-2-ol and its ( 2
R”, 3R”)-1=1 mixture of isomers [JP-A-1986
-Synthesized by the method described in Publication No. 36468]13
9 n+g (0.45 nemole) was dissolved in 2.8 ml of tetrahydrofuran-water (5:2) mixed solvent,
Sodium metaperiodate 290 mg (1,32 mmo
le) 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 brine. After drying, the oily substance obtained by distilling off the solvent was subjected to column chromatography using 4 g of silica gel and eluted with a mixed solvent of ethyl acetate and hexane (4:5). ''')-isomer 27 mg, (2R
25 rag of a mixture of the ",3R")- and (zs",3Ra-isomers) and then 31 mg of the (2S",3R")-isomer were obtained.

The separated (2R'', 3Ra-isomer was recrystallized from benzene to give a pure product with a melting point of 150-151°C.

In addition, the (2S'', 3R'')-isomer was recrystallized from a benzene-ethyl acetate mixed solvent, with a melting point of 155-157°C.
A pure product with .

Infrared absorption spectrum ν,,,LX(CHCL3) co
+-1: 3400, 1715° NMR spectrum (CDC13) δppm: 0.96
(3H, d, J=7 Hz); 3.47 (LH, qd
, J=7.3 Hz); 4.64 (IH, d, J=1
4 Hz); 5.30 (IH, br, ); 5.42 (
IH, d, J = 14 Hz); 7.11 (IH, dd
.

J = 8.2 Hz); 7.31 (LH, d, J = 2
Hz); 7.52 (LH, d.

J=8 Hz); 7.77 (IH, s); 7.85
(IH, s); 9.88 (IH, d.

J = 3 Hz).

[(2S", 3R")-isomer] NMR spectrum (CDC13) δppm: 1.40
(3H, d, J=7 Hz); 3.52 (IH, qd
, J = 7, 1.5 Hz); 4.50 (IH, d, J
= 1.4 Hz); 5.42 (LH, d, J = 14
Hz); 5.5 (IH, br, ); 7.11 (F,
dd, J = 8,2 Hz); 7.35 (LH, d, J
= 2 Hz); 7.54 (IH, d, J = 8 Hz)
; 7.77 (LH, s); 7.86 (IH, s);
9.39 (It(,d,,I=1.5 Hz).

[(2R", 3R")-isomer] 4-IH-124-1azol-1-yl-13-
When butane was added, a pure product with a U point of 176-177°C was obtained.

(2R", 3R")-3-(2,4-dichlorophenyl)-3-hydroxy-2-methyl-4-(1B-1,2
,4-to-1noazol-1-yl)butanal and its (
2S”, 3R”)-1:1 mixture of isomers 85 rlg
The mixture was dissolved in 1.5 ml of methanol, and 15 mg of sodium hydroxide was added to the solution under ice-cooling and stirring.

After 10 minutes, ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine. The crude product obtained by distilling off the solvent was subjected to column chromatography using 3 g of silica gel and eluted with ethyl acetate to obtain the target compound (2R'').

3R8)-isomer 31- was obtained.

Benzene-hexane mixed solvent force 1 recrystallizes and melts 12
A pure product with a temperature of 0-122'C was obtained.

Next, elution was performed with a 7% methanol-ethyl acetate mixed solvent to obtain the (2S", 3R")-isomer of the target compound at 33 m
The obtained product was recrystallized from benzene-hexane mixed solvent) and melted [(2
R'', 3R monoisomer] NMR spectrum (CDC13) δppmt: 1.3
9 (3H, d, J = 7 Hz); 2.85 (18, m
); 3.40 (IH, s); 3.45 (LH, s)
; 4.50 (IH, d, J=14 Hz); 5.3
1 (IH, d, J=14 Hz); 7.05 (IH.

dd, J=8,2 Hz); 7.25(LH, d, J
=2 Hz); 7. '52 (IH, d.

J=8 Hz); 7.66 (IH, s); 7.91
(LH,s).

[(2S", 3R")-isomer] Infrared absorption spectrum v*ax (nujol) cm-1
:3400, 3140°NMR spectrum [CDCl3:CD30D (1:1)
] δppm: 0.77 (3H, d, J=7 Hz);
2.9 (1M, m); 3.6-4.3 (2H, m)
;4.74 (IH, d, J=14.5 Hz); 5.
44 (II, d, J = 14.5 Hz); 7.04 (I
H, dd, J=9,2 Hz); 7.30 (IH, d
, J=2 Hz); 7.48(18,d, J=9 Hz
); 7.67 (IH, s); 8.07 (LH, s)
.

Sando Medical Center (2R"3S" -2-24-Jiku O'C1) -t,
knee) Ll -4-:) evening') (25", 3R") -3
-(2,4-dichlorophenynoly2-methyl-4-(
IH-1,2,4-triazol-1-yl)-1,3
-Butanediol 74 mg (0,231 mmole)
was dissolved in 2 ml of methylene chloride, and while stirring at 0°C, 61 mg (0.61 mmole) of triethylamine was added.
and methanesulfonyl chloride 64 mg (0.56 mn
+ole) was added. After 15 minutes, cooled sodium hydrogen oxide solution was added and extracted with ethyl acetate.

The extract was washed with saturated brine and the solvent was distilled off to obtain crude product 9.
2 mg was obtained.

NMR spectrum (CDC13) δppm: 0.70
(3H, d, J=7 Hz); 3.07 (3H, s)
; 2.9-3.4 (IH, m); 4.22 (IH,
dd, J=10°5 Hz); 4.59(IH, d,
J=14.5 Hz); 4.71(II, dd, J=
10°7 Hz); 5.18 (LH,br,); 5
．． 51 (LH, d, J = 14.5 Hz); 7.04 (
IH, dd, J=J3,2 Hz); 7.27 (IH
, d, J = 2 Hz); 7.43 (IH, d, J = 8
Hz); 7.73(1)1. s); 7,81 (IH
,s).

2R"3S"-4-Amino-2-24-dichlorophenyl-3-methy-1-IH-124-rAzo-1
--2-(2R", 3S")-4-azido-2-(2,
4-dichlorophenyl)-3-methyl-1-(IH-1
, 2,4-triazol-1-yl)-2-butanol was dissolved in 4 ml of ethanol, 30 mg of 10% palladium on carbon was added, and the mixture was stirred for 1.5 hours under a hydrogen gas atmosphere at normal pressure. After the reaction is completed, the reaction solution is filtered using Celite, and the filtrate is concentrated to obtain the crystalline target compound 1.
00 mg was obtained. Recrystallization was performed from a mixed solvent of ethyl acetate and benzene to obtain a pure product with a melting point of 154-156°C.

NMR spectrum (CDCb) δppm: 0.76
(3B, d, J=7)1z); 2.5-3.5(3
H, m); 3.80 (3H, br, s); 4.69
(IH, d, J=14.5 Hz); 5.24 (IH
, d, J=14.5Hz); , 7.07 (IH, dd
, J=9.2 Hz); 7.31 (IH, d, J=2
Hz); 7.60 (IH, d, J=9 Hz);
7.68 (IH, s); 8.09 (LH, s).

The method of Kenyon et al. [J, Kenyon, et al.
, J. Chem.

Soc, 1925.399].
120 g (0,491 mole) of S)-2-(p-toluenesulfonyloxy)propionic acid was dissolved in 700 ml of methylene chloride, and 55 ml of oxalyl chloride (
0,63 mole) and dimethylformamide 12 m
1 was added thereto, and the mixture was stirred at room temperature for 2 hours.

After the reaction, the solvent was distilled off under reduced pressure and the resulting oil was
1,3-difluorobenzene 112 g (0,98 mo
1) of aluminum chloride while stirring under water cooling.
96.4 g (1,474 mole) was added. After 1 hour, the mixture was returned to room temperature and stirred overnight. The reaction solution was poured into ice, 300 ml of concentrated hydrochloric acid was added, and the mixture was stirred for 15 minutes. The extract was extracted with benzene, washed successively with water, diluted sodium bicarbonate solution, and saturated brine, and the solvent was distilled off. The obtained oil was distilled to obtain the target compound 8 having a boiling point of 60-62°C (1 mmHg).
0.6 g (80% yield) was obtained.

Specific optical rotation [α]D”5-27.3° (C=0.95, C
HCl3).

Infrared absorption spectrum v,, (CHCl3) cm-1
:1690, 1610° NMR spectrum (CDC13) δppm: 1.70
(3H, d, J=6.5Hz); 5.15 (IH, q
, J=6.5 Hz); 6.7-7.2 (2H, m)
;7.75-8.25 (IH, m).

17.1 g of magnesium (0
, 704 rnole) and 10 g (0,082 mole) of chloromethyltrimethylsilane were added, and the mixture was refluxed under a nitrogen atmosphere. A small amount of a suspension of magnesium activated with methyl iodide in ether was added to initiate the reaction. Next, 76.3 g of chloromethyltrimethylsilane
A solution of (0,622 mole) dissolved in 800 ml of ether was added dropwise over about 30 minutes. After refluxing for an additional 30 minutes, the reaction solution was cooled to -10°C. (R)-(2,4
-difluorophenyl)1-chloroethyl ketone 72
A solution of g (0,352 mole) dissolved in 720 ml of ether was added dropwise to the above reaction solution over about 20 minutes.

After the dropwise addition, the mixture was stirred at 0°C for 1 hour, then saturated ammonium chloride solution was added, and the mixture was extracted with hexane. After washing with saturated brine, the solvent was distilled off to obtain 105 g of an oily substance. This oil was dissolved in 850 ml of methylene chloride, and while stirring under water cooling, 28 g (0,200 mol) of boron trifluoride ether complex was added.
e) was added.

After 1 hour, hexane 11 was added, and the mixture was washed with diluted sodium bicarbonate solution and saturated brine. The oil obtained by distilling off the solvent was distilled under reduced pressure to give a boiling point of 80-82°C (11 mmHg
62 g (yield: 82%) of the target compound having the following properties were obtained.

Specific optical rotation [α]o” +39.7° (C=1.04, C
HCl3).

Infrared absorption spectrum v, X(CHCl3) cm-1
:1610, 1595.1500°NMR spectrum (CDC13) δppm: 1.65
(3H, d, J=6.5Hz); 4.92 (IH, q
, J=6.5 Hz); 5.25 (IH, s); 5
．． 64 (IH, s); 6.5-7.1 (2H, m);
7.1-7.6 (LH, m).

Dissolve 55.4 g (273 mmole) of 12-butanediol (R)-3-chloro-2-(2,4-difluorophenyl)-1-butene in 550 ml of tetrahydrofuran, and dissolve 51.8 g of N-methylmorpholine oxide ( 443mmole)
, 10 ml (556 mmole) of water and 600 mg of osmium tetroxide were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with dilute hydrochloric acid and saturated brine. The crystalline residue obtained by distilling off the solvent was recrystallized from a benzene-hexane mixed solvent to obtain 46.8 g of the target compound having a melting point of 71.5-72.5°C.
I got it.

Specific optical rotation [α D25 +6.3° (C=1.12, C
HCl3).

Infrared absorption spectrum w,, (CHCl3) cm-1
:3550, 3400(br,).

NMR spectrum (CDC13)・δppm: 1.2
5 (3H, d, J = 6.5Hz); 2.15 (LH,
br, ); 3.34 (IH, s); 3.7-4.4
(2H, m); 4.64 (LH, q, J-6,5Hz
); 6.6-7.2 (2H, m); 7.5-8.0
(IH, m).

The mother liquor was concentrated, separated and purified by column chromatography (eluted with ethyl acetate-hexane), and recrystallized from a benzene-hexane mixed solvent to obtain an additional 6.5 g (total yield: 82%) of the target compound. Ta.

Melting point: 70-72°C.

Specific optical rotation [α1025+6.1° (C=1.22, CH
Cl3) - Also, 7.9 g of its stereoisomer (yield 12%)
)Obtained.

Hz); 4.7&(2H,s); 6.6-7.2(
2H, m); 7.4-8.13 (IH.

m).

(2R,3R)-3-chloro-2-(2,4-difluorophenyl)-1,2-butanediol, 3 g (1
87 mmole) was dissolved in 440 ml of methylene chloride, and while stirring under water cooling, 23 g (227 mmole) of triethylamine was dissolved in 440 ml of methylene chloride.
mole) was added. Next, 25.8 g (225 mmole) of methanesulfonyl chloride was quenched over about 10 minutes, and the mixture was stirred at the same temperature for 30 minutes. Ice water was added and the organic layer was separated, washed with saturated brine, and the solvent was distilled off under reduced pressure to obtain 59 g of the target compound.

Infrared absorption spectrum v maw (CHCl3) cn
s-1: 3560° NMR spectrum (CDC13) δppm: 1.26
(3H, d, J=6.5Hz); 2.89 (3H, s
); 3.17 (IH, s); 4.63 (IH, q,
J=6.5 silane 55% sodium hydride 24 g (550 mmole)
After washing with dry hexane, dimethylformamide 60
40.1 g of triazole
(580 mmole) was added slowly. When the generation of hydrogen gas has stopped, (2R,3R)-3-chloro-2-
(2,4-difluorophenyl)-1-(methanesulfonyloxy)-2-butanol 59 g (187 mmo
le) was added, stirred at room temperature for 10 minutes, and then heated at 60° C. for 2.5 hours. The mixture was cooled down, water was added to the reaction mixture, and the mixture was extracted with benzene. After drying, the solvent was distilled off to obtain 38.5 g (yield: 82%) of the crystalline target compound.

Recrystallization was performed from a benzene-hexane mixed solvent to obtain a pure product having a melting point of 8°C and -39.5°C.

Specific optical rotation [α conn25-7.55° (C=1.0[5,
C) (Cb).

NMR spectrum/L/(CDC13)δppm: 1
．． 64 (3H, d, J = 5.5Hz); 3.16 (I
H, q, J = 5.5 Hz); 4.40 (IH, d,
J=15 Hz); 4.88 (IH, d, J215
Hz); 6.5-7.2 (3H, m); 7
．． 79 (IH.

s); 7.98 (IH, s).

Infrared absorption spectrum shift (KBr) cm-1:32
10, 1620.1600°NMR spectrum (CDC13) δppm: 0.84
(3H, d, J=6.5Hz); 1-04-1-9
1(2Ht br-) t 3-61(IHy q t
J=6-5 Hz) ;4.3-5.5(IH,br
, ); 4.6&(2H,s); 6.5-7.1(2
H, n+); 7.2-7.84 (IH, m); 7.8
1(IH,s); 8.01(1)f,s).

(2R,3R)-3-azido-2-(2,4-difluorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2-butanol 5.00 g was added to 100 g of ethanol. Dissolve in 1.3 mL of palladium on carbon.
g was added thereto, and the mixture was stirred for 1 hour under a hydrogen gas atmosphere at normal pressure. After the reaction was completed, the reaction solution was filtered through Celite and the solvent was distilled off, yielding 4.56 g of the target compound as a crystalline residue.
(yield 100%).

Recrystallization from benzene gave a pure product with a melting point of 154-155°C.

Specific optical rotation [α 25-73° (C=1.06, CHC
l3).

The method of Cohen et al. [S, G, Cohen, J, Am
, CheTn.

Soc, 85.1685 (1963)] (S)-2-acetoxypropionic acid 20
g (0.15 mole) was dissolved in 100 ml of methylene chloride, and 16.9 ml of oxalyl chloride (0.197 mole) was dissolved in 100 ml of methylene chloride.
le) and 1.0 ml of dimethylformamide were added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction, the solvent was distilled off under reduced pressure and 25 m-difluorobenzene was added to the obtained oil.
．． 9 g (0,227 mole) was added, and then 50.5 g (0,379 mole) of aluminum chloride was added under water cooling and stirring.
le) was added. After 1 hour, the temperature was returned to room temperature, and stirring was continued overnight. After adding 60 ml of methylene chloride, the reaction solution was added little by little into water. 400 ml of ethyl acetate was added, and the organic layer was separated, washed successively with water, cooled sodium hydrogen oxide solution, and saturated brine, and the solvent was distilled off.

36 g of the obtained oil was dissolved in 1.80 ml of methanol, and while stirring while cooling with water, 15 ml of concentrated sulfuric acid diluted with 18 ml of water was added, and the mixture was returned to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, 400 ml of ethyl acetate was added, and the mixture was washed successively with water, cold aqueous sodium hydrogen oxide, and saturated brine, and the solvent was distilled off. The residual oil was distilled to a boiling point of 65-67°C (
18.65 g (yield: 66.8%) of the target compound having a molecular weight of 3 mmHg) was obtained.

Specific optical rotation [α] D25-61. (C=1.17, CH
Cl3).

Infrared absorption spectrum ν, aX (CHC: 13) cm-
1:3500, 1680° NMR spectrum (CDCb+D20) δppm:
1.42 (3H, dd.

J = 6.5, 2 Hz); 5.0 (IH, qd, J =
6.5, 2 Hz); 6.7-7.3 (2H, 01)
77.8-8.2 (IH, m).

5.00 g (26.9 mmo
le) in 25 ml of pyridine, and while stirring at -10°C, add 10.24 ml of p-toluenesulfonyl chloride.
g (53.7 mmole) was added thereto, and the mixture was stirred at the same temperature for 6 hours. After the reaction was completed, the reaction solution was cooled to -20°C, and cooled sodium hydrogen oxide solution and then 100 ml of ethyl acetate were added. The organic layer was separated, washed successively with cold sodium hydrogen oxide solution and saturated brine, and the solvent was distilled off. The obtained crystalline product was recrystallized from an acetone-cyclohexane mixed solvent to obtain the target compound 5.4 having a melting point of 88-90°C.
9 g (yield 60%) was obtained.

Specific optical rotation [α]. ”-19.3° (C=0.92, CH
Cb).

Infrared absorption spectrum v, &, (CHCl3) am-
1:1695°NMR spectrum (CDC; b) δppm: 1.53
(3H, dd, J=7°2 Hz); 2.42 (3H
,s); 5.67 (IH, q, J-7Hz); 6.
7-7.1 (2H, m); 7.27 (2H, d, J=
9 Hz); 7.78 (2H, d, J-9Hz);
7.6-8.1 (IH, aa).

It matched the thing.

(S)-(2,4-difluorophenyl) 1-(p
-Toluenesulfonyloxy)ethyl ketone 5.00
Dissolve g (14.7 mmole) in 50 ml of dimethylformamide, and add 20 ml of water with stirring at -15°C.
352 mg of lithium hydroxide (14,
7 mmole) was added dropwise over 2 hours.

After the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and 20 ml of 5% ammonium chloride aqueous solution was added. The mixture was extracted with 100 ml of ethyl acetate, washed successively with dilute ammonium chloride water and saturated brine, and the solvent was distilled off. The obtained oil was treated with silica gel 75
The residue was subjected to column chromatography using 100 g and eluted with a mixed solvent of benzene-ethyl acetate (20:1) to obtain 2.00 g (yield 73.2%) of the target compound as an oil.

Specific optical rotation [α]D2' +64.2° (C=0.74,
CHCl1).

Infrared and NMR spectra of the compound of Reference Example 37 (
Dissolve 2.00 g (10.7 mmole) of R)-(2,4-difluorophenyl)1-hydroxyethyl ketone in 20 ml of methylene chloride, and add 2.
, 3-dihydropyran 1.17 g (13.9 mmol
e) and pyridinium P-toluenesulfonate 135
mg (0.54 mmole) was added. After returning to room temperature and standing overnight, 50 ml of ethyl acetate was added, and after washing with saturated brine, the solvent was distilled off.

The obtained oil was subjected to column chromatography using 100 ml of silica gel, and benzene-hexane (5
:1) to obtain 2.54° of the target compound (yield: 87.5%) as an oil.

Specific optical rotation [α], 25 + 51.1° (C = 1.35, C
HCb).

Infrared absorption spectrum ν, ax (CHCl3) cm-1
:1695°NMR spectrum (CDC13) δppm: 1.42
(1,5H, dd, J=6.5.3 Hz); 1.4
5 (1,5H, dd, J=6.5, 1.5 Hz);
1.3-2.0 (6H, m); 3.1-4.1 (2
H, m); 3.6-3.8 (LH, m); 4.86 (
0,5H,qd,J=6.5.2)1z); 5.1
0 (0,5H, qd, J=6.5°2 Hz); 6.
7-7.2 (2H, m); 7.7-8.2 (IH, m
).

An aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate.

After washing the organic layer with saturated brine, the solvent was distilled off to obtain 4.02 g of the target compound as an oil.

Infrared absorption spectrum y,,X(CHCla) cm-1
: 60 ml of ether, 0.50 g of magnesium (
20.6 mmole) and 3.03 g (18.2 mmole) of chloromethyldimethylisopropoxysilane were added, and the mixture was refluxed under nitrogen atmosphere. The reaction was started by adding a small amount of a suspension of magnesium activated with methyl iodide in ether. After refluxing for 3 hours, the reaction solution was cooled to 0°C and while stirring, (R)-(2,4-difluorophenyl)
1-(2-tetrahydropyranyloxy)ethyl
A solution of 2.62 g (9.7 mmole) of ketone dissolved in 15 ml of tetrahydrofuran was added dropwise over 10 minutes. After dropping, the temperature was returned to room temperature, stirred for 15 minutes, cooled to 0°C, and saturated (2S, 3R)-2-(2,4-difluorophenyl)-1-(dimethylisopropoxysilyl)-
4.54 g (11.28 mmole) of 3-(2-tetrahydropyranyloxy)-2-butanol was added to 50 ml of a mixed solvent of tetrahydrofuran-methanol (1:1).
1 and 0.7 g of sodium hydrogen carbonate (8,33
mmole) and 7 ml of 35% hydrogen peroxide solution,
The mixture was heated and stirred at 0°C. After 1.5 hours, the reaction solution was returned to room temperature, and 100 ml of ethyl acetate was added. After washing with saturated brine, the solvent was distilled off to obtain 4.5 g of the target compound.

Infrared absorption spectrum v n @ x (CHCl3)
am-1: 3550° NMR spectrum (CDC13) δppm: 0.92
(1,5H,d, J=6.5 Hz); 1.03(1
, 5H, d, J=6.5 Hz); 1.3-2.0 (
6H, m); 3.2-4.8 (8H, m); 6.5
−7.1 (2H, m); 7,78 (IH, td, J=
9.7 Hz).

3430 (br,), 3370 (br,).

NMR spectrum (CD3COCD3) δppm: 0
．． 87 (3H, d, J=6.5 Hz); 3.5-4
．． 7 (6H, m); 6.7-7.2 (2H, s);
7.81 (IH, td, J=9.7 Hz).

(2R,3R)-2-(2,4-difluorophenyl)
-3-(2-tetrahydropyranyloxy)-1,2-
2.85 g (9.43 mmole) of butanediol was dissolved in 40 ml of methanol, 120 mg (0.63 mmole) of p-toluenesulfonic acid was added, and the mixture was stirred at room temperature for 30 minutes. Triethylamine 0.097 ml
(0.70 mmole) and stirred for 5 minutes.

The crystalline product obtained by distilling off the solvent was recrystallized from acetone-cyclohexane to obtain 1.58 g (yield 77%) of the target compound having a melting point of 81-82°C.

Specific optical rotation [α], “5+11.4° (C=1.11.C
HCl3).

Infrared absorption spectrum νmaX (KBr) cm-1: (
2R,3R)-2-(2,4-difluorophenyl)-
1,2,3-butanetriol 1.54 g (7,06
mmole) in 6 ml of pyridine, and while stirring at 0°C, add 1.51 ml of methanesulfonyl chloride.
(19.5 mmole) was added and stirred at the same temperature for 30 minutes. After the reaction was completed, pyridine was distilled off under reduced pressure, and 50 ml of ethyl acetate was added to the obtained oil, which was washed successively with cooled sodium hydrogen oxide solution and saturated brine. Distill the solvent,
2.64 g (yield 96%) of the target compound was obtained as an oil.

NMR spectrum (CDC13) δppm: 1.23
(3H, d, J=6.5Hz); 2.95 (3H, s
); 3.10 (3H, s); 3.82 (iH, s)
;4.70(2H,s);5.32(IH,q,J=
6.5 Hz); 6.7-7.2 (2H.

m); 7.6-8.0 (IH, m).

Silane 55% sodium hydride 1.08 g (24.7 mmo
After washing le) with dry hexane, it was suspended in 30 ml of dimethylformamide, stirred at 0°C, and then 1) 1-1
．． 1.95 g of 2,4-triazole (28,2 mmo
le) was added gradually.

Once the generation of hydrogen gas has stopped, (2R,3R)-2-
(2,4-difluorophenyl)-1,3-bis(methanesulfonyloxy)-2-butanol 2.62 g (
7.05 mmole) in 5 ml of dimethylformamide
A solution dissolved in was added and stirred at 65-70°C for 2 hours. Distill the solvent under reduced pressure, add cold water, and add 50 m of benzene.
Extracted twice with l. After washing the organic layer with saturated brine, the solvent was distilled off and the obtained oil was subjected to column chromatography using 30 g of silica gel, eluting with a benzene-ethyl acetate (2:1) mixed solvent, The obtained crystals were recrystallized from benzene-hexane and had a melting point of 88-89.5°C.
1.40 g of the target compound with a yield of 79% was obtained.

Specific optical rotation [α], 25-7.55° (C = 1.06, C
HCl3) NMR spectrum was consistent with that of the compound described in Reference Example 35.

95% magnesium in 6ml anhydrous tetrahydrofuran
mg (3,91 mmole) and vinyl bromide 0.
44 ml (6.22 mmole) was added, and the mixture was heated and stirred at 45-50°C for 5 minutes under a nitrogen atmosphere. Once the reaction started, the temperature was returned to room temperature and the mixture was stirred for 20 minutes. The reaction solution was cooled with dry ice-acetone, and a solution of 420 mg (1,55 mmole) of (R)-(2,4-difluorophenyl)1-(2-tetrahydropyranyloxyethyl ketone) dissolved in 4 ml of anhydrous tetrahydrofuran was added. , under stirring 1
Disappeared in 0 minutes.

After raising the temperature to -30°C and stirring for 20 minutes, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. After washing the organic layer with saturated brine, the solvent was distilled off to obtain 464 mg (yield 100%) of the target compound as an oil.

NMR spectrum (CDC13) δppm: 0.92
(1,5H,d, J=6.5 Hz); 1.01(1
, 5H, d, J: 6.5 Hz); 1, 2-2.0 (
6H, m); 3.19 (IH, d, J=4 Hz);
3.3-4.1 (3H, m); 4.1-4.6 (I
H, m); 4.6-4.9 (IH, m); 5.0-
5.6 (2H, m); 6.2-7.0 (3H, m);
7.6-8.0 (IH, m)- and eluted with benzene-ethyl acetate (10:1) mixed solvent to obtain the target compound 2.
80 mg (84% yield) was obtained as an oil.

Specific optical rotation [α] D25-49.3° (C = 1.22, C
HCl3).

NMR spectrum (CDC1i:Ih0=20:1) δ
ppm: 0.98 (3H, d, J=6.5 Hz);
4.38 (11(, qd, J: 6.5.3 Hz);
5.23 (IH, br, d, J=11 Hz); 5.
44 (IH, br, d, J=18 Hz); 6.50
(IH, ddd, J=18.11, 3 Hz); 6.
5-7.0 (2H, m); 7.5-8.0 (IH, m)
.

(3S,4R)-3-(2,4-difluorophenyl)
-4-(2-tetrahydropyranyloxy)-1-penten-3-ol 464 mg (1,56 mmole)
was dissolved in 5 ml of methanol, 30 mg (0.16 mmole) of p-toluenesulfonic acid was added, and the mixture was stirred at room temperature for 20 minutes. 50 ml of ethyl acetate was added, and the mixture was washed successively with diluted sodium bicarbonate water and saturated brine, and the solvent was distilled off. The obtained oil was subjected to column chromatography (2R, 3S) -3-(2
,4-difluorophenyl)-4-pentene-2,3-
280 mg (1,31 mmole) of diol was dissolved in 4 ml of pyridine, and 0.18 ml (2,32 mmole) of methanesulfonyl chloride was added while stirring at 0°C.

After 15 minutes, pyridine was distilled off under reduced pressure and 50ml of ethyl acetate was added.
1 was added thereto, and the mixture was washed successively with diluted sodium hydrogen carbonate solution and saturated brine. The solvent was distilled off to obtain 382 mg of the desired product as an oil.

Infrared absorption spectrum ν□, (CDC13) cm-1:
3600, 1350.1180° NMR spectrum (CDC13) δpptn: 1.2
5 (3H, d, J=6.5Hz); 3.03 (3H,
s); 4.30(1) f, q, J = 6.5 Hz);
5.2-5.7 (2H, m); 6.54 (LH, d
dd, J=17.11.3 Hz); 6.6-7.1
(2H, m); 7.4-8.0 (IH, m).

Chromatography was performed using benzene-hexane (4:
1) Elution with a mixed solvent yielded 86 mg of the target compound (yield: 7
0%) was obtained as an oil.

Specific optical rotation [α]o"-61,1' (C=0.71,
CHCb).

NMR spectrum (CDC13) δppm: 1.40
(3H, d, J=5.5Hz); 3.17 (IHtq
? J=5.5 Hz); 5.15(LH, dt, J=
17°1.5 Hz); 5.30 (IH, dd, J=
11.1.5 Hz); 6.03 (IH.

ddd, J: 17.11, 1.5 Hz); 6.6-
7.6 (3H, m).

55% sodium hydride 32 mg (0.98 mmol
After washing e) with dry hexane, it was suspended in 4 ml of dimethylformamide. (3S,4R)-3- dissolved in 2 ml of anhydrous tetrahydrofuran with stirring at 0°C.
(2,4-difluorophenyl)-4-(methanesulfonyloxy)-1-penten-3-ol 191 mg
(0.65 mmole) was dissipated in 5 minutes. After returning to room temperature and stirring overnight, ice water was added and extracted with hexane. The solvent was distilled off, and the resulting oil was added to 10 g of silica gel.
Column using (2S,3S)-2-(2,4-difluorophenyl)-3-methyl-2-vinyloxirane 5
0 mg (0,255 mmole) was dissolved in 3 ml of methanol-water (5:2) mixed solvent, 164 mg of sodium metaperiodate (0,76 mmole) and 1.5 mg of osmium tetroxide were added, and the mixture was heated to room temperature. The mixture was stirred overnight.

After adding ethyl acetate and washing with saturated brine, the solvent was distilled off to obtain 50 mg of the target compound as an oil.

NMR spectrum (CDC13) δppm: 1.60
(3H, d, J = 5.5Hz); 3.42 (IH, q
, J=5.5 Hz); 6.7-7.0 (2H, m)
; 7.1-7.5 (IH, m); 9.65 (IH, d
, J=2 Hz).

Hz); 2.02 (IH, s); 3.10 (IH,
q, J=5.5 Hz); 3.83(IH, d, J=
12 Hz); 4.17 (IH, dd, J=12,0
．． 5 Hz); 6.6-7.1 (2H, m); 7.
2-7.6 (LH, m).

(2S,3S)-2-(2,4-difluorophenyl)-2,3-epoxybutanal 50 mg (0,2
8 mmole) was dissolved in 1.6 ml of methanol, and while stirring under water cooling, 10.5 mg of sodium borohydride (0
, 28 mmole) and stirred at the same temperature for 1 hour.

Ethyl acetate was added, and the mixture was washed with saturated brine. The oily substance obtained by distilling off the solvent was subjected to chromatography using 10 g of silica gel, and benzene-hexane (4:1
) Elution with a mixed solvent yielded 38 mg of the target compound (yield 75
%) was obtained as an oil.

Specific optical rotation [α]o” +18.2° (C=1.14, C
HCh).

Infrared absorption spectrum νNaX (CDC13) cm (
:3500, 1100°NMR spectrum ((1:DCb)δppm: 1.4
8 (3H, d, J = 5.5 (2R, 3S) -2-(difluorophenyl)-2,3-epoxy-1-butanol 76 mg (0.38 mmole) was dissolved in 1.5 ml of methylene chloride. , 42 n+g (0.42 mmole) of triethylamine and 0.42 mmole of methanesulfonyl chloride were added with stirring at 0°C.
After 0 minutes, sodium hydrogen carbonate water was added and extracted with ethyl acetate.

After drying, the solvent was distilled off to obtain 103 mg (yield: 98%) of the target compound as an oil.

NMR spectrum (CDC13) δppm: 1.50
(3H, d, J=5.5Hz); 2.91 (3H, s
); 3.12 (IH, q, J=5.5 Hz); 4
．． 41 (IH, d, J=11.5 Hz); 4.80
(IH, d, J=11.5 Hz); 6. Kano 7.1 (
2H, m); 7.2-7.7 (LH, m).

Reference 11 Reference 1 Reference A 2- IH-124-r Azol-1-ruthioxirane 5 Sodium hydride 47 mg (1,08 mmole
) with dry hexane, dimethylformamide 2
Suspend in 1 ml and add triazole 86 while cooling with water and stirring.
．． 8 mg (1.26 mmole) was added. When the generation of hydrogen gas has stopped, (2R,3S) -2-(2,4
-difluorophenyl)-3-methyl-2-(methanesulfonyloxymethyl)oxirane 100 mg (0,
A solution of 36 mmole) dissolved in 2 ml of dimethylformamide was added, and the mixture was stirred at 85°C for 35 minutes. cold welding,
Water was added to the reaction solution, and the mixture was extracted with benzene. The solvent was distilled off to obtain 69 mg of crude product. Recrystallization was performed from a benzene-mixed solvent to obtain the target compound having a melting point of 88-89.5°C.

The specific optical rotation and NMR spectrum were consistent with those of the compound described in Reference Example 35.

The method of Kenyon et al. [J. Kenyon, et al.
, J. Chew.

(S) synthesized by Soc, Kawasui, 399
-10 g (41 mmole) of -2-(p-toluenesulfonyloxy)propionic acid was added to 50 ml of methylene chloride.
5.73 g (45 mmol) of oxalyl chloride
e) and 0.10 g of dimethylformamide were added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and 9.23 g of chlorobenzene was added to the obtained oil.
(82 mmole) and then 13.67 g (102.6 mmole) of aluminum chloride while stirring under water cooling.
added. After 1 hour, the temperature was returned to room temperature and stirring was continued overnight.

100 ml of hexane was added, ice was added little by little while stirring under water cooling, and further 50 ml of 2N hydrochloric acid was added and stirred for 30 minutes. 50 oxl of benzene was added and the organic layer was separated, washed successively with water, cooled aqueous sodium hydrogen oxide, and saturated brine, and the solvent was distilled off.

Perform vacuum distillation to reduce the boiling point to 115-120℃ (4mmHg
) was obtained (5.44 g (yield 65%)) of the target compound.

Specific optical rotation [α]o”-25,6° (C=2.20.C
HCl3)-infrared absorption spectrum v v*ax (CH
Cl3) am-1: 1695, 1595° NMR spectrum (CDC13) δppm: 1.72
(3H, d, J=6.5Hz); 5.15 (IH, q
, J=6.5 Hz); 7.45 (2H, d); 7
．． 98(2) (, cl).

1.40 g of magnesium (57,
6 mmole) and chloromethyltrimethylsilane i, o
g (8.2 mn+ole) was added thereto, and the mixture was refluxed under nitrogen atmosphere.

After starting the reaction by adding a small amount of magnesium in a suspension activated with methyl iodide in ether, chloromethyltrimethylsilane 6, Og (49,2 mmole) was dissolved in ether) I/30 mI. The solution was added dropwise to the above reaction solution over about 15 minutes. After the addition, the mixture was further stirred for 30 minutes and then cooled to 0°C.

(R)-4-chlorophenyl 1-lyloloethyl ketone 5.85 g (28.8 mmole) was dissolved in ether 25
The solution dissolved in nil was added to the above reaction solution under stirring for about 20 minutes.
It was dripped in minutes. After dropping and stirring at 0°C for 15 minutes,
Saturated ammonium chloride solution was added and extracted with hexane.

After washing with saturated saline, the solvent was distilled off to obtain 8.50 g of an oily substance.
I got it. Dissolve this oil in 60 ml of methylene chloride,
Boron trifluoride ether complex 2.8 with stirring at 0°C
g (20 mmole) was slowly added and stirred for 30 minutes. After neutralizing the reaction solution by adding cooled sodium oxyhydrogen aqueous solution, the organic layer was separated and the solvent was distilled off.

The obtained oil was subjected to column chromatography using 30 g of silica gel and eluted with a 1% ethyl acetate-hexane mixed solvent, yielding 5.16 g of the target compound (yield: 89%).
) was obtained as an oil.

Specific optical rotation [αkoo” +21.2° (C=2.0O1C
HC13).

Infrared absorption spectrum v, a, (CHCb) cm-i:
1625, 1494° NMR spectrum (CDC13) δppm: 1.6
6 (3H, d, J=6.5Hz); 4.94 (IH,
q, J=6.5 Hz); 5.34 (IH, s);
5.49 (IH, br, s); 7.34 (4H, s)
.

11 Hikikei 6.5 Hz); 7.38 (4H, s).

(R)-3-chloro-2-(4-chlorophenyl)-1
- Butene 5.02 g (25 mmole) was dissolved in tetrahydrofuran 50 ml, N-methylmorpholine oxide 4.50 g (38.4 nt mole), water 0
．． 70 ml (38.9 mmole) and 50 mg of osmium tetroxide were added and stirred overnight at room temperature.

After the reaction was completed, the reaction solution was diluted with ethyl acetate and washed with saturated brine. The oily substance obtained by distilling off the solvent was subjected to column chromatography using silica gel.
Elution was performed with a 0% ethyl acetate-hexane mixed solvent to obtain 5.87 g (yield 100%) of the target compound as an oil.

Specific optical rotation [(E]D” +16.Oo (C=0.94,
CHCl3).

Infrared absorption spectrum y, a, (CHCl3) cm-1
:3570, 3400(br,).

NMR spectrum (CDC13) δppm: 1.25
(3H, d, J=6.5Hz); 2.15 (IH, b
r, ); 3.00 (IH, br, ); 3.81 (I
H,d.

J=12 Hz); 4.00 (IH, d, J=12
Hz); 4.40 (IH, q, J=(2R,3R)-
Dissolve 5.78 g (2,46 mmole) of 3-chloro-2-(4-chlorophenyl)-1,2-butanediol in 60 ml of methylene chloride, and add 3.25 g (32,4 mmole) of triethylamine with stirring at -15°C. 2 o1e)
and methanesulfonyl chloride 3.38 g (29.5 m
mole) was added. After 15 minutes, ice water was added and the organic layer was separated and washed with saturated brine.

The oil obtained by distilling off the solvent under reduced pressure was subjected to column chromatography using silica gel and eluted with a 20% ethyl acetate-hexane mixed solvent to obtain the target compound 6.77.
g (yield: 88 g) was obtained as an oil.

Specific optical rotation [α]n” +13.4°=i, oa, CHC
l3).

Infrared absorption spectrum v v, ax (CHCl3) a
m-1: 3560° NMR spectrum (CDC13) δppm: 1.27
(3H, d, J=6.5Hz); 2.88 (3H, s
); 4.42 (IH, q, J=6.5 Hz); 4
．． 52 (2H, s); 7,38 (4H, s).

2.76 g of 55% sodium hydride (63,3nxm
ole) was washed with dry hexane, suspended in 50 ml of dimethylformamide, stirred and cooled with water, and 4.37 g (63.3 mmole) of triazole was slowly added thereto. When the generation of hydrogen gas stops, (2R, 3R)
-3-chloro-2-(4-chlorophenyl)-1-(methanesulfonyloxy)-2-butanol 6.59 g
(21,1 mmole) in 10 m of dimethylformamide
A solution dissolved in 1 was added to the mixture, and the mixture was allowed to stand at room temperature for 30 hours. Water was added to the reaction solution, extracted twice with benzene, and the solvent was distilled off. 6 g of the obtained oil was subjected to column chromatography using 50 g of silica gel and eluted with a mixed solvent of ethyl acetate-hexane (1:5-5:1) to obtain 4.56 g of the target compound (yield: 87)) was obtained as an oil.

Specific optical rotation [α]D”-7.1° (C=1.16, CHC
l3).

NMR spectrum (CDC13) δppi*: 1.6
0 (3H, d, J=5.5Hz); 3.11 (IH,
q, J=5.5 Hz); 4.39(IH, d, J=
15 Hz); 4.82 (LH, d, J=15 Hz
); 6.95-7.35 (4H, m); 7.86 (
IH, s); 7.95 (IH, s).

2.47 g of (2R,3R)-3-azido-2-(4-chlorophenyl)-1-(IH-1,2,4-triazol-1-yl)-2-butanol was added to 60 g of ethanol.
ml, 700 mg of 10% palladium on carbon was added thereto, and the mixture was stirred for 1 hour under a hydrogen gas atmosphere at normal pressure. After the reaction was completed, the reaction solution was filtered using Celite, and the solvent was distilled off to obtain 2.25 g of the target compound as an oil.

NMR spectrum (CDC13) δppm: 0.8
6 (3H, d, J=6.5Hz); 2.6 (3H, b
r, ); 3.31 (IH, q, J = 6.5 Hz);
4.49 (2H, s); 7.25 (4H, s);
7.88 (2H, s).

Experimental medical competition S-24-difluorophenyl 1-2-1trahy(S
)-(2,4-difluorophenyl)l-hydroxyethyl ketone 10. Og (53,7 mmole) was dissolved in 100 ml of methylene chloride, and while cooling with water and stirring, 5.87 g of 2,3-dihydropyran (69,8a+
mole) and 945 rng of pyridinium p-toluenesulfonate were added.

After returning to room temperature and allowing it to stand for 3.5 hours, ethyl acetate was added, and the mixture was washed with aqueous sodium hydrogen carbonate and saturated brine.

After drying, the solvent was distilled off and the obtained oil was subjected to silica gel chromatography, and benzene-hexane (4:
1) Elution with a mixed solvent yielded 13.0 g of the target compound as an oil.

Specific optical rotation [cz] o”-56,3° (c = 1.11
, CHCl3)-infrared absorption spectrum and NMR spectrum were consistent with those of the compound of Reference Example 40.

Reference example μ, S-3-24-difluorophenyl-3-zone-2
- In 20 ml of ether, add 2.01 g of magnesium (82
, 6a+mole and chloromethyltrimethylsilane 1.
00 g (8.13 mmole) was added thereto, and the mixture was refluxed under a nitrogen stream. After starting the reaction by adding a suspension obtained by activating a small amount of magnesium with methyl iodide in ether, 9.02 g (7
A solution of 4.8 mmole) dissolved in 130 ml of ether was added dropwise over about 30 minutes. After further refluxing for 30 minutes, the reaction solution was cooled on ice. Then, (S)-(2,4-
difluorophenyl) 1-(2-tetrahydropyranyloxy)ethyl ketone 11.2 g (41.4 m
A solution of 50 ml of ether was added dropwise to the above reaction solution over about 10 minutes. After quenching, the mixture was stirred for 1 hour under water cooling, an aqueous ammonium chloride solution was added, and the mixture was extracted with benzene.

After washing with saturated saline, the solvent was distilled off to obtain 15.0 g of an oily substance.
I got it. This oil was dissolved in 100 ml of methanol, and 0.50 g of P-toluenesulfonic acid was added.

After 12 hours, benzene was added, and the mixture was washed with aqueous sodium hydroxide solution and saturated brine. The oil obtained by distilling off the solvent was distilled under reduced pressure, and the boiling point was 49-51°C (1.5 mmHg).
7.0 g of the target compound having the following properties were obtained.

Specific optical rotation [αcoD25+49° (c=1.22, CHC
l3).

Infrared absorption spectrum sea ax (CHCl3) cni-
1:3600, 3430 (br,).

NMR spectrum (CDC13) δppm: 1.2
8 (3H, d, J=6.5Hz); 2.1 (IH, b
r, ); 4.69 (IH, br, q, J = 6.5 H
z); 5.17 (IH, br, s); 5.54 (IH
, t, J=1.5 Hz); 5.5-7.6 (3H,
m).

Elute with a mixed solvent of hexane (1:3) and obtain the target compound 6.
．． 58 g were obtained as an oil.

Specific optical rotation [α] n25-26.4° (c=1.25, C
HCl3).

Infrared absorption spectrum ν+5ax (CHCl3) Cm-
1:3560, 3500 (br,).

NMR spectrum (CDC13) δppm: 1.
19 (3H, dd, J=6.5°1.5 Hz); 2
．． 4 (IH, br, ); 2.89 (IH, d, J=5
Hz); 3.26 (LH, d, J=5 Hz); 4
．． 10 (IH, q, J=6.5 Hz); 6.6-7
．． 1 (2H, m); 7.2-7.6 (LH, m).

(S)-3-(2,4-difluorophenyl)-3-buten-2-ol 7.00 g (38 mmole),
Dissolved in 35 ml of benzene, 9.8 g of t-butyl hydroperoxide (70% purity, 76 mmole) and 140 g of vanadium(IV) oxyacetylacetonate.
mg and stirred overnight at room temperature. The reaction solution was washed with saturated brine, dried, and then the solvent was distilled off. The obtained oil was subjected to column chromatography using silica gel, and 55 m of ethyl acetate (2S, 3R)-(2,4-difluorophenyl)-3,4-epoxy-2-butanol was added.
g (27,5n+mole) in tetrahydrofuran l
144 mg (55 mmole) of triphenylphosphine, 67 mg of benzoic acid (
55 mmole) and then 96 mg (55 mm+nole) of azodicarboxylic acid diethyl ester. The reaction solution was returned to room temperature, stirred for 1 hour, condensed water was added, and extracted with benzene. The oil obtained by distilling off the solvent was purified by preparative thin layer chromatography on silica gel [developing solvent: hexane-ethyl acetate (7:1) mixed solvent] to obtain target compound 71 nag as an oil. Obtained.

Specific optical rotation [α] D”-52,6° (cm1.33, CH
Cl3).

Infrared absorption spectrum9. ,,,(CHCl3) C1m
-1:1716°NMR spectrum (CDC13) δppm: 1.35
(3H, dd, J=6.5°1.5 Hz); 2.8
8 (IH, d, J = 4.5 Hz); 3.22 (IH
, d, J = 4.5 Hz); 5.44 (IH, q, J
=6.5 Hz); 6.6-7.1 (2H, m); 7
．． 2-7.8 (4H, m); 7.9-8.2 (2H,
n+).

The resulting oil was purified by preparative thin layer chromatography on silica gel [developing solvent: hexane-ethyl acetate (4:1) mixed solvent] to obtain 40 mg of the target compound as an oil.

Specific optical rotation [(EID”-54.9° (cm1.45, C
HCl3).

Infrared absorption spectrum y,,X(CHCl3) cm-1
:3590, 3470(br,).

NMR spectrum (CDC13) δppm: 1.15
(3H, dd, J=6.5°1.5 Hz); 2.2
(IH, br, ); 2.79 (IH, d, J=5 H
z); 3.28 (IH, d, J=5 Hz); 4.1
5 (IH, br, ); 6.6-7.1 (2H.

m); 7.2-7.7(IH,m)-(2R,3R)
71 rsg of -(2,4-difluorophenyl)-3,4-epoxy-2-butyl benzoate was added to a solution of 1 mg of sodium dissolved in 1.5 ml of methanol, and the mixture was allowed to stand overnight at room temperature. Water was added to the reaction solution, extracted with ethyl acetate, dried, and the solvent was distilled off. Obtained (2R
,3R)-3-(2,4-difluorophenyl)-3,
4-epoxy-2-butanol 40 mg (0.20 m
mole) in 1 ml of methylene chloride, -15
While stirring at °C, add 30 mg of triethylamine (0,
3On+mole) and methanesulfonyl chloride 30
mg (0.26 ml 1 ole) was added.

After 10 minutes, water was added to the reaction solution, and the mixture was extracted with ethyl acetate.

After drying, the solvent was distilled off to obtain 53 mg of the target compound as an oil.

NMR spectrum (CDCb) δppm: 1.41 (
3H, dd, J=6.5°1.5 Hz); 3.01
(IH, d, J=5 Hz); 3.08 (3H, s)
; 3.20 (IH, d, J=5 Hz); 4.75
(LH, q, J=6.5 Hz); 6.6-7.1 (
2H, m); 7.2-7.7 (IH, n+).

Silane 55% Sodium hydride 25 mg (0.57 mmol
After washing e) with dry hexane, it was suspended in 1 ml of dimethylformamide. Under water-cooled stirring, triazole 45m
g (0,65 mmole) and when the generation of hydrogen gas subsides, (2R,3R)-3-(2,4-difluorophenyl)-3,4-epoxy-2-butyl methanesulfonate 53 rag(0, A solution of 19 mmole) dissolved in 0.5 ml of dimethylformamide was added, and the mixture was stirred at 60°C for 3 hours. After cold addition, ethyl acetate was added, the mixture was washed with saturated brine, and the solvent was distilled off. The obtained oil was purified by preparative thin layer chromatography on silica gel [developing solvent: hexane-ethyl acetate (2:3) mixed solvent] to obtain 37 mg of the target compound. Recrystallized from benzene-hexane mixed solvent, melting point 88-89.5℃
A pure product with .

Specific optical rotation [(EID”-9.5° (cm0.78, CH
Cl3).

Infrared absorption spectrum and NMR spectrum are Reference Example 35
It was consistent with that of the compound.

According to a known method [8th Medicinal Chemistry Symposium Abstracts, p. 11 (1986)], α
- The target compound was obtained using bromobutyryl bromide.

no'L3=1.5035°Mass spectrum (m/e): 368.294.266
, 224° NMR spectrum (CDC13) δpp
m: 0.81 (3H, t, J=7.2Hz); 1.
10-2.00 (8H, m); 3.15-3.78 (
IH, m); 3.79-4.28 (3H, m); 4
．． 32-4.70 (2H, m); 4.78 (IH, s
); 6.43-6.92 (2H, m); 7.15-7
．． 47 (IH, m); 7,60 (0,5H.

s); 7.65 (0,5H, s); 7.83 (0,
5H,s); 7.92 (0,5H,s).

゛ 1 hard capsule 100 j in each standard bipartite hard gelatin capsule
lg powdered active ingredient, 150 mg lactose, 5
Unit capsules were prepared by filling 0 mg cellulose and 6 mg magnesium stearate, washed and dried.

! Notice 2 Soft Capsules Soft capsules containing 100 mg of active ingredient are prepared by preparing a mixture of the active ingredient in a digestible oil, such as soybean oil, cottonseed oil or olive oil, and injecting it into gelatin with a positive displacement pump. was obtained, washed and dried.

Packaging Example 1: 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg.
of starch and 98.8 mg of lactose. A coating was applied if desired.

The product was prepared by stirring 1.5% by weight of the active ingredient in 10 volumes of propylene glycol, making up the volume with water for injection, and sterilizing it.

100 mg of micronized active ingredient in 5 ml
mg sodium carboxymethyl cellulose, 5
mg of sodium benzoate, 1.0 g of sorbitol solution (Pharmacopoeia) and 0.025 mg of vanillin.

5 grams of 40% white petrolatum, 3z microcrystalline wax, 10% lanolin, 5% span 20, 0.3% Tween 20 and 41.7% water. was prepared by incorporating 100 mg of micronized active ingredient into a cream.

Production example to Futari Shiji Active ingredients, 2 parts by weight, 1,2-propanediol, 5 parts by weight, glycerol stearate, 5 parts by weight, whale wax,
A mixture of 5 parts by weight, 10 parts by weight of isopropyl myristate, and 4 parts by weight of polysorbate was heated, cooled, and then 69 parts by weight of water was added while stirring to prepare a cream.

Add 1 part by weight of Yufuri liquid active ingredient to 300% polyethylene glycol.
A coating liquid was prepared by mixing 99 parts by weight.

Active ingredient, 2 parts by weight, polyethylene glycol 400.
40 parts by weight and 1,500.58 parts by weight of polyethylene glycol were mixed and dissolved under heating, and then cooled to produce an ointment.

9.2 ゛8 active ingredients, 2% sodium alkylnaphthalene sulfonate, 2% sodium lignin sulfonate, 3% synthetic amorphous silica, and 1-13% kaolina are mixed, crushed in a hammer mill, mixed again and packaged. .

τ゛10゛・1 15% of the wettable powder of Preparation Example 9, 69% of gypsum and 16% of potassium sulfate were mixed in a rotary mixer or fluid bed mixer and granulated by spraying with water. Mostly 1.0-0
．． When the weight reached 4211111, the granules were taken out, dried, and passed through a sieve. Grinds oversized materials, and
Another granule was obtained.

98.5% of active ingredients, 0.5% of silica airgel, 1.0% of synthetic amorphous fine silica are mixed, and then crushed in a hammer mill, all with a 0.297 am hole. A high concentration concentrate was produced that passed through.

゛ 12 ・ Active ingredient 25'1, hydrated attapulgite 3z, crude calcium lignin sulfonate 10%, sodium dihydrogen phosphate 0.5z, water 61.5% until the solid particles are reduced to a diameter of 10 microns or less. Milled together in a ball mill, sand mill or roller mill.

τ"13" 30% of the active ingredient and 70% of dimethylformamide were combined and stirred to obtain a solution.

15% active ingredient, 25% blend of calcium sulfonate and nonionic surfactant, and 60% xylene were combined and stirred to dissolve the active ingredient. A fine sieve filter is included during packaging operations to ensure there is no undissolved material attached.

Claims (3)

[Claims] (1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) {In the formula, Ar is a phenyl group that may be substituted with one or two substituents (the substituents include a halogen atom or a trifluoromethyl group), and R^1 represents a lower alkyl group, or R^3 and a group having the formula -Xm-Yn-R^2 together [in the formula , R^2' is a lower alkyl group, a halogenated lower alkyl group, an optionally substituted phenyl group (the substituent is one or more groups selected from the following substituent groups (a) and (b)). ), a naphthyl group, or an optionally substituted 5- to 6-membered heterocyclic group (the substituents include 1 to 3 groups selected from the following substituent group (a)). , p represents 0 to 1, and q represents 0 to 1. ]
When it shows, it shows a hydrogen atom or a lower alkyl group. X is a lower alkylene group, a lower alkenylene group, a lower alkynylene group, a cycloalkylene group, a cycloalkenylene group, a (lower alkylene-cycloalkylene) group, or (
Cycloalkylene (lower alkylene) group. m represents 0 to 1. Y is a group having the formula -N(R^5)CO- (wherein R^5 represents a hydrogen atom or a lower alkyl group), a group having the formula -N(R^5)CO-CH=CH- (In the formula, R^5 has the same meaning as above.), a group having the formula -OCO-, a group having the formula -OCO-CH=CH-, a group having the formula -
Indicates a group having SCO- or a group having the formula -SCO-CH=CH-. R^3 represents a hydrogen atom or has the formula -Xm-Yn-R^2
Together with the group having the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (II) (In the formula, R^2', p and q have the same meanings as above.)
shows. n indicates 0 to 1, and when n is 0, R^2 is
A group having the formula R^2" [wherein R^2" is an azide group,
an optionally substituted phthalimide group (the substituent is one or more groups selected from the following substituent groups (a) and (b)), an optionally substituted 1-oxo-2,
3-dihydro-2-isoindolyl group (the substituent is one or more groups selected from the following substituent groups (a) and (b)), protected hydroxyl group or formula -OSO_2R
A group having ^4 [wherein R^4 is a lower alkyl group, a halogenated lower alkyl group, or an optionally substituted phenyl group (the substituent is selected from the following substituent group (a) represents one or more groups). ]. ]. When n is 1, R^2 represents the same group as R^2' above. } and its salt. However, R^1 is a methyl group, m is 0, n is 0, R^2 is a protected hydroxyl group or the formula -OSO_2R^4 (R^4 is
Indicates the same meaning as above. ) is excluded. ¥ Substituent group (a) ¥ Nitro group, cyano group, halogen atom, lower alkyl group, and halogenated lower alkyl group. ¥ Substituent group (b) ¥ Lower alkoxy group, halogenated lower alkoxy group, hydroxyl group, benzyloxy group, hydroxymethyl group, formula -CH
_2-OCO-R^6 (in the formula, R^6 represents a lower alkyl group or a halogenated lower alkyl group), a group having the formula -CO-R^6 (in the formula, R^6 represents the above-mentioned ), a group having the formula -COOR^6 (in which R^6
indicates the same meaning as above. ), a group having the formula -SO_r
R^6 (wherein, R^6 has the same meaning as above, and r is
Indicates 0 to 2. ), an amino group, a mono- or di-lower alkyl-substituted amino group, and an acylamino group. (2) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) {In the formula, Ar is a phenyl group that may be substituted with one or two substituents (the substituents include a halogen atom or a trifluoromethyl group), and R^1 represents a lower alkyl group, or R^3 and a group having the formula -Xm-Yn-R^2 together form the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R^2' is a lower alkyl group, a halogenated lower alkyl group, an optionally substituted phenyl group (the substituents include the following substituents) represents one or more groups selected from groups (a) and (b)), a naphthyl group, or an optionally substituted 5- to 6-membered heterocyclic group (the substituents include the following substituent groups (a). ) represents 1 to 3 groups selected from ), p represents 0 to 1, and q represents 0 to 1. ] indicates a hydrogen atom or a lower alkyl group. X represents a lower alkylene group. m represents 0 to 1. Y is a group having the formula -N(R^5)CO- (wherein R^5 represents a hydrogen atom or a lower alkyl group), a group having the formula -N(R^5)CO-CH=CH- (In the formula, R^5 has the same meaning as defined above.), a group having the formula -SCO-, or a group having the formula -SCO-CH=CH-. R^3 represents a hydrogen atom or has the formula -Xm-Yn-R^2
Together with the group having the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (II) (In the formula, R^2', p and q have the same meanings as above.)
shows. n indicates 0 to 1, and when n is 0, R^2 is
A group having the formula R^2" [wherein R^2" is an azide group,
an optionally substituted phthalimide group (the substituent is one or more groups selected from the following substituent groups (a) and (b)), an optionally substituted 1-oxo-2,
3-dihydro-2-isoindolyl group (the substituent is one or more groups selected from the following substituent groups (a) and (b)) or a group having the formula -OSO_2R^4 [wherein, R^4 represents a lower alkyl group, a halogenated lower alkyl group, or an optionally substituted phenyl group (the substituent is one or more groups selected from the substituent group (a) below). show. ]. ]. When n is 1, R^2 represents the same group as R^2' above. } or a salt thereof. However, compounds in which R^1 is a methyl group, m is 0, n is 0, and R^2 is a group having the formula -OSO_2R^4 (R^4 has the same meaning as above) are excluded. ¥ Substituent group (a) ¥ Nitro group, cyano group, halogen atom, lower alkyl group, and halogenated lower alkyl group. ¥ Substituent group (b) ¥ Lower alkoxy group, halogenated lower alkoxy group, hydroxyl group, benzyloxy group, hydroxymethyl group, formula -CH
_2-OCO-R^6 (in the formula, R^6 represents a lower alkyl group or a halogenated lower alkyl group), a group having the formula -CO-R^6 (in the formula, R^6 represents the above-mentioned ), a group having the formula -COOR^6 (in which R^6
indicates the same meaning as above. ), a group having the formula -SO_r
R^6 (wherein, R^6 has the same meaning as above, and r is
Indicates 0 to 2. ), an amino group, a mono- or di-lower alkyl-substituted amino group, and an acylamino group. (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, Ar is a phenyl group that may be substituted with one or two substituents (the substituent is a halogen atom) or a trifluoromethyl group), and R^1 represents a lower alkyl group, or R^3 and a group having the formula -Xm-Yn-R^2 together form the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R^2' is a lower alkyl group, a halogenated lower alkyl group, an optionally substituted phenyl group (the substituents include the following substituents) represents one or more groups selected from groups (a) and (b)), a naphthyl group, or an optionally substituted 5- to 6-membered heterocyclic group (the substituents include the following substituent groups (a). ), p represents 0 to 1, and q represents 0 to 1.] indicates a hydrogen atom or a lower alkyl group. X is a lower alkylene group, a lower alkenylene group, a lower alkynylene group, a cycloalkylene group, a cycloalkenylene group, a (lower alkylene-cycloalkylene) group, or (
Cycloalkylene (lower alkylene) group. m represents 0 to 1. Y is a group having the formula -N(R^5)CO- (wherein R^5 represents a hydrogen atom or a lower alkyl group), a group having the formula -N(R^5)CO-CH=CH- (In the formula, R^5 has the same meaning as above.), a group having the formula -OCO-, a group having the formula -OCO-CH=CH-, a group having the formula -
Indicates a group having SCO- or a group having the formula -SCO-CH=CH-. R^3 represents a hydrogen atom or has the formula -Xm-Yn-R^2
Together with the group having the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (II) (In the formula, R^2', p and q have the same meanings as above.)
shows. n indicates 0 to 1, and when n is 0, R^2 is
A group having the formula ^R2" [wherein R^2" is an azide group,
an optionally substituted phthalimide group (the substituent is one or more groups selected from the following substituent groups (a) and (b)), an optionally substituted 1-oxo-2,
3-dihydro-2-isoindolyl group (the substituent is one or more groups selected from the following substituent groups (a) and (b)), protected hydroxyl group or formula -OSO_2R
A group having ^4 [wherein R^4 is a lower alkyl group, a halogenated lower alkyl group, or an optionally substituted phenyl group (the substituent is selected from the following substituent group (a) represents one or more groups). ]. ]. When n is 1, R^2 represents the same group as R^2' above. An agricultural fungicide containing a compound represented by } or a salt thereof. ¥ Substituent group (a) ¥ Nitro group, cyano group, halogen atom, lower alkyl group, and halogenated lower alkyl group. ¥ Substituent group (b) ¥ Lower alkoxy group, halogenated lower alkoxy group, hydroxyl group, benzyloxy group, hydroxymethyl group, formula -CH
_2-OCO-R^6 (in the formula, R^6 represents a lower alkyl group or a halogenated lower alkyl group), a group having the formula -CO-R^6 (in the formula, R^6 represents the above-mentioned ), a group having the formula -COOR^6 (in which R^6
indicates the same meaning as above. ), a group having the formula -SO_r
R^6 (wherein, R^6 has the same meaning as above, and r is
Indicates 0 to 2. ), an amino group, a mono- or di-lower alkyl-substituted amino group, and an acylamino group.