JPH04360883A - Production of oxetane derivative - Google Patents

Abstract

PURPOSE:To stereoselectively obtain the title new compound having an oxetane skeleton, an intermediate for a compound having high agricultural germicidal activity and fungicidal activity reacting specific two kinds of compounds by irradiation with light rays. CONSTITUTION:A compound shown by formula I (X<1> to X<3> are H, halogen, lower alkyl, etc.; R is lower alkyl, aralkyl, etc.) is reacted with a compound shown by formula II (R<1> and R<2> are lower alkyl) in a solvent (preferably benzene or toluene) preferably in a solvent such as toluene while irradiating with light rays at about 350nm at 10-40 deg.C to give the objective compound shown by formula III [e.g. (2R*,4R*)-2-(4-chlorophenyl)-3,4-dimethyl-2-ethoxycarbonyl-oxetane (* is racemic modification). The compound is reduced unprotected OH of the prepared alcohol compound is converted into a nucleophilic eliminable group to give a compound shown by formula IV (Y is nucleophilic eliminable group), which is reacted with triazole, etc., to give a compound shown by formula V (A is N or CH) such as (2R',3S*4R*)-2(4-chlorophenyl)-3,4-dimethyl-2-[(1 H-1,2,4-triazol-1-yl)methyl]oxetane.

Description

[Detailed description of the invention]

0001

【the purpose】

0002

[Industrial Application Field] The present invention provides compounds of the general formula (I) having excellent agricultural fungicidal and antifungal activities.

0003

[C6]

[In the formula, X1, X2 and X3 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a halogeno-lower alkyl group or a halogeno-lower alkoxy group, and R1 and R2 are the same or differently denotes a lower alkyl group, where A is N or C
Indicates H. This invention relates to a method for stereoselectively producing a compound represented by

That is, the compound represented by the general formula (I) has three asymmetric carbon atoms and four diastereoisomers. These diastereoisomers are
The general formula (I) has different agricultural bactericidal activity and antifungal activity, and has a more active steric configuration.
Provided is a method for stereoselectively producing an isomer represented by

[0006]

BACKGROUND OF THE INVENTION A variety of triazole compounds having agricultural fungicidal and antifungal activities are known, but a compound having an oxetane skeleton is described in European Patent Publication (EP-318214A) (A ) are only manufactured.

[0007]

[C7]

However, the method for producing compound (A) is

0
009]

[Chemical formula 8]

##STR1## The configuration of the 4-position of the oxetane ring cannot be controlled, and both an isomer in which the 4-position is α-coordinated and an isomer in which the 4-position is β-coordinate are produced. For this reason, compound (c)
The isomers of compound (A) are separated by chromatography, and each of the obtained isomers is used to perform a cyclization reaction to obtain an isomer in which the 4-position of compound (A) is α-coordinated and an isomer in which the 4-position is β-coordinated. I am getting .

[0011] Further, as a method for producing an oxetane ring, see Sato and Tamura, Tetrahedron Letters, Vol. 25, pp. 1821 to 1824 (1984): T. Sa
to, K. Tamura. , Tetrahedron
Letters, vol 25, 1821-1824
(1984),

0012

[Chemical formula 9]

Compound (d) is formed by the photoreaction represented by
There is a report that compound (f) was obtained from compound (e). However, there is no description regarding its yield, physical properties, and optimum wavelength. Furthermore, no consideration has been given to the steric structure at the 4-position of the oxetane ring of compound (f).
), there are no stereoisomers at the 3-position of the oxetane ring.

On the other hand, the oxetane ring (
i) was reported to have been obtained by T. Openlaender
and P. schoenholzer [Helv
etica Chimica Acta, Vol. 72
, 1792, (1989)]. However, although there is a description of the asymmetry of the 2-position of the oxetane ring, the 3- or 4-position of the oxetane ring is not an asymmetric carbon, and as a matter of course there is no description of the stereochemistry at those positions.

[0015]

[Chemical formula 10]

[0016]

[Problems to be Solved by the Invention] As a result of many years of intensive research into the synthesis of derivatives having a triazole skeleton and their physiological activities, the present inventors have found that they have a structure different from that of conventional triazole compounds. It has been discovered that novel triazole compounds having an oxetane skeleton have excellent agricultural fungicidal activity and antifungal activity, and a method for stereoselectively producing the more highly active isomers of these compounds. They discovered this and completed the present invention.

[0017]

【composition】

[0018]

SUMMARY OF THE INVENTION The present invention comprises a novel method for producing oxetane derivatives or salts thereof, and a method for separating them.

The present invention provides the general formula (V)

[0020]

[Chemical formula 11]

[In the formula, X1, X2, X3 and R have the same meanings as above, and A represents N or CH. ] and the general formula (VI)

[0022]

[Chemical formula 12] R1 -CH=CH-R2
(VI) [wherein R1 and R2 have the same meanings as above. ] under light irradiation to form a compound represented by the general formula (IV)

[0023]

[Chemical formula 13]

[In the formula, X1, X2, X3, R1
, R2 and R have the same meanings as above. ] A method for stereoselectively producing a compound represented by formula (II)

[0025]

[Chemical formula 14]

[In the formula, X1, X2, X3, R1
and R2 have the same meanings as above, and Y represents a nucleophilic leaving group. ] is reacted with triazole or imidazole to form a compound represented by the general formula (I)

[0027]

[Chemical formula 15]

[In the formula, X1, X2, X3, R1
and R2 have the same meanings as above, and A represents N or CH. This invention relates to a method for stereoselectively producing a compound represented by

The present invention is expressed by the following formula.

[0030]

[Chemical formula 16]

The present invention further relates to a process for isolating a compound of general formula (I) from a reaction mixture by derivatizing the compound into a salt.

The "halogen atom" in the definitions of X1, X2 and X3 refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

[0033] In the above, X1, X2, X3,
The "lower alkyl group" in the definitions of R1, R2 and R is, 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, 1,1
-dimethylbutyl, 1,2-dimethylbutyl, 1,
A straight or branched alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms, such as 3-dimethylbutyl or 2,3-dimethylbutyl. is a methyl group or an ethyl group.

[0034] In the above, X1, X2, X3,
The "lower alkoxy group" in the definitions of R1, R2, and R is a group in which the above-mentioned "lower alkyl group" is bonded to an oxygen atom.

In the above, X1, X2 and X3
"Lower halogenoalkyl group" in the definition of
- A group in which the above-mentioned "lower alkyl group" is substituted with 1 to 3 halogen atoms, such as trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, and 2,2-dibromoethyl, and is preferably is a lower alkyl group having 1 to 2 carbon atoms, such as trifluoromethyl, trichloromethyl, difluoromethyl, 2-bromoethyl, 2-chloroethyl or 2-fluoroethyl, in which 1 to 1 fluorine atom, chlorine atom or bromine atom is present. A 3-substituted group, more preferably trifluoromethyl, trichloromethyl, difluoromethyl, 2-bromoethyl,
2-chloroethyl or 2-fluoroethyl.

In the above, X1, X2 and X3
The "lower halogenoalkoxy group" in the definition is a group in which the "lower halogenoalkyl group" is bonded to an oxygen atom.

In the above, the "aralkyl group" in the definition of R refers to a group in which an "aryl group" is bonded to the "lower alkyl group", such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenyl Lower alkyl groups substituted with 1 to 3 aryl groups such as methyl, triphenylmethyl, α-naphthyldiphenylmethyl, 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) Groups such as lower alkyl groups such as methyl and piperonyl, lower alkyl groups substituted with 1 to 3 aryl groups whose aryl rings are substituted with lower alkoxy, nitro, halogen, and cyano groups. and preferably a group in which one or two aryl groups having 6 to 12 carbon atoms are bonded to a lower alkyl group having 1 or 2 carbon atoms, such as a benzyl group or a diphenylmethyl group. , more preferably a benzyl group or a diphenylmethyl group.

[0038] In the above, the "bicyclic terpene hydrocarbon residue" in the definition of R includes, for example, 3-pinanyl,
Camphenyl, nocaladienyl, nocalanyl, bornenyl, norboranyl groups, etc.

The "protecting group" in the definition of R is a protecting group for a hydroxyl group in a reaction, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl, tridecanoyl. ,
Alkanoyl groups such as palmitoyl and stearoyl,
Halogenated alkanoyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower alkoxyalkanoyl groups such as methoxyacetyl, unsaturated alkanoyl groups such as (E)-2-methyl-2-butenoyl, etc. Aliphatic acyl group; arylcarbonyl group such as benzoyl, α-naphthoyl, β-naphthoyl, halogenated arylcarbonyl group such as 2-bromobenzoyl, 4-chlorobenzoyl, 2
, 4,6-trimethylbenzoyl, lower alkylated arylcarbonyl groups such as 4-trioyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, nitrated arylcarbonyl groups such as 4-nitrobenzoyl, 2-nitrobenzoyl. groups, aromatic acyl groups such as lower alkoxycarbonylated arylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl, arylated arylcarbonyl groups such as 4-phenylbenzoyl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t- Butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl,
Tri-lower alkylsilyl group such as triisopropylsilyl, tri-lower alkylsilyl group substituted with 1 or 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisolopylsilyl, phenyldiisolopylsilyl Silyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl,
Lower alkoxymethyl groups such as butoxymethyl, t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, 2,2,2
- Alkoxymethyl groups such as halogenated lower alkoxymethyl such as trichloroethoxymethyl, bis(2-chloroethoxy)methyl; 1-ethoxyethyl, 1-(
Lower alkoxylated ethyl groups such as isoproxy)ethyl, halogenated ethyl groups such as 2,2,2-trichloroethyl, arylzelenenylated ethyl groups such as 2-(phenylzelenenyl)ethyl, etc. Substituted ethyl group; lower alkyl substituted with 1 to 3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethole 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-cyanobenzyldiphenyl Lower alkyl groups such as methyl, bis(2-nitrophenyl)methyl, and piperonyl, lower alkyl groups substituted with 1 to 3 aryl groups whose aryl rings are substituted with lower alkoxy, nitro, halogen, and cyano groups, etc. Aralkyl group; lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2
, 2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl; alkoxycarbonyl groups such as lower alkoxycarbonyl groups substituted with halogen or tri-lower alkylsilyl groups; alkenyloxy such as vinyloxycarbonyl, allyloxycarbonyl; Carbonyl group; benzyloxycarbonyl,
The aryl ring is substituted with one or two lower alkoxy or nitro groups, such as 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl. It is a protecting group in the reaction such as an optional aralkyloxycarbonyl group, and preferably an aliphatic acyl group, a tri-lower alkylsilyl group or an alkoxymethyl group.

The "cycloalkyl group" in the definition of R is, for example, a cycloalkyl group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and preferably cyclohexyl.

[0041] The "nucleophilic leaving group" in the definition of Y is
For example, halogen atoms such as chlorine, bromine, and iodine; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno-lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; benzene It represents a leaving group such as an arylsulfonyloxy group such as sulfonyloxy or p-toluenesulfonyloxy, preferably a halogen atom or a lower alkanesulfonyloxy group, and more preferably a chlorine atom or a methanesulfonyloxy group. It is.

The compounds represented by the general formulas (I) to (V) of the present invention are preferably those represented by the general formulas (I) and (II).
, (III) and (IV), R1 and R2 are both methyl groups, X1 is a chlorine atom or a fluorine atom at the 4-position of the benzene ring, and X2 and X3 are hydrogen atoms. In the formula (V), compounds in which X1 is a chlorine atom or a fluorine atom at the 4-position of the benzene ring and X2 and X3 are hydrogen atoms can be mentioned.

The first step of this method is to prepare a carbonyl compound (
This is a step of subjecting V) and an olefin compound (VI) to a photoreaction to stereoselectively produce an oxetane compound (IV).

R is preferably an alkyl group branched at the 1-position such as isopropyl group, s-butyl group, or s-hexyl group, or the above-mentioned "aryl group" such as benzhydryl group. 2 or 3 substituted methyl group, or (-)-menthyl group, (+)-menthyl group, 8-phenylmenthyl group, (-)-2-phenylcyclohexyl group, (+)-2-phenylcyclohexyl group, 2-hydroxycyclohexyl group, 2-acetoxycyclohexyl group, 2-methoxyethoxycyclohexyl group, 2-(t
-butyldimethylsilyloxy)cyclohexyl group, 2
- A cyclohexyl group having an alkyl group, phenyl group, aralkyl group, hydroxyl group, or a hydroxyl group protected with a hydroxyl group-protecting group as a substituent at the 2-position of the "cyclohexyl group" such as a benzylcyclohexyl group, and more preferably , an alkyl group, a phenyl group, an aralkyl group at the 2-position,
It is a cyclohexyl group that has a hydroxyl group or a hydroxyl group protected with a hydroxyl protecting group as a substituent.

The optimum wavelength of the light to be irradiated differs depending on the carbonyl compound and olefin compound used as raw materials, but there is no restriction on the light source as long as it contains light of approximately 280 to 600 nm, but it is preferably 300 to 400 nm. , more preferably around 350 nm. If wavelengths of 280 nm or less are included, it is preferable to remove them using a filter or the like.

This step is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction, such as benzene, toluene, xylene,
Aromatic hydrocarbons such as chlorobenzene, nitriles such as acetonitrile and benzonitrile, alcohols such as methanol, ethanol and i-propanol, ethers,
Ethers such as tetrahydrofuran, lower aliphatic hydrocarbons such as hexane, pentane, cyclohexane, or a mixed solvent thereof are used. Preferably, in order to prevent light of 285 nm or less from being transmitted, the solvent acts as a filter while being a solvent. aromatic hydrocarbons (especially benzene,
Toluene, chlorobenzene) or a mixed solvent thereof is used.

[0047] The filter that prevents light of 285 nm or less from passing through is not particularly limited, but examples include Pyrex glass, glass filters that cut specific wavelengths, resin filters, and fluorescent dyes. Also, when using these filters,
The solvent does not necessarily need to be benzene, toluene, chlorobenzene, etc. as described above, as long as it dissolves the raw materials.

[0048] The reaction temperature is not particularly limited, and is preferably -2
It is carried out at 0°C to 80°C, more preferably at 10°C to 40°C.

The reaction time mainly depends on the reaction temperature, raw material compounds,
Although it varies depending on the irradiated light and the type of solvent used, the time is usually 1 hour to 4 days, preferably 2 hours to 2 days.

The second step is a step of reducing the ester compound (IV) to produce the alcohol compound (III).

This step can be carried out using a general ester reduction method, for example, the method described in New Experimental Chemistry Course (edited by the Chemical Society of Japan), Vol. 15, Oxidation and Reduction [II]. The reducing agent is preferably a borohydride compound such as lithium aluminum hydride, sodium borohydride-lithium chloride, or lithium borohydride.

The solvent used is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and ethylene glycol dimethyl ether are preferred.

The reaction time varies depending on the reagents used, temperature, etc., but is usually 30 minutes to 5 hours, preferably 1 hour.
3 hours to 3 hours.

The third step is alcohol compound (III)
converting the unprotected hydroxyl group of into a nucleophilic leaving group Y,
This is a process for producing compound (II).

For example, when Y is a halogen atom, the reaction is carried out using a halogenation reagent that is generally considered to be a halogenation reagent, but preferably a thionyl halide such as thionyl chloride, thionyl bromide, and thionyl iodide. kind,
Sulfonyl halides such as sulfonyl chloride and sulfonyl bromide; phosphorus trihalides such as phosphorus trichloride and phosphorus tribromide; phosphorus pentahalides such as phosphorus pentachloride, phosphorus pentabromide, and phosphorus pentaiodide. Alternatively, phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide are used, and phosphorus oxyhalides or thionyl halides are preferably used.

Note that when alcohol compound (III) with a ratio of 3α:3β≒1:1 is chlorinated with thionyl chloride,
Chloride (II) (Y
=Cl) is produced. This is extremely convenient for producing Compound (I), which has higher biological activity than other stereoisomers.

When Y is a sulfonyl group, for example, the compound (I
II) and a compound having the general formula R3 SO2 -O-SO2 R3 (wherein R3 is a lower alkyl group such as methyl or ethyl; a halogen lower alkyl group such as trifluoromethyl or pentafluoroethyl; benzene, p
- indicates an aryl group such as toluene. ) or formula R3
This is achieved by reacting a compound having SO2 -Z (wherein R3 has the same meaning as above, and Z represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom).

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. ; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as ether, tetrahydrofuran, dioxane, dimethoxytane, or dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphorotriamide, more preferably aromatic hydrocarbons such as toluene or halogenated hydrocarbons such as methylene chloride.

The base to be used is not particularly limited as long as it is used as a base in ordinary reactions, but preferably alkali metal hydrogen such as lithium hydride, sodium hydride, potassium hydride Inorganic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-
dimethylamino)pyridine, N,N-dimethylaniline, 1,5-diazabicyclo[4.3.0] nona-
5-ene, 1,4-diazabicyclo[2.2.2]
Octane, 1,8-diazabicyclo[5.4.0]
Organic bases such as undec-7-ene (DBU) or organometallic bases such as butyllithium and lithium diisopropylamide are preferred, and more preferably organic bases such as pyridine and triethylamine are used.

The reaction temperature for halogenation is room temperature to 150°C.
The temperature is preferably 80°C to 120°C. Sulfonation is carried out at -20°C to 50°C, preferably -15°C to room temperature.

[0061] The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually from 5 minutes to 10 hours.

The fourth step is a step of producing triazole compound (I) from compound (II).

In this step, among the isomers related to the 3-position of the oxetane ring of compound (II), only the isomer (IIa) in which the 3-position is α-coordinated reacts selectively, stereospecifically converting the compound ( A single stereoisomer of I) is formed; the β-coordinated isomer (IIb) remains unreacted.

[0064]

[Chemical formula 17]

The selectivity of the reaction is controlled by the coordination of the substituent at the 3-position, so the 3-position is an α-coordinated isomer, and the 3-position is a β-coordinated isomer.
Even if the reaction is carried out in the coexistence of coordination isomers, the desirable 3
Only the isomer with the α-coordinated position reacts, and the isomer with the β-coordinated position at the 3rd position remains unreacted and is quantitatively recovered. Therefore, it is not necessary to separate the isomer in which the 3-position is α-coordinated and the isomer in which the 3-position is β-coordination of starting compound (II) prior to this reaction, and the compound (
This is extremely advantageous in the production of I).

Compound (I) has 3 asymmetric carbon atoms and exists in 4 diastereomers, but according to this method, the compound (I) with the more active stereoisomer (
Only I) can be produced in just four steps, making it extremely useful.

[0067] In this step, 1 equivalent or more of 1H-1 is added in the solvent.
, 2,4-triazole or imidazole in the presence of 1 equivalent or more of a base, or 1H-1,
This is achieved by reacting a base salt of 2,4-triazole or imidazole.

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 hexane, heptane, ligroin,
Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; Ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol , cyclohexanol, alcohols such as methyl cellosolve; nitro compounds such as nitroethane, nitrobenzene;
Nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, 1,3
Amides such as dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide and sulfolane, more preferably formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, 1,3-dimethyl Amides such as -2-imidazolidinone.

The base to be used is not particularly limited as long as it is used as a base in ordinary reactions, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate and carbonate. Alkali metal bicarbonates such as potassium hydrogen; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide; Sodium methoxide, sodium ethoxide, potassium-t-
Alkali metal alkoxides such as butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N
, N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2. 2] Octane (DABCO), 1
, 8-diazabicyclo[5.4.0]undec-7-ene (DBU) or butyllithium,
Organometallic bases such as lithium diisopropylamide, and more preferably alkali metal carbonates such as sodium carbonate and potassium carbonate.

In order to carry out the reaction effectively, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, alkali halides such as sodium iodide, sodium bromide, and lithium bromide are used. earth metal, dibenzo-18-
Crown ethers such as Crown-6 can also be added.

The reaction temperature is -78°C to 200°C, preferably -20°C to 150°C.

[0072] The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually from 1 hour to 24 hours.

[0073] After completion of the reactions in each of the above steps, the target compound is collected from the reaction mixture according to a conventional method.

For example, it can be obtained by adding a water-immiscible organic solvent 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.

Regarding the isolation of compound (I), it may be easier to isolate it as a salt using a conventional method for obtaining a salt. Such salts include, for example, inorganic acids such as hydrofluoric acid, hydrobromic acid, perchloric acid, nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, etc. It is a salt of lower alkylsulfonic acid, benzenesulfonic acid, arylsulfonic acid such as p-toluenesulfonic acid, and organic acid such as oxalic acid and succinic acid.

Among these salts, for example, nitrate, oxalate, and hydrochloride are prepared by adding an organic solvent and each acid to the crude target product obtained by treating the reaction mixture, isolating the target product as crystals, and filtering. Alternatively, it can be separated from the organic solvent as an aqueous solution of the salt of the target product by separating the solution using a separatory funnel. When the salt is collected by filtration as crystals, the desired product can be obtained by suspending the salt in water again, adding a base, adding an organic solvent that dissolves the target product, and separating and dissolving it in the organic solvent. In the case of separation as an aqueous solution of the salt of the target product, the target product can be obtained by subsequently adding a base to the obtained aqueous solution, adding an organic solvent that dissolves the target product, and performing separation and dissolution in the organic solvent. can. Among these salts, nitric acid has an inherent risk of explosion, so care must be taken when mass-synthesizing it. Oxalate does not have very good isolation efficiency as a crystal, so it is not very preferable. Furthermore, when nitrates and oxalates are isolated as crystals and liberated again with a base, it is necessary to use a large amount of solvent and water, and at the same time, it is necessary to filter the salt crystals.

On the other hand, when it is isolated as a hydrochloride, there is no danger of explosion and isolation efficiency is also good, which is preferable. In the case of hydrochloride, unlike nitrate and oxalate, it has a very high solubility in water, so it can be efficiently dissolved into an aqueous solution by simply adding hydrochloric acid and an organic solvent to the crude target substance and separating the liquids. There is no need to use large amounts of water. At the same time, the operation of filtering the salt as crystals becomes unnecessary, making this a very advantageous isolation method.

[0078] When the crude target product is separated between an organic solvent and hydrochloric acid, the organic layer contains the compound (II) whose oxetane ring 3-position is β-coordinated and which did not participate in the reaction in the fourth step. The isomer is quantitatively recovered. The hydrochloric acid used for this purpose is preferably 1N to 12N hydrochloric acid, more preferably 4 to 7N hydrochloric acid.

[0079] When separating the crude target product as a water-soluble salt,
The solvent used to recover the isomer in which the 3-position of the oxetane ring of unreacted compound (II) is β-coordinated is not particularly limited, but preferably heptane, hexane, petroleum ether, ligroin, petroleum Hydrocarbons such as benzine and cyclohexane, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as methylene chloride, dichloroethane, and chloroform, esters such as ethyl acetate and propyl acetate, diethyl ether, and tetrahydrofuran. and more preferably hydrocarbons such as heptane, hexane, petroleum ether, ligroin, petroleum benzene, and cyclohexane.

The base added to the salt dissolved in the aqueous solution is not particularly limited as long as it is a base used in the aqueous solution, but preferably alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate, and hydrogen carbonate. Alkali metal bicarbonates such as potassium, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, and organic bases such as triethylamine and pyridine, more preferably are alkali metal carbonates such as sodium carbonate and potassium carbonate.

In the above method, the compound synthesized as a racemate is optically resolved by adding a well-known resolution reagent, for example, an optically active acid such as camphorsulfonic acid, to the racemate to form a crystalline salt. By doing so, only one optically active substance can be taken out.

The present invention will be explained in more detail with reference to Examples below.

[0083] The mark "*" in the text indicates a racemic body. That is, (
The designation 2R*,3S*) means a 1:1 mixture of the (2R,3S) and (2S,3R) isomers, which has the same meaning as (2S*,3R*). on the other hand,(
The designation 2R*, 3R*) means a 1:1 mixture of the (2R, 3R) and (2S, 3S) isomers, which has the same meaning as (2S*, 3S*).

[0084]

【Example】

Example 1 (2R*,4R*)-2-(4-chlorophenyl)
-3,4-Dimethyl-2-ethoxycarbonyl-oxetane 2-butene was bubbled into benzene (200 ml) at 0°C until the volume became about 1.25 times the volume. Here, ethyl 4-chlorophenylglyoxylate (24.3 g, 114
．． 450 manufactured by Hanovia at 15°C.
It was irradiated with a W medium pressure mercury lamp for 3 hours. Concentrate the reaction mixture;
The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain the desired product as an oil (23.4 g).

Yield: 76% Boiling point: 141-14
The ratio of isomers was determined using a 2°C/2.7 torr NMR spectrum, and it was found that α:β≒1:1 regarding the coordination at the C3 position.
It was a mixture of

NMR (CDCl3) δppm: 0.76
(d, J=7.66Hz), 1.23 ~ 1.31 (m
), 1.34 (d, J = 6.04Hz), 2.83 (q
uint, J=7.25Hz), 3.55(quint
, J=7.25Hz), 4.16 ~ 4.32 (m),
4.56 (quint, J=6.45Hz), 5.06
(quint, J=7.25Hz), 7.26-7.4
7 (m) mass spectrum (m/z): 268 (M+),
224,213,195,178,167 Example 2 (2R*,4R*)-2-(4-chlorophenyl)
Ethyl 4-chlorophenylglyoxylate (53.16 g, 0.25 mol) was added to -3,4-dimethyl-2-ethoxycarbonyl-oxetane benzene (700 ml), and 2-butene (69.0 g, 1.5 mol) was added thereto at room temperature. 23mo
l) was injected. It was irradiated with a Toshiba 20W black light blue fluorescent lamp for 50 hours at room temperature. After the reaction was completed, the solvent was distilled off to obtain 67 g of the desired product.

According to the NMR spectrum, this product is C3
It was a mixture of α:β≈1.25:1.00 regarding the positional coordination.

Yield: 99.7% Oil The following compound was produced according to the method of Example 1.

[0089]

[Chemical formula 18]

[0090]

[Chemical formula 19]

[0091]

[C20]

[0092] The NMR spectra and MS data obtained in each example are shown below.

Example 3 NMR spectrum (CDCl3) δppm: 7.4
2 (2H, dd, J=2.2, 8.8Hz), 7.28
(2H, dd, J=3.6, 8.8Hz), 5.03(
dq, J = 7.2, 7.7 Hz), 4.54 (dq, J
= 7.2, 7.4Hz), 4.15 (2H, t, J = 7
．． 5Hz), 3.51(dq, J=7.7, 7.8Hz
), 2.80 (dq, J=7.4, 7.5Hz), 1.
58 (2H, m), 1.20-1.35 (m), 0.8
0-1.95 (3H, m), 0.75 (d, J=7.8
Hz) Example 4 NMR spectrum (CDCl3) δppm: 7.4
4 (2H, dd, J=2.5, 8.8Hz), 7.32
(2H, dd, J=3.8, 8.8Hz), 5.01~
5.12 (m), 4.54 (bdq, J=6.2Hz)
, 3.51 (bdq, J=7.6Hz), 2.81 (b
dq, J=7.1Hz), 1.17-1.34(m),
0.75 (d, J=7.6Hz) mass spectrum (m
/z): 282 (M+), 195, 139 Example 5 Mixture of diastereomers derived from chirality of alcohol moiety NMR spectrum (CDCl3) δppm: 7.2
7-7.50 (4H, m), 4.87-5.09 (m
), 4.55 (dq, J=6.4, 6.8Hz), 4.
54 (dq, J=6.4, 6.8Hz), 3.54 (d
q, J=7.7, 7.9Hz), 3.50(dq, J=
7.7, 7.9Hz), 2.83 (dq, J=6.8,
7.1Hz), 2.81(dq, J=6.8, 7.1H
z), 1.44 ~ 1.67 (2H, m), 1.10 ~
1.40(m), 0.67-0.97(m) Mass spectrum (m/z): 296(M+), 241,197,1
39 Example 6 NMR spectrum (CDCl3) δppm: 7.2
7-7.45 (4H, m), 5.03 (dq, J=6.
5,7.7Hz), 4.53 (dq, J=6.3,6.
7Hz), 3.51 (dq, J=7.6, 7.7Hz)
, 2.79 (dq, J=6.7, 7.0Hz), 1.4
4 (3H, s), 1.43 (6H, s), 1.31 (d
, J=6.3Hz), 1.31(d, J=7.0Hz)
, 1.23 (d, J = 6.5Hz), 0.74 (d, J
=7.6Hz) Mass spectrum (m/z): 296 (M
+), 239, 195, 139 Example 7 Mixture of diastereomers derived from chirality of alcohol moiety NMR spectrum (CDCl3) δppm: 7.2
5-7.45 (4H, m), 5.04 (bdq, J=6
．． 7Hz), 5.03 (bdq, J=6.7Hz), 4
．． 88 (bdq, J = 7.0Hz), 4.77 (q, J
= 6.7Hz), 4.71 (q, J = 6.7Hz), 4
．． 56 (bdq, J=7.0Hz), 3.56 (bdq
, J=8.1Hz), 3.48(bdq, J=8.1H
z), 2.87 (bdq, J=7.4Hz), 2.84
(bdq, J=7.4Hz), 0.67 ~ 1.35 (
14H, m) Mass spectrum (m/z): 324 (M+
), 269, 195, 139 Example 8 NMR spectrum (CDCl3) δppm: 7.2
0-7.45 (14H, m), 6.94 (s), 6.8
8(s), 5.07(dq, J=6.5, 7.9Hz)
, 4.56 (dq, J=6.5, 6.7Hz), 3.5
6 (dq, J=7.3, 7.9Hz), 2.89 (dq
, J=6.7, 6.9Hz), 1.34(d, J=6.
5Hz), 1.26 (d, J=6.5Hz), 1.07
(d, J=6.9Hz), 0.78(d, J=7.3H
z) Example 9 NMR spectrum (CDCl3) δppm: 7.4
5 (2H, dd, J=4.0, 9.9Hz), 7.32
(2H, dd, J=4.4, 9.9Hz), 5.06(
dq, J=6.7, 7.9Hz), 4.80 ~ 4.9
5 (1H, m), 4.56 (dq, J = 6.5, 6.5
Hz), 3.52 (dq, J=7.9, 8.1Hz),
2.83 (dq, J=6.5, 6.5Hz), 0.80
~1.94 (10H, m), 1.34 (d, J=6.7
Hz), 1.30 (d, J=6.5Hz), 1.26 (
d, J = 6.5Hz), 0.78 (d, J = 8.1Hz
) Example 10 Mixture of diastereomers derived from chirality of alcohol moiety NMR spectrum (CDCl3) δppm: 7.2
5-7.48 (4H, m), 5.04 (dq, J=7.
2,8.0Hz), 4.65-4.82 (1H, m),
4.55 (dq, J=6.4, 7.2Hz), 4.53
(dq, J=6.4, 7.2Hz), 3.55 (dq,
J=8.0, 8.0Hz), 3.48(dq, J=8.
0,8.0Hz), 2.84(dq, J=7.2,7.
2Hz), 2.82 (dq, J=7.2, 7.2Hz)
, 0.50-2.05 (24H, m) Example 11 Mixture of diastereomers derived from chirality of alcohol moiety NMR spectrum (CDCl3) δppm: 7.2
5-7.48 (m), 5.04 (dq, J = 7.2, 8
．． 0. Hz), 4.65-4.82 (m), 4.55 (
dq, J = 6.4, 7.2 Hz), 4.53 (dq, J
=6.4, 7.2Hz), 3.55(dq, J=8.0
, 8.0Hz), 3.48 (dq, J=8.0, 8.0
Hz), 2.84 (dq, J=7.2, 7.2Hz),
2.82 (dq, J=7.2, 7.2Hz), 0.50
~2.05 (m) Mass spectrum (m/z): 378 (M+), 323,
195,139 Example 12 NMR spectrum (CDCl3) δppm: 7.1
0-7.51 (9H, m), 5.00 (dq, J=6.
9,7.2Hz), 4.85(m), 4.57(dq,
J=6.5, 6.7Hz) 3.36(dq, J=7.2
, 7.2Hz), 2.77 (dq, J=6.7, 6.9
Hz), 1.85-2.10(m), 0.70-1.7
5 (m) Mass spectrum (m/z): 454 (M+), 215,
195,139 Example 13 Mixture of diastereomers derived from chirality of alcohol moiety NMR spectrum (CDCl3) δppm: 7.0
5-7.38 (9H, m), 5.00-5.20 (m
), 4.73 (dq, J=7.2, 7.5Hz), 4.
51 (dq, J=7.2, 7.5Hz), 4.36 (d
q, J=7.2, 7.2Hz), 4.12(dq, J=
7.2, 7.2Hz), 2.52-3.08(m), 1
．． 19-2.18 (7H, m), 1.22 (d, J=7
．． 2Hz), 1.11 (d, J=7.2Hz), 0.8
4 (d, J = 7.5 Hz), 0.59 (d, J = 7.5
Hz) Mass spectrum (m/z): 398 (M+), 3
43,195,139 Example 14 Mixture of diastereomers derived from chirality of alcohol moiety NMR spectrum (CDCl3) δppm: 7.0
5-7.38 (9H, m), 5.00-5.20 (m
), 4.73 (dq, J=7.2, 7.5Hz), 4.
51 (dq, J=7.2, 7.5Hz), 4.36 (d
q, J=7.2, 7.2Hz), 4.12(dq, J=
7.2, 7.2Hz), 2.52-3.08(m), 1
．． 19-2.18 (7H, m), 1.22 (d, J=7
．． 2Hz), 1.11 (d, J=7.2Hz), 0.8
4 (d, J = 7.5 Hz), 0.59 (d, J = 7.5
Hz) Mass spectrum (m/z): 398 (M+), 3
43,195,139 Example 15 NMR spectrum (CDCl3) δppm: 7.4
4 (2H, d, J = 8.8Hz), 7.35 (2H, d
, J=8.8Hz), 5.07(dq, J=6.5,7
．． 8Hz), 4.50 ~ 4.71 (m), 3.45 ~
3.58 (m), 2.87 (dq, J=7.8, 7.8
Hz), 2.20-2.70 (1H, m), 1.84
~2.18 (2H, m), 1.55 ~1.80 (2H
, m), 1.10 to 1.50 (m), 0.78 (d,
J=7.8Hz) Mass spectrum (m/z): 338(
M+), 197, 141, 139 Example 16 Cis-trans mixture NMR spectrum of alcohol moiety (CDCl3) δppm: 7.25-7.50
(4H, m), 4.75 ~ 5.21 (m), 4.54
(bdq, J=6.6Hz), 4.52 (bdq, J=
6.6Hz), 3.50 (bdq, J=7.1Hz),
3.38 (bdq, J=7.1Hz), 2.86 (bd
q, J=7.3Hz), 2.82(bdq, J=7.3
Hz), 1.20-2.20 (m), 1.24 (d, J
= 6.6Hz), 0.78 (d, J = 7.3Hz) Mass spectrum (m/z): 380 (M+), 325, 19
5,139 Example 17 Mixture of diastereomers derived from chirality of alcohol moiety NMR spectrum (CDCl3) δppm: 7.4
5 (2H, dd, J=3.1, 8.7Hz), 7.33
(2H, dd, J=3.9, 8.7Hz), 5.31(
dq, J = 6.6, 8.1 Hz), 5.03 (dq, J
=7.0,8.1Hz)4.45 ~4.90(m),
4.06-4.32 (1H, m), 3.30-3.6
5 (m), 3.54 (s), 3.26 (s), 3.23
(s), 3.12 (s), 2.87 (bdq, J=7.
4Hz), 2.80 (bdq, J=7.4Hz), 1.
08~2.15(m), 0.75(d, J=7.4Hz
) Oil mass spectrum (m/z): 382 (M+), 295,
265,197,141 Example 18 Mixture of diastereomers derived from chirality of alcohol moiety NMR spectrum (CDCl3) δppm: 7.4
7 (2H, d, J = 8.9Hz), 7.32 (2H, d
d, J=3.8, 8.9Hz), 5.03(dq, J=
7.2, 8.0Hz), 4.62-4.80 (1H, m
), 4.55 (dq, J=6.8, 7.0Hz), 3.
58-3.77 (1H, m), 3.52 (bdq, J=
8.0Hz), 2.78(dq, J=7.0, 7.2H
z), 1.03 to 2.05 (m), 0.75 to 0.94
(m), 0.77 (s), 0.75 (s), 0.04 (
s), -0.04 (s), -0.07 (s), -0.1
8 (s) Mass spectrum (m/z): 452 (M+), 395,
351,297,255,195,141 Example 19 (2R*,3S*,4R*)-2-(4-chlorophenyl)-3,4-dimethyl-2-hydroxymethyl-oxetane (A) and (2R* ,3R*,4R*)-2-(4-chlorophenyl)-3,4-dimethyl-2-hydroxymethyl-oxetane (B) 2-(4-chlorophenyl)-3,4-dimethyl-2-
Ethoxycarbonyl-oxetane (920mg, 3.4
2 mmol, which is (2R*, 3R*, 4R*
) and (2R*, 3S*, 4R*), which is a 1:1 mixture of It was added dropwise and stirred at the same temperature for 30 minutes. Saturated ammonium chloride water and then 1N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5:1) to obtain (2
R*, 3S*, 4R*) of target compound A (336
．． 4 mg) and (2R*, 3R*, 4R*) of target compound B (349.5 mg) were obtained.

Compound A NMR spectrum (CDCl3) δppm: 0.7
0 (3H, d, J = 7.66Hz), 1.24 (3H,
d, J = 6.44Hz), 3.33 (1H, d, J = 7
．． 66Hz), 3.63 (1H, d, J=12.08H
z), 3.87 (1H, d, J=12.08Hz), 4
．． 96 (1H, dq, J=6.44, 7.66Hz),
7.25 (2H, d, J = 8.46Hz), 7.35 (
2H, d, J = 8.46Hz) Mass spectrum (m/z
):223,195,181,167,153,139
Compound B NMR spectrum (CDCl3) δppm: 1.3
6 (3H, d, J = 6.04Hz), 1.36 (3H,
d, J=7.25Hz), 2.18(1H, brdd,
J=5.53, 7.25Hz), 2.65(1H, qu
int, J=7.25Hz), 3.71(1H, dd,
J=5.53, 12.09Hz), 4.02(1H, d
d, J = 7.25, 12.09Hz), 4.56 (1H
, dq, J=6.04, 7.25Hz), 7.24(2
H, d, J = 8.46Hz), 7.33 (2H, d, J
=8.46Hz) Mass spectrum (m/z): 195,
167,139,129,125,115 Example 20 (2R*,4R*)-2-(4-chlorophenyl)
-3,4-dimethyl-2-hydroxymethyl-oxetane ethylene glycol dimethyl ether (400ml)
Sodium borohydride (11.4 g, 0.3
mol) to lithium chloride (12.7 g, 0.3 mo
l) was added and stirred for 50 minutes. (2R*, 4R*
)-2-(4-chlorophenyl)-3,4-dimethyl-2-ethoxycarbonyloxetane (107 g, 0.
4 mol, which is a 1:1 mixture of 3R* and 3S*) was added dropwise over 20 minutes and incubated at 60°C for 2 hours.
Stir for hours. Pour the reaction solution into ice water and adjust the pH with 3N hydrochloric acid.
After adjusting the concentration to 2 to 3, the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 93 g of the target compound. This product was a 1:1 mixture of Compound A and Compound B obtained in Example 19, and each peak could be observed in the NMR spectrum.

Yield 100% Oil Example 21 2-(4-chlorophenyl)-3,4-dimethyl-2-
methanesulfonyloxymethyl-oxetane 2-(4-
chlorophenyl)-3,4-dimethyl-2-hydroxymethyl-oxetane (123 mg, 0.543 mmol
) in dichloromethane (10 ml) at 0°C, methanesulfonyl chloride (0.13 ml, 1.68 mm
ol), then triethylamine (0.24 ml, 1
．． 708 mmol) was added thereto, and the temperature was raised to room temperature while stirring for 4 hours. Add saturated deuterated water to the reaction mixture,
Extracted with dichloromethane. After drying over anhydrous magnesium sulfate, it was concentrated, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain the target compound (107 mg).

Yield: 65% NMR spectrum (CDCl3) δppm: 0.7
2 (3H, d, J = 7.25Hz), 1.21 (3H,
d, J=6.44Hz), 3.02 (3H, s), 3.
25 (1H, quint, J=7.25Hz), 4.3
3 (1H, d, J = 11.68Hz), 4.60 (1H
, d, J=11.68Hz), 5.04(1H, dq,
J=6.44, 7.25Hz), 7.28(2H, d,
J=8.86Hz), 7.37(2H,d,J=8.8
6Hz) Example 22 (2R*, 3S*, 4R*)-2-(4-chlorophenyl)-2-chloromethyl-3,4-dimethyl-oxetane (2R*, 4R*)- obtained in Example 20 2-(4-
chlorophenyl)-3,4-dimethyl-2-hydroxymethyl-oxetane (0.5 g, 2.2 mmol, a mixture of 3S*:3R* ≒1:1), pyridine (0.35 g, 4.4 mmol) ) and toluene (1
thionyl chloride (0.52 g
, 4.4 mmol) was added thereto, and the mixture was heated and stirred at 110° C. for 3 hours. After cooling, it was poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 133 mg of the target product. Ta.

Yield: 49% NMR spectrum (CDCl3) δppm: 0.7
3 (d, J = 7.6 Hz), 1.24 (d, J = 6.4
Hz), 3.25 (dq, J=7.6Hz, 7.6Hz
), 3.80 (d, J=11.9Hz), 4.00 (d
, J=11.9Hz), ), 5.05(dq, J=6.
4Hz, 6.4Hz), 7.2 ~ 7.4 (m) Mass spectrum (m/z): 248, 246, 244,
236, 221, 208, 191, 179, 166, 1
39 Example 23 (2R*,3S*,4R*)-2-(4-chlorophenyl)-3,4-dimethyl-2-[(1H-1,2
,4-triazol-1-yl)methyl]oxetane (
2R*,3S*,4R*)-2-(4-chlorophenyl)-3,4-dimethyl-2-methanesulfonyloxymethyloxetane (107 mg, 0.351 mmo
l), 1H-1,2,4-triazole (51.5 mg
, 0.746 mmol) and sodium iodide (45.
6 mg, 0.304 mmol) of dimethylimidazolidinone (10 ml) was added at 0°C to a suspension of sodium hydride (approximately 60% oil containing 38 mg, 0.950 mmol) in dimethylimidazolidinone (10 ml).
1) was added and stirred at room temperature for 30 minutes. Furthermore, 1 at 90℃
After stirring for 2 hours, an aqueous sodium thiosulfate solution was added. It was extracted with ethyl acetate-hexane (1:1, V/V), washed with water, and dried over anhydrous magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1:1) to obtain the target compound (76.3 mg).
I got it. Yield 78% NMR spectrum (CDCl3) δppm: 0.7
0 (3H, d, J = 7.25Hz), 1.17 (3H,
d, J=6.45Hz), 3.16(1H, quint
, J=7.25Hz), 4.41(1H, d, J=14
．． 5Hz), 4.4 to 4.53 (1H, m), 4.7
6 (1H, d, J = 14.5Hz), 7.25 (2H
, d, J=8.46Hz), 7.36(2H, d, J=
8.46Hz), 7.98(1H,s), 8.42(1
H, s) Mass spectrum (m/z): 278 (M+1), 256
,222,197,164,149,141,139,
129,111,104 Example 24 (2R*,3S*,4R*)-2-(4-chlorophenyl)-3,4-dimethyl-2-[(1H-1,2
,4-triazol-1-yl)methyl]oxetane (2R*,3S*,4R*)-2 obtained in Example 22
-(4-chlorophenyl)-2-chloromethyl-3,4
-dimethyl-oxetane (245mg, 1mmol)
1H-1,2,4-triazole (26 mg, 0.38 mmol) and potassium carbonate (2 ml) were added to a DMF solution (2 ml) of
26mg, 0.19mmol) was added and heated at 130℃ for 5 minutes.
Stir for an hour. After cooling, the mixture was poured into ice water, extracted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, dried over Glauber's salt, and the solvent was distilled off to obtain 260 mg of residue. This material was subjected to silica gel column chromatography.56.
2 mg (yield 81%) of the target product was obtained.

This compound corresponded in all respects to the compound obtained in Example 23.

Example 25 (2R*,3S*,4R*)-2-(4-chlorophenyl)-3,4-dimethyl-2-[(1H-1,2
,4-triazol-1-yl)methyl]oxetane N
, 1H-1 in 1 liter of N-dimethylformamide,
55.3 g (0.4 mol) of potassium carbonate was added to 55.3 g (0.8 mol) of 2,4-triazole, and 120
The mixture was stirred at ℃ for 1 hour. After that (2R*, 4R*)
-2-(4-chlorophenyl)-3,4-dimethyl-2
-Methanesulfonyloxyoxetane (121.9g,
0.4 mol, this one is 3S*:3R* ≒1:1
) was added thereto, and the mixture was stirred at 120°C for 7 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed successively with water and saturated brine, dried, and concentrated. The residue was dissolved in toluene and extracted with 6N hydrochloric acid. Potassium carbonate was added to the hydrochloric acid layer to make the liquid neutral, and the mixture was extracted with methylene chloride. After sequentially washing the methylene chloride layer with water and saturated saline, drying,
Concentrate to (2R*, 3S*, 4R*)-2-(4
-chlorophenyl)-3,4-dimethyl-2-(1H-
1,2,4-triazol-1-yl)oxetane 41
．． 9 g (yield 76%) was obtained. In addition, the toluene layer was sequentially washed with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, dried, and concentrated (2R*, 3R*, 4R*)-2
-(4-chlorophenyl)-3,4-dimethyl-2-methanesulfonyloxyoxetane 56.6 g (recovery rate 9
4%).

The following compound was produced in the same reaction as in Example 25.

[0101]

[C21]

0102] ──────────────────────────
────────────Example number Ar
physical properties
─
──────────────────────────
────────── 26 2,4-F
2-Ph oily substance
27
2-Cl-Ph
oily substance
28 2-Cl, 4-F-Ph
oily substance
29 4-Cl,
2-F-Ph oily substance
30
2,4-Cl2 -Ph oil

31 4-OCF3-Ph
oily substance
32 4-Br-Ph
oily substance
33
4-CF3 -Ph oil
34 2,6-F2-Ph
oily substance
35 Ph
oily substance
36 2,4-F2-Ph
Melting point 145-150℃ (oxalate)
37 2,4-F2-Ph
Melting point 160-177℃ (nitrate) 38
2,4-Cl2-Ph
Melting point 160-164℃ (nitrate) 39
4-Cl-Ph Melting point 135-144℃ (nitrate) 40
4-Cl-Ph Melting point 12
9-142℃ (oxalate) ────────────
────────────────────────Example 41 (2R*, 3S*, 4R*)-2-(4-chlorophenyl)-3,4- diethyl-2-[(1H-1,2
,4-triazol-1-yl)methyl]oxetane Melting point 94-102°C NMR spectrum (CDCl3) δppm: 0.7
2 (3H, t, J = 7.28Hz), 0.96 (3H,
t, J = 7.28Hz), 1.11 (2H, dq, J =
7.28Hz, 7.28Hz), 1.3-1.5 (1H
, m), 1.5-1.7 (1H, m), 2.90 (1H
, dt, J=7.28Hz, 8.26Hz), 4.12
(1H, ddd, J=3.80Hz, 8.26Hz, 1
0.10Hz), 4.36 (1H, d, J=14.65
Hz), 4.73 (1H, d, J=14.65Hz),
7.3-7.4 (4H, m), 7.94 (1H, s),
8.27 (1H, s) MS (m/z): 308,306 (M+1)+ ,29
3,279,265,250,225,141 Example 4
2 (2R*, 3S*, 4R*)-2-(4-fluorophenyl)-3,4-diethyl-2-[(1H-1,
2,4-triazol-1-yl)methyl]oxetane Melting point 92-97°C NMR (CDCl3) δppm: 0.72 (3H, t
, J=7.5Hz), 0.97(3H,t,J=7.3
Hz), 1.12 (2H, quint, J=7.5Hz
), 1.39-1.70 (2H, m), 2.88 (1H
, q, J=7,5Hz)4.16(1H,ddd,J=
3.8, 7.5, 10.2Hz), 4.40 (1H, d
, J=4.6Hz), 4.77(1H, d, J=4.6
Hz), 7.02-7.13 (2H, m), 7.32-
7.39 (2H, m), 7.96 (1H, s), 8.3
7 (1H, s). MS (m/z): 290 (M+1)+, 207.

0
103]

[Reference example]

Reference Example 1 Ethyl 4-chlorophenylglyoxylate To a mixture of chlorobenzene (22.5 g, 0.2 mol), anhydrous aluminum chloride (26.66 g, 0.2 mol) and dichloromethane (50 ml) was added ethyl chloroglyoxylate (13.65 g, 0.2 mol). 0.1 mol) was added under ice cooling and stirring. After the addition, the reaction mixture was stirred at room temperature for 30 minutes, poured into ice water, extracted with ethyl acetate, washed with water, washed with dilute aqueous sodium bicarbonate solution, and finally washed once again with water.
It was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain 15.1 g of the target product.

Yield: 71% Boiling point: 165°C/6
torr (bath temperature) NMR spectrum (CDCl3) δppm: 1.3
9 (3H, t, J = 7, 2Hz), 4.42 (2H, q
, J=7.2Hz), 7.45(2H, d, J=8.6
Hz), 7.95 (2H, d, J = 8.6 Hz) Reference example 2 n-butyl 4-chlorophenylglyoxylate 4-
Ethyl chlorophenylglyoxylate (2.12 g,
10 mmol) in n-butanol solution (20 ml)
) to paratoluenesulfonic acid monohydrate (1.05 g,
5.5 mmol) was added. The reaction mixture was heated at 130°C for 1
After heating for 4 hours, the mixture was concentrated, and the residue was poured into ice and extracted with ethyl acetate. The extract was washed with water and then dried over sodium sulfate. The residue obtained after concentration was distilled under reduced pressure and bp. 150
The target product (2.28 g
, 9.5 mmol) was obtained.

Yield 95% NMR spectrum (CDCl3) δppm: 7.9
8 (2H, d, J = 8.6Hz), 7.50 (2H, d
, J=8.6Hz), 4.39(2H,t,J=6.7
Hz), 1.35 to 1.84 (4H, m), 0.97
(3H, t, J=8.2Hz) Oil (150-16
(5°C/3mmHg) The following compound was produced in the same manner as in Reference Example 2.

[0106] Various data of the compounds produced in each reference example are shown below.

Reference Example 3 NMR spectrum (CDCl3) δppm: 7.9
6 (2H, d, J = 8.8Hz), 7.37 (2H, d
, J=8.8Hz), 5.32 (1H, qq, J=6.
3,8.0Hz), 1.38 (3H, d, J=6.3H
z), 1.37 (3H, d, J = 8.0Hz) Oil mass spectrum (m/z): 225,167,139
Reference example 4 NMR spectrum (CDCl3) δppm: 7.9
7 (2H, d, J = 8.4Hz), 7.50 (2H, d
, J=8.4Hz), 5.16 (1H, tq, J=6.
3,7.0Hz), 1.10-1.89 (2H, m),
1.39 (3H, d, J = 6.3Hz), 0.97 (3
H, t, J=7.5Hz) Oil (165℃/3tor
r) Reference Example 5 NMR spectrum (CDCl3) δppm: 7.9
5 (2H, d, J = 9.0Hz), 7.50 (2H, d
, J=9.0Hz), 1.63 (9H, s) m. p.
104℃ Mass spectrum (m/z): 241(M+1)+,1
41,113 Reference Example 6 NMR spectrum (CDCl3) δppm: 7.9
3 (2H, d, J = 8.6Hz), 7.47 (2H, d
, J=8.6Hz), 4.98(1H, q, J=6.5
Hz), 1.30 (3H, d, J=6.5Hz), 0.
95(9H,s) Oil mass spectrum (m/z): 269(M+1)+,1
68,139 Reference Example 7 NMR spectrum (CDCl3) δppm: 7.9
7 (2H, d, J = 8.8Hz), 7.50 (2H, d
, J=8.8Hz), 5.09 (1H, tt, J=3.
8,9.0Hz), 1.20-2.08 (10H, m) Oil (150-155°C/2mmHg) Mass spectrum (m/z): 266 (M+), 187
, 141, 111 Reference Example 8 NMR spectrum (CDCl3) δppm: 7.9
4 (2H, d, J = 8.8Hz), 7.48 (2H, d
, J=8.8Hz), 4.99 (1H, dt, J=4.
5, 10.9Hz), 2.10 ~ 2.18 (1H, m
), 1.80 ~ 2.02 (1H, m), 1.65 ~
1.77 (2H, m), 1.45 ~ 1.60 (2H,
m), 1.05 to 1.26 (2H, m), 0.75
~1.04 (10H, m) Oil Reference Example 9 NMR spectrum (CDCl3) δppm: 7.9
4 (2H, d, J = 8.8Hz), 7.48 (2H, d
, J=8.8Hz), 4.99 (1H, dt, J=4.
5, 10.9Hz), 2.10 ~ 2.18 (1H, m
), 1.80 ~ 2.02 (1H, m), 1.65 ~
1.77 (2H, m), 1.45 ~ 1.60 (2H,
m), 1.05 to 1.26 (2H, m), 0.75
~1.04 (10H, m) Oil mass spectrum (m/z): 322 (M+), 278
, 182, 139 Reference Example 10 NMR spectrum (CDCl3) δppm: 7.9
2 (2H, d, J = 8.7Hz), 7.48 (2H, d
, J=8.7Hz), 6.94-7.29 (5H, m)
, 5.02 (1H, dt, J=4.3, 10.8Hz)
, 2.03 to 2.15 (1H, m), 1.40 to 1.
72 (3H, m), 0.85 ~ 1.36 (4H, m)
, 1.36 (3H, s), 1.30 (3H, s), 0.
90 (3H, d, J = 6.3Hz) Oil mass spectrum (m/z): 398 (M+), 214
, 119 Reference Example 11 NMR spectrum (CDCl3) δppm: 7.2
3-7.40 (5H, m), 7.21 (2H, d, J=
8.7Hz), 7.12 (2H, d, J=8.7Hz)
, 5.42 (1H, dt, J=5.3, 11.0Hz)
, 2.76 (1H, dt, J=3.7, 11.0Hz)
, 2.20 ~ 2.31 (1H, m), 1.25 ~ 2
．． 08(H,m) Oil Reference Example 12 NMR spectrum (CDCl3) δppm: 7.2
3-7.40 (5H, m), 7.21 (2H, d, J=
8.7Hz), 7.12 (2H, d, J=8.7Hz)
, 5.42 (1H, dt, J=5.3, 11.0Hz)
, 2.76 (1H, dt, J=3.7, 11.0Hz)
, 2.20 ~ 2.31 (1H, m), 1.25 ~ 2
．． 08(H,m) Oil Reference Example 13 NMR spectrum (CDCl3) δppm: 8.0
1 (2H, d, J = 7.9Hz), 7.48 (2H, d
, J=7.9Hz), 4.90 (1H, dt, J=5.
4, 10.2Hz), 3.59 (1H, dt, J=5.
0.10.2Hz), 2.02-2.24 (2H, m)
, 1.65 ~ 1.86 (2H, m), 1.25 ~ 1
．． 60 (4H, m) oil mass spectrum (m/z): 283 (M+1)+,1
85,139 Reference example 14 Oil mass spectrum (m/z): 324 (M+), 139
Reference example 15 NMR spectrum (CDCl3) δppm: 7.9
8 (2H, d, J = 8.7Hz), 7.47 (2H, d
, J=8.7Hz), 5.03 (1H, dt, J=5.
5, 10.0Hz), 4.68 (1H, d, J = 7.3
Hz), 4.64 (1H, d, J=7.3Hz), 3.
61 (1H, dt, J=4.4, 10.0Hz), 3.
29 (3H, s), 2.05 ~ 2.10 (2H, m)
, 1.65 ~ 1.82 (2H, m), 1.20 ~ 1
．． 63 (4H, m) Oil Reference Example 16 NMR spectrum (CDCl3) δppm: 7.9
9 (2H, d, J = 8.9Hz), 7.48 (2H, d
, J=8.9Hz), 4.90 (1H, dt, J=4.
8, 8.6Hz), 3.70 (1H, dt, J=4.8
, 8.6Hz), 1.20-2.40 (8H, m), 0
．． 83 (9H, s), 0.05 (3H, s), -0.0
2(3H,s) Oil mass spectrum (m/z): 397(M+1)+,3
39,244,213,169,141 Reference Example 17 Aqueous solution of potassium 4-chlorophenylglyoxylic acid hydroxide (13 g, 0.23 mol) (
Add ethyl 4-chlorophenylglyoxylate (26.1 g, 0.12 mol) to 150 ml) and stir at room temperature for 30 minutes.
Stir for a minute. After adjusting the pH to 3 by adding concentrated hydrochloric acid, the precipitated crystals were filtered. The crystals were dissolved in ethanol and subjected to azeotropy to remove water and obtain the target compound (22 g, 0.12 mol).
) was obtained.

Yield: 100% Melting point: >300°C
NMR spectrum (DMSO-d6) δppm: 7
．． 57 (2H, d, J = 8.5Hz), 7.87 (2H
, d, J=8.5Hz) IR spectrum (cm-1)
:1662,1600,1589 Reference Example 18 Diphenylmethyl 4-chlorophenylglyoxylate 4
-chlorophenylglyoxylic acid (1.12 g, 6.
Oxalyl chloride (3.8 g, 30 mmol) was added to a methylene chloride solution (25 ml) of oxalyl chloride (1 mmol), and the mixture was stirred at room temperature for 30 minutes. After concentrating to dryness, acetonitrile (12 ml) was added to form a suspension. This suspension was added to a solution of benzhydrol (540 mg, 2.9 mmol) in acetonitrile (10 ml), stirred at room temperature for 1 hour, and then neutralized by adding triethylamine. The reaction solution was poured into ice, extracted with ethyl acetate, washed with water, and then dried over magnesium sulfate. The residue obtained after concentration was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate 9:1 to obtain the target compound (620 mg, 1.77 mmol).
I got it.

Claims (3)

[Claims] Claim 1: General formula (V) [In the formula, X1, X2 and An alkoxy group, R is a lower alkyl group, an aralkyl group, a bicyclic terpene hydrocarbon residue, or a phenyl group which may be substituted at any position on the ring with a lower alkyl group, halogen, lower alkyl, or lower alkoxy. , a lower alkoxy group, an aralkyl group, a hydroxyl group, or a cycloalkyl group substituted with a hydroxyl group protected with a protective group. ] and general formula (VI) [Chemical formula 2] R1 -CH=CH-R2
(VI) [wherein R1 and R2 are the same or different and represent a lower alkyl group. A reaction is carried out under light irradiation with a compound represented by the general formula (IV) [In the formula, X1, X2, X3, R1, R2 and R have the same meanings as above. ] A method for stereoselectively producing a compound represented by [Claim 2] General formula (II) [In the formula, X1, X2 and It represents an alkoxy group, R1 and R2 are the same or different and represent a lower alkyl group, and Y represents a nucleophilic leaving group. ] and triazole or imidazole to form a compound represented by the general formula (I) [wherein, X1, X2, X3, R1 and R2 have the same meanings as above, and A is N or CH shows. ] A method for stereoselectively producing a compound represented by [Claim 3] Claims 1 to 2, wherein R1 and R2 are both methyl groups, X1 is a chlorine atom or a fluorine atom at the 4-position of a benzene ring, and X2 and X3 are hydrogen atoms.
the method of.