WO1998016517A1

WO1998016517A1 - Process for producing isoxazole derivatives and intermediates for producing the same

Info

Publication number: WO1998016517A1
Application number: PCT/JP1997/003584
Authority: WO
Inventors: Hiroyuki Kai; Akira Takase; Minoru Tomida
Original assignee: Shionogi & Co., Ltd.
Priority date: 1996-10-11
Filing date: 1997-10-07
Publication date: 1998-04-23
Also published as: AU4400397A

Abstract

A process for producing compounds represented by general formula (I) (wherein R?1 and R2¿ represent each hydrogen, alkyl, alkoxy, halogeno or -(CH¿2?)n-M-R?3¿ (wherein R3 represents optionally substituted aryl, etc.; M represents oxygen, etc.; and n is 0 or 1)), characterized by reacting a compound represented by general formula (II) (wherein R?1 and R2¿ are as defined above) with acetylene under basic conditions; and a process for producing compounds represented by general formula (VII) which are useful as agricultural germicides from the compounds represented by general formulae (I) and (II) as given above.

Description

/ JP 584

Specification

Method for producing soxoxazole derivative and intermediate for its production

Technical field

The present invention relates to 3—benzoylisoxazoles, which are important intermediates such as antifungal agents and agricultural germicides, and more particularly to unsubstituted 3-benzoyl rings at the 4- and 5-positions of the isoxazole ring. The present invention relates to a novel method for producing soxazole, an intermediate for producing the same, and a novel method for producing a 3-((1-alkoxyminobenzyl) isoxazole derivative which is useful as an agricultural fungicide using the same as a raw material.

Background art

3-Benzyl isoxazoles, which are unsubstituted in the 4- and 5-positions of the isoxazole ring, are isoxazolyl ethanol derivatives that are useful as antifungals and fungicides for agriculture. 5 — 6 9 8 3 5) and 3 — (α-alkoxysiminobenzil) isoxoxazole derivative (W095Z26695) useful as an agricultural fungicide (See No. 6). As a method for producing the intermediate, there is a method based on a Freedel-Craft reaction of 3-isoxazole carboxylic acid chloride and substituted benzene (Japanese Patent Publication No. 5-69835). , 3 — Isoxazole carboxylic acid chloride or 3 — Cyanoisoxazole, etc., 3 — Isoxazole Reactive derivative of carboxylic acid and substituted benzene greener Reaction of urea reagent (W095 Z266956), a dipole of benzoyl nitrile oxide and 1,4-epoxy-1,4-dihydronaphthalene A method using a transductant (T. Sasaki et al., J., S. Perkin I, 1972, 2750—2755), similarly to Benzoi norrenitolinoleoxyside and 2,3-dimethoxycarbonyl 7—Oxa bicyclo [2, [2, 1], a method via a dipole adduct of butadiene [Lubor Fisera, et al., Collection, zechoslovak and hem. Commun., 48, 3144-1 3153 (1983)] is known.

However, there is still room for improvement in these production methods, and a more economical and efficient industrial production method is desired.

Disclosure of the invention

An object of the present invention is to provide an industrially advantageous method for producing 3-benzoylisoxazole in which the 4- and 5-positions of the isoxazole ring are unsubstituted, and an intermediate for the production thereof. Further, the present invention has an object to provide a novel method for producing a 3— (α-alkoxyiminobenzyl) isosoxazole derivative which is useful as an agricultural germicide using them as a raw material. I do.

The present inventors have conducted intensive studies in order to achieve the above object, and as a result, reacted benzohydroxamic acid chloride produced from substituted acetophenone with acetylene in the presence of a base. Aim to produce 3-benzoyl oxoxazole 3-benzoinoleic 5-anorecoxy-1-2-isoxazoline after reacting with butyl or alkyl butyl ether and treat it with acid or base 3— (2—Methylbenzinole) isoxazole Then, phenol is added to this to react with ketoxime etc. for the purpose of 3-benzoynoleic soxazole. It was Heading a way to elephants. Furthermore, the present inventors have found a method for producing a 3- (α-alkoxyiminobenzyl) isosoxazole derivative by oxidizing 3-benzoyl-5-alkoxy-1-2-isosoxazoline to complete the present invention. did. That is, the present invention

General formula (II)

[Where the formula is ¹ ! ^ ² each independently represent a hydrogen atom, an alkyl, Anoreko alkoxy, Nono b Gen atoms, Application Benefits off Noreoro methyltransferase or a (CH ₂₎

-M-R ³ (R ³ is an optionally substituted aryl, M is an oxygen atom or —O—N = C (R ⁴ ) (R ⁴ is a hydrogen atom, alkyl, alkynolechio, cyano , Trifnorolemethyl), and n represents 0 or 1). Acetylene is reacted under basic conditions with the compound represented by the general formula (I):

[Wherein each symbol is as defined above]. 2. General formula (II):

[Wherein each symbol is as defined above], a compound represented by the general formula (III):

R ⁵ OCH = CH ₂ III

[Wherein, R ⁵ represents alkyl. Is reacted under basic conditions to give a compound of the general formula (IV):

[Wherein each symbol is as defined above], and then reacting the compound with an acid or a base.

Wherein each symbol is as defined above,

3. General formula (II):

R ⁵ OCH = CH ₂ III

Wherein the compound represented by the formula: wherein R ⁵ is as defined above, is reacted under basic conditions. The compound represented by the general formula (IV):

[Wherein each symbol is as defined above], 4. A method for producing a compound represented by the following general formula (II):

Wherein each symbol is as defined above, a compound represented by the general formula (III) _:

R ⁵ OCH = CH ₂ III

[Wherein R ⁵ is as defined above] and reacted under basic conditions to give a compound of the general formula (IV):

[Wherein each symbol is as defined above] to obtain a compound represented by the formula

(1) Reaction of an acid or a base with the general formula (I)

[Wherein each symbol has the same meaning as described above], a compound represented by the general formula (V):

NH ₂ OR ⁶ V

[Wherein, R ⁶ represents a hydrogen atom or an alkyl. ] The ability to react the compound represented by

(2) The compound represented by the general formula (V) is reacted to form a compound represented by the general formula (VI):

[Wherein the wavy line (~) indicates an E-form, a Z-form or a mixture thereof, and the other symbols have the same meanings as above.] ,, Or

(3) — a general formula characterized by reacting with the mineral salt of the general formula (V)

(V I I):

Wherein each symbol is as defined above, a method for producing a 3 — (aalkoxyminobenzyl) isosoxazole derivative,

5. General formula (Ia):

Halogenating the compound represented by the general formula (XI

[In the formula, X represents a halogen atom. ], And the compound represented by General formula (XII)

R ³ MH XII

[Wherein each symbol is as defined above], a compound represented by the following general formula (Ib):

The term “lower” used in the present specification for the process for producing the compound represented by the formula (wherein each symbol is as defined above), unless otherwise specified, preferably has 1 to 8 carbon atoms. Or a group having 1 to 6 carbon atoms, more preferably a group having 1 to 4 carbon atoms.

Examples of the alkyl represented by R 1 and R ² include, for example,

Six, preferably 1 to 4 alkyls, specifically methyl, ethyl propynole, isopropynole, butyl, isobutynole, sec-butyl, tert-butyl and the like.

Alkoxy represented by R 1 and R ² includes, for example, alkoxy having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, specifically, methoxy, ethoxy, and prooxy. Poxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

Is a Nono b Gen atoms represented by R l and R ^2, full Tsu atom, chlorine atom, bromine atom and iodine atom.

Examples of the optionally substituted aryl represented by R ³ include aryl having 6 to 14 carbon atoms, such as phenyl and naphthyl. . T 5

Examples of the substituent of the substituted aryl represented by R ³ include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.) and lower alkoxy (eg, methoxy, Ethoxy, propoxy, isopropoxy, butoxy, etc.), cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl, etc.), phenol, halogenated (lower) alkyl

(E.g., trifluoromethyl), Nodogenated (lower) alkyloxy (e.g., difluoromethyoxy), trifluoromethyoxy, etc. Phenyl, halogen atom (e.g., fluorine, chlorine) Atom, bromine atom, iodine atom). Of these, lower alkyls, lower alkoxys, norogenated (lower) alkyls (especially trifluoromethyl), nordogenated (lower) alkoxys (especially difluoromethyoxy) and Halogen atoms are preferred.

These substituents may be located at any substitutable position of the ring. The number of the substituents is 1 to 5, preferably 1 to 4, and more preferably 1 to 3, and they may be the same or different.

Preferred specific examples of R ³ include lower alkyl (preferably methyl), lower alkoxy (preferably methoxy), trifluoromethyl difluoromethylyloxy and halogen atoms ( A phenyl having 1 to 3 substituents selected from the group consisting of preferably chlorine atoms (eg, 2—closed phenyl, 3—closed phenyl, 4— Black mouth fuinore, 2-mechinore fuinore, 3—mechinore fuinore, 4—mechinore fuinore, 2, 5—dimechinore fuinore, 3, 4— Dimethyl phenol, 41-crop _2-dimethyl phenol, 3,4-Dichloro phenol, 3 — Trifrenolelo, Chinole feninole, 41 Trifrenole, Chinolefe Ninore, 4 — Difnoleolo Mech Okishifu enyl, 4 - main DOO Kishifu enyl, etc.) and unsubstituted full E sulfonyl and the like. J

Examples of the alkyl represented by R ⁴ to R ⁶ include the same as those exemplified as the alkyl represented by R ¹ and R ² . R ⁴ is methyl or ethyl, R ⁵ is alkyl having 2 to 5 carbon atoms (eg, ethyl, propynole, isopropynole, butyl, pentyl, etc.),

R ⁶ is preferably methyl.

Examples of the alkylthio represented by R ⁴ include, for example, alkylthio having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, specifically, methylthio, ethylthio, propylthio, isopropylthio, Butylthio and the like. Of these, methylthio is preferred.

Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The compounds represented by the general formulas (VI) and (VII) include E-isomer and Z-isomer, and the present invention includes these isomers and a mixture of these isomers in any ratio. I do. In the present specification, this is indicated by using a wavy line (）) in the general formula.

Hereinafter, preferred specific examples of the production method of the present invention will be described for each step.

0 scheme

(In the formula, each symbol has the same meaning as described above.)

That is, the compound represented by the general formula (II) can be obtained by converting the compound (VIII) with alkyl nitrite and hydrogen chloride in a suitable solvent (single or mixed) by a known method, for example, the method described in Brachwitz, Z. Chera. , 6, 313 (1966).

Alkyl nitrite that can be used includes, for example, methyl nitrite, ethyl nitrite, propyl nitrite, isopropyl nitrite, butyl nitrite, isoamyl nitrite, and the like. The amount of use is 2 or more equivalents, preferably 2 to 6 equivalents, relative to compound (VIII).

Hydrogen chloride can be added by dissolving it in a suitable solvent as a gas to introduce it into the reaction solution. The amount of use is 1 equivalent or more, preferably 1 to 6 equivalents, relative to the compound (VIII). Solvents that can be used include, for example, ethers (eg, dimethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (eg, , Dichloromethane, 1,2-dichloroethane, chlorohonolem, etc.) and mixed solvents of these solvents and aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.) Preference is preferred. .

The reaction temperature is between −20 and 60 ° C., preferably between 0 and 40 ° C.

The reaction time varies depending on the compound, but the reaction may be carried out for 1 to 72 hours. <The desired compound (II) obtained may be used as a reaction solution or in a crude form. Can be purified by recrystallization etc. and used in the next step Scheme 2

(In the formula, each symbol has the same meaning as described above.)

That is, the compound represented by the general formula (IX) can be prepared by converting the compound (VIII) with an alkyl nitrite in a suitable solvent (single or mixed) in the presence of a base in a known manner, for example, in 0. Touster's review: Org. React., 7, 327 (1953).

For example, alkyl nitrites that can be used include methyl nitrite, ethyl nitrite, propyl nitrite, isopropyl nitrite, butyl nitrite, isoamyl nitrite, and the like. The amount of use is 1 equivalent or more, preferably 1 to 1.2 equivalents, relative to compound (VIII).

Examples of the base that can be used include metal alkoxides (eg, sodium methoxide, sodium ethoxide, etc.), and the amount used is based on the compound (VIII). One or more equivalents, preferably one to two equivalents, can be used.

Solvents that can be used include, for example, ethers (eg, dimethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (eg, Examples: dichloromethane, 1,2-dichloroethane, cross-linked form, etc., aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), alcohols (eg, Tano, Eno, Puno, Isopanol, Butano ), Water, and a mixed solvent thereof.

The reaction temperature is from 120 to 120 ° C, preferably from 0 to 50 ° C. The reaction time varies depending on the compound, but the reaction may be carried out for 30 minutes to 24 hours.

The obtained compound (IX) can be used as is in the next step after purification, either as a reaction mixture or crude, or by a conventional method (eg, column chromatography, recrystallization, etc.). can do.

Scheme 3

(In the formula, each symbol has the same meaning as described above.)

That is, the compound represented by the general formula (II) can be produced by chlorinating the compound (IX) in an appropriate solvent (single or mixed). Chlorinating agents that can be used are chlorine, nitrosyl chloride, N-chlorosuccinic acid imid / N, N—dimethylformamide, hydrogen chloride N-dimethylformamide / For example, OXONE (registered trademark) and the like can be used in an amount of 1 equivalent or more, preferably 1 to 2 equivalents, relative to compound (IX).

Solvents that can be used include, for example, ethers (eg, dimethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (eg, Dichloromethane, 1,2-Dichloroethane, chloroform, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), N, N-dimethylforma And a mixed solvent thereof. The reaction temperature is from 120 to 80 (:, preferably from 0 to 40 ° C.

The reaction time varies depending on the compound, but the reaction may be carried out for 30 minutes to 24 hours.

The obtained desired compound (II) can be used as is in the next step after being purified as a reaction solution or a crude product, or by recrystallization or the like.

Scheme 4

(In the formula, each symbol has the same meaning as described above.)

That is, the compound represented by the general formula (II) can be produced by reacting the compound (X) with an alkyl nitrite in a suitable solvent (single or mixed) in the presence of hydrogen chloride. .

Alkyl nitrites that can be used include methyl nitrite, ethyl nitrite, propyl nitrite, isopropyl nitrite, butyl nitrite, isoamyl nitrite, and the like. One or more equivalents, preferably 1 to 3 equivalents, can be used relative to compound (X).

Hydrogen chloride can be introduced into the reaction solution as a gas or dissolved in a suitable solvent and added. The amount of use is 0.1 equivalent or more, preferably 1 to 4 equivalents, relative to compound (X).

Solvents that can be used include, for example, ethers (eg, getyl ether, diisopropinoleether, dibutyl ether, tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (eg, , Dichloromethane, 1,2-dichloroethane, chloroform, etc.), aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.) and their mixed solutions Medium is preferred. .

The reaction temperature is from 120 to 120 ° C, preferably from 0500C. The reaction time varies depending on the compound, but it is sufficient to carry out the reaction for 17 2 hours. The desired compound (II) obtained is purified as it is, in the form of a reaction solution or a crude product, or by recrystallization. Can be used in the next process.

The compound (X) has the ability to use a commercially available product, the chlorination of the corresponding compound (VIII), the corresponding Grignard reagent of a substituted benzene, and the commercially available product 2-chloro N-methoxy. N — easily prepared by methods known in the art, such as the reaction of methyl acetate amide or the Freedel-Crafts reaction of substituted benzene with chloroacetyl chloride. In addition, the following general formula (IIa) included in the compound (II) obtained in the steps of the above-mentioned schemes 13 and 4

(Wherein, R ⁷ and R ⁸ each independently represent a hydrogen atom, an alkyl, an alkoxy, a halogen atom or a trifluoromethyl). The compound represented by the formula: Included in the invention.

Examples of the alkyl, alkoxy, and halogen atoms represented by R ⁷ and R ⁸ include the same groups as those exemplified as the groups represented by R ¹ and R ² .

Scheme 5

(In the formula, each symbol has the same meaning as described above.)

That is, the compound represented by the general formula (I) is produced by reacting the compound (II) with acetylene in a suitable solvent (single or mixed) under basic conditions. Can be done.

Acetylene is used as a gas or diluted with a suitable solvent. The amount of use can be one equivalent or more with respect to the compound (II).

Examples of bases that can be used include metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate, etc.) and metal carbonates (eg, sodium bicarbonate, potassium carbonate) , Calcium carbonate, etc.), organic bases (eg, tertiary amines such as pyridin triethylamine) and the like, and the amount of use is 1 equivalent or 1 equivalent to the compound (II). More than one to five equivalents can be used, preferably.

Solvents that can be used include, for example, ethers (eg, dimethyl ether, diisopropinoleone tenor, dibutyl ether, tetrahydrofuran, dioxane, etc.), ketones (eg, Acetone, methylethyl ketone, etc., halogenated hydrocarbons (eg, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, etc.), aromatic hydrocarbons (eg, , Benzene, tosoleene, xylene, etc.), N, N-dimethylformamide, dimethylsulfoxide, alcohols (eg, methanol, ethanol, phenol, isopropanol) , Butanol) and their mixed solvents.

The reaction temperature is between −10 and 150 ° C., preferably between 0 and 100 ° C. The reaction time varies depending on the compound, but the reaction may be carried out for 30 minutes to 120 hours.

The desired compound (I) thus obtained can be purified as it is, in the form of a crude reaction mixture, or by a conventional method (eg, column chromatography, recrystallization, etc.) and then purified in the next step. Can be used.

Scheme 6

(In the formula, each symbol has the same meaning as described above.)

That is, the compound represented by the general formula (IV) is produced by reacting the compound (II) with the compound (III) in a suitable solvent (single or mixed) under basic conditions. be able to.

Examples of the compound (III) include lower alkyl vinyl ethers such as ethyl vinyl ether and butyl vinyl ether. The amount of the compound used is 1 equivalent or more, preferably 1 to 8 equivalents, based on the compound (II). Can be used.

Examples of bases that can be used include metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate, etc.) and metal carbonates (eg, sodium bicarbonate, potassium carbonate) , Calcium carbonate, etc.), organic bases (eg, tertiary amines such as pyridin triethylamine, etc.), and the amount of use is 1 equivalent or 1 equivalent relative to compound (II). More than one to five equivalents can be used, preferably.

Solvents that can be used include, for example, ethers (eg, getyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran) Lanthanum, dioxane, etc., ketones (eg, acetone, methylethylketone, etc.), halogenated hydrocarbons (eg, dichloromethane, 1,2-dichloroethane) , Carbon tetrachloride, etc.), aromatic hydrocarbons (eg, benzene, tonorenene, xylene, etc.), N, N-dimethylformamide, dimethylsnorreoxide, alcohols (eg, meta- And ethanol, ethanol, propylene, isopropanol, butanol, and the like, and mixed solvents thereof.

The reaction temperature is from 110 to 150 ° C, preferably from 0 to 100 ° C. The reaction time varies depending on the compound, but the reaction may be carried out for 30 minutes to 120 hours.

The desired compound (IV) obtained is purified as it is in the form of a reaction solution or in the form of a crude product, or by a conventional method (eg, column chromatography, recrystallization, etc.). Can be used.

Scheme 7

(In the formula, each symbol has the same meaning as described above.)

That is, the compound represented by the general formula (I) can be produced by reacting the compound (IV) with an acid in a suitable solvent (single or mixed). Acids that can be used include hydrohalic acids (eg, hydrochloric acid, hydrobromic acid, etc.), hydrogen halides (eg, hydrogen chloride, hydrogen bromide, etc.), sulfuric acid, or aromatic sulfone Acids (eg, toluenesulfonic acid, etc.).

The amount of the acid to be used is 0.01 to 1 equivalent, preferably 0.1 to 1 equivalent, relative to compound (IV). Or 0.05 to 0.5 equivalent.

Solvents that can be used include, for example, aromatic hydrocarbons (eg, toluene, benzene, xylene), and saturated hydrocarbons (eg, cyclohexane, hexane, etc.). ), Halogenated hydrocarbons (eg, chloroform, 1,2-dichloroethane, etc.), and their mixed solvents. The reaction temperature is from 20 to: L 80 ° C, preferably from 60 to: 130 ° C. The reaction time varies depending on the compound, but if the reaction is performed for 0.5 to 48 hours,

'Good.

The compound represented by the general formula (I) can also be produced by reacting the compound (IV) with a base in a suitable solvent (single or mixed). Examples of the base that can be used include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), and the amount of the compound used is a compound.

It is 0.5 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to (IV). Solvents that can be used include, for example, ethers (eg, tetrahydrofuran, dioxane, etc.), alcohols (eg, methanol, ethanol, propanol) Etc.), water and a mixed solvent thereof.

The reaction temperature is from 0 to 100 ° C, preferably from 10 to 50 ° C.

The reaction time varies depending on the compound, but it is recommended that the reaction be performed for 5 to 48 hours.

The desired compound (I) obtained is purified as it is in the form of a reaction mixture or a crude product, or by a conventional method (eg, column chromatography, recrystallization, etc.) and then purified in the next step. Can be used.

Scheme 8

(In the formula, X represents a halogen atom.)

That is, the compound represented by the general formula (XI) can be produced by subjecting the methyl group of the benzene ring of the compound (Ia) to nodogenation by a known method.

For example, in an inert solvent (eg, carbon tetrachloride, cyclohexane, benzene benzene, etc.), chlorine, bromine, N-methyl succinate imide or N-promote If necessary, react with a halogenating agent such as succinic acid imidizer using a mercury lamp under light irradiation, or use a mercury lamp such as α, α'-azoisobutyryl nitrile or dibenzoyl peroxide. It can be produced by reacting in the presence of a dical initiator. In this reaction, the halogenating agent is used in an amount of 1 equivalent or more, preferably 1 to 1 equivalent to the compound (la).

5 equivalents can be used. The radical initiator can be used in an amount of 0.01 equivalent or more, preferably 0.05 to 0.5 equivalent, relative to the compound (Ia).

The reaction temperature is from 20 to 120 ° C, preferably from 50 to 90 ° C.

The reaction time varies depending on the compound, but the reaction may be carried out for 5 minutes to 3 hours. The desired compound (XI) obtained is purified as it is in the form of a reaction solution or as a crude product, or by a conventional method (eg, column chromatography, recrystallization, etc.) and then purified. Can be used with

The compound (Ia) used as a raw material in this reaction and the obtained compound (XI) are both novel compounds and are included in the present invention. Compound (Ia) can be produced according to the method of Scheme 5 or 7 above. And can

Skim 9

(In the formula, each symbol has the same meaning as described above.)

That is, the compound represented by the general formula (Ib) is produced by reacting the compound (XI) with the compound (XII) in the presence of a base without solvent or in an appropriate solvent (single or mixed). be able to.

In this reaction, compound (XII) can be used in one or more equivalents, preferably one to two equivalents, relative to compound (XI). Bases that can be used include, for example, metal hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), metal carbonates (eg, sodium carbonate, Metal carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium mono-ieri-butoxide, etc.), metal hydride (E.g., sodium hydride, potassium hydride, etc.). One or more equivalents, preferably one to three equivalents, of the compound (XI) are used. Can be done.

Examples of the solvent that can be used include N, N-dimethylformamide dimethylsulfoxide, aromatic hydrocarbons (eg, toluene, benzenexylene), and saturated hydrocarbons (eg, cyclohexane). Hexane, hexane, etc.), ethers (eg, tetrahydrofuran, dioxane, etc.), ketones (eg, acetate, methylethylketone, etc.), nitrile Water (eg, acetonitrile), water and their mixed solvents, and the like.

Two The reaction temperature is from 120 to 130 ° C, preferably from 0 to 100 ° C. The reaction time varies depending on the compound, but the desired compound (Ib) obtained by reacting for 10 minutes to 72 hours can be used as a reaction solution or in a crude form, or by a conventional method (eg, It can be purified by chromatography (eg, recrystallization) and used in the next step.

Scheme 10

(In the formula, each symbol has the same meaning as described above.)

That is, compound (VI) can be produced by reacting compound (IV) with compound (V) or a salt thereof in an appropriate solvent (single or mixed).

Compound (V) can be used in an amount of 1 equivalent or more, preferably 1 to 4 equivalents, relative to compound (IV).

Examples of the salt of the compound (V) include mineral salts such as hydrochloride and sulfate. When the salt is used, the reaction is carried out after neutralization with a base. Bases that can be used include, for example, metal hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), metal carbonates (eg, sodium carbonate, carbonate) Such as calcium), metal alkoxides (eg, sodium methoxide, sodium ethoxide), and amines (eg, pyridin). The amount is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to the salt of compound (V).

Solvents that can be used include, for example, hydrocarbons (eg, benzene, Benzene, xylene, etc.), halogenated hydrocarbons (eg, chloro-form 1,2-dichloroethane), ethers (eg, tetrahydrofuran, dioxane) ), Alcohols (eg, methanol, ethanol propanol, butanol, etc.), water, and mixed solvents thereof.

The reaction temperature is 0 to 130 ° C, preferably 20 to 110 ° C. The reaction time is usually about 15 minutes to 48 hours.

The resulting compound (VI) is used as is in the next step after purification, either as a reaction solution or in crude form, or by a conventional method (eg, column chromatography, recrystallization, etc.). can do.

Scheme 1 1

(In the formula, each symbol has the same meaning as described above.)

That is, the compound represented by the general formula (VII) can be produced by reacting the compound (VI) with an acid or a base in a suitable solvent (single or mixed) in the same manner as in the method described in the above scheme 7. it can.

The desired compound (VII) thus obtained can be purified, if necessary, by a conventional method (eg, Karamuk's mouth chromatography, recrystallization, etc.).

Scheme 1 2

(In the formula, each symbol has the same meaning as described above.)

That is, the compound represented by the general formula (VII) is obtained by converting a salt (eg, hydrochloride, sulfate, etc.) of the compound (IV) with the compound (V) into an appropriate solvent (single or mixed). During the reaction, it can be produced by reaction.

In this reaction, the salt of compound (V) can be used in an amount of 1 equivalent or more, preferably 1 to 4 equivalents, relative to compound (IV). Solvents that can be used include, for example, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), alcohols (Eg, methanol, ethanol, propanol, butanol, etc.), water and mixed solvents thereof.

The reaction temperature is between 0 and 130 ° C, preferably between 20 and 110 ° C. Although the reaction time varies depending on the compound, the reaction may be performed for 15 minutes to 48 hours. The desired compound (VII) thus obtained can be purified, if necessary, by a conventional method (eg, Karakku-guchi chromatography, recrystallization, etc.).

The compound (VII) obtained by the above schemes 11 and 12 has excellent bactericidal activity and is useful as an agricultural fungicide (W095 / 2695) 6).

BEST MODE FOR CARRYING OUT THE INVENTION

Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. The ¹ H-NMR values described in the examples were measured at 270 MHz in tetrahydroform with tetramethylsilyl as an internal standard, and the chemical shift value was δ (ppm ). Coupling constants (J) were title in H _Z. In the data, s is a singlet, d is a doublet, t is a triplet, q is a quadruple, sept is a sevenfold, and m is a multiplet. [Example 1]

Synthesis of 3- [2- (2,5-Dimethyl pentoxymethyl) benzoyl] isoxazole

(a) Synthesis of 3-[2 — (2, 5 — dimethyl ethoxymethyl) benzoyl] — 5 — ethoxy-1 2 — isoxoxolin

2 '― (2, 5 — dimethylinophenoxymethyl) acetophenone 7.63 g (0.03 monole), 90 ml of dry ether and 5N hydrochloric acid (dioxane solution) 2 To 4 ml (0.12 mol) of the solution, 7.01 ml (0.06 mol) of butyl nitrite was added over 5 minutes under ice-cooling, and the mixture was stirred at room temperature for 19 hours. After the reaction, 200 ml of ether was added, and the mixture was washed twice with 150 ml of brine, and the ether layer was dried over anhydrous magnesium sulfate. , 5—Dimethyl phenoxymethyl) 1—2-Hydroxyiminoacetophenone was obtained as a crude product. The obtained crude product was dissolved in 90 ml of isopropanol, and 8.51 ml (0.09 mol) of ethyl vinyl ether and 7.56 g of sodium hydrogen carbonate (0.09 mol) were dissolved. Mol) was added and the mixture was stirred at 40 to 45 ° C for 4 hours. After the reaction, 250 ml of ether was added, and the mixture was washed twice with 200 ml of a saline solution. The ether layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purified with matrograph (ethyl acetate n-hexane) and 3— [2— (2,5—dimethylphenoxymethyl) benzoinole] —5—ethoxy-1 2—isoxazoly 8.17 g (77.17%) of the compound were obtained as colorless crystals. One part was recrystallized from n-hexane to obtain crystals having a melting point of 87 to 88 ° C.

_{Ή-NMR (CDC1 3) δ} : 1.21 (3Η, t, J = 7.3), 2.18 (3Η, s), 2.30 (3H, s), 3.13-3.30 (2H, ra), 3.55 - 3.67 (1H, m ), 3.83-3.94 (1H, m), 5.20 (1H, d, J = 13.4), 5.29 (1H, d, J = 13.4), 5.67 (1H, dd, J-6.1, 3.1), 6.67-6.69 (2H, m), 7.00 (1H, d, J = 7.9), 7.43 (1H, d, J = 7.3) 7.57 (1H, td, J = 7.3, 1, 2), 7.70 ( 1H, d, J = 7.9), 7.91 (12H, dd, J = 7.9, 1.2).

(b) Synthesis of 3— [2- (2,5—dimethyl ethoxymethyl) benzoyl] isosoxazole

3-[2-(2, 5-dimethyl phenoxymethyl) benzoyl]-5-ethoxy 1 2 _ isoxazoline 7.07 g (0.02 mol) of toluene 4 O To the mixture were added 0.38 g (0.002 mol) of p-tonolene-norephonic acid-hydrate and the mixture was stirred for 5 hours while heating under reflux. After the reaction, add 200 ml of toluene, wash twice with 200 ml of saline, dry the toluene layer with anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain a residue obtained by silica gel filtration. Purified by chromatography (ethyl acetate-hexane) and purified by 3— [2— (2,5—dimethylphenoxymethyltinole) benzoinole] isosoxazole 6.01 g (96.6%) Was obtained as colorless crystals. Give crystals of melting point ⁹ 0 5 ~ 9 ² ° C and recrystallized from hexanes -. 1 part acetate Echiru / n.

_{'H-NMR (CDC1 3)} δ: 2.16 (3H, s), 2.29 (3Η, s), 5.32 (2Η, s),

6.66-6.68 (2Η, m), 6.86 (1H, d, J = l.8), 7.00 (1H, d, J = 7.3),

7.47 (1H, t, J = 7.3), 7.64 (1H, td, J = 7.9, 1.2), 7.81 (1H, d, J = 7.9), 8.01 (1H, dd, J = 7.3, 1.2), 8.51 ( 1H, d, J = l.8).

(b ') 3 — Synthesis of [2 — (2, 5 — dimethyl ethoxymethyl) benzoyl] isoxazole

3-[2 — (2,5 — dimethyl ethoxymethyl) benzoyl]-5-ethoxy 2-isoxoazoline ◦. 18 g (0.5 mimol) in tetrahydro Add 1 ml of furan, 0.5 ml of ethanol and 0.5 ml (0.5 mmol) of 1N aqueous sodium hydroxide solution at room temperature. The mixture was stirred for 6 hours. After the reaction, add 5 O ml of ether, wash with 50 ml of saline, dry the ether layer with anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain a residue gel chromatographic graph. (Ethyl acetate

/ n-Hexane) to give 3— [2- (25-dimethylthioenoxymethyl) benzoyl] isoxazole 011 g (68.9%) as colorless crystals. .

[Example 2]

Synthesis of 3-(4 — black benzoinole) y soxazole

(a) 3 — (4 — black benzoinole) 1-5 ethoxy 2 Synthesis of isozosazolin

4.09 g (0.02 mol) of 4,1-chloroacetophenone and 4 ml of dry ether and 16 ml (0.08 mol) of 5N hydrochloric acid (dioxane solution) 4.68 ml (0.04 mol) of butyl nitrite was added to the above solution over 5 minutes under ice-cooling, and the mixture was stirred at room temperature for 4 hours. After the reaction, 200 ml of ether was added, and the mixture was washed twice with 150 ml of a saline solution. The ether layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2,4'-dichloro-2-. — A crude product of hydroxyiminoacetophenone was obtained. The obtained crude product was subjected to isoprono. After dissolving in 60 ml of ethanol, 5.74 ml (0.06 mol) of ethyl vinyl ether and 5.04 g (0.06 mol) of sodium hydrogen carbonate were added. The mixture was stirred at 335 ° C. for 14 hours. After the reaction, 200 ml of ether was added, and the mixture was washed twice with 200 ml of saline, and the ether layer was dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was silica gel gel. Purified by chromatography (ethyl acetate / n-hexane) to give 3 — (4 — benzobenzene) 15 — ethoxy 12 — isooxozolin 3.26 g ( 64.2%) as a colorless oil.

_{Ή-NMR (CDC1 3) δ} 1.25 (3Η, t, J = 7.3), 3.23 (1Η, dd, J = 18.3, 2.4), 3.37 (1H, dd, J = 18.3, 6.7), 3.61-3.72 (1H, m), 3.91- 4.00 (1H, m), 5.72 (1H, dd, J = 6.7, 2.4), 7.43-7.46 (2H, m), 8.19- 8.22 (2H, m).

(b) Synthesis of 3 — (4 — benzobenzene) isosoxazole 3-(4 — benzobenzene) 1 5 — ethoxy 1 2 — isoxazoline 2.5 4 g (0 To 0.1 ml of tosoleene was added 0.19 g (0.01 mol) of ³ / ³ -toluenesulfonate monohydrate, and the mixture was stirred under heating and reflux for 5 hours. After the reaction, 15 O ml of toluene was added, and the mixture was washed twice with 150 ml of brine, and the toluene layer was dried over anhydrous magnesium sulfate. Recrystallization from hexane gave 1.48 g (71.3%) of 3-((4-chlorobenzoyl) isoxazole) as colorless crystals. Mp 57-58.50C.

'Eta -丽_{(CDC1 3) δ: 6.92 (} 1Η, d, J = 1.8), 7.48 - 7.53 (2H, m), 8.28- 8.33 (2H, m), 8.55 (1H, d).

[Example 3]

Synthesis of 3 — (4-benzoyl) benzoxazole

(a) 5-Butoxy 1 3-(4-Benzoyl benzoyl)-1 2-Synthesis of isooxazoline

4.3.8 g (0.1 mol) of 1,1-fluoroacetophenone, 300 ml of dry ether and 7.14.3 ml of 5.6 N hydrochloric acid (dioxane solution) the solution nitrite butyl 3 5). 0 7 ml (0. 3 mol) was added over 2 0 minutes under ice-cooling, after _c reaction was stirred for 2 0 hours at room temperature, the ether 1 0 0 m 1 was added, After washing twice with 400 ml of saline solution, the ether layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2'-chloro-1-4'-funoleo-1-2-hydroxymino. A crude product of acetophenone was obtained. The obtained crude product was dissolved in 200 ml of isopropanol, 38.8 m 1 (0.3 monole) of petil vinyl ether and 16.80 g (0.2 mol) of sodium hydrogen carbonate were added, and the mixture was stirred at room temperature for 48 hours. After the reaction, add 400 ml of ether, wash twice with 400 ml of brine, dry the ether layer with anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain a residue obtained by silica gel chromatography. Purified by graphite (ethyl acetate / n-hexane) to give 5—butoxy 3— (4—fluobenzoyl) —2—isosoxazoline 19.9.3 g (73) .0%) as a colorless oil.

-壓_{(CDC1 3) δ: 0.93 (} 3Η, t, J = 7.3), 1.31-1.47 (2Η, m), 1.54- 1.64 (2Η, m), 3.23 (1Η, dd, J = 18.3, 1.8), 3.38 (1H, dd, J = 18.3, 6.7), 3.54-3.63 (1H, m), 3.85- 3.93 (1H, m), 5.70 (1H, dd, J = 6.7, 2.5), 7.11-7.19 ( 2H, m), 8.26-8.36 (2H, m).

(b) Synthesis of 3- (4-fluorobenzoyl) isoxazole 5-butoxy-3- (4-benzobenzoyl) 1-2-isooxozolin: 15.92 g (0.006 monole), 120 ml of toluene and 0.59 g (0.006 mol) of concentrated sulfuric acid were added, and the mixture was stirred under heating and reflux for 4 hours. The mixture was washed with sodium chloride solution (200 ml) twice, the toluene layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate / η-hexane. Then, 30.1% (87.3%) of 3- (4-fluorobenzoyl) isoxazole was obtained as pale brown crystals. Mp 78-79 ° C.

'H -瞧_{(CDC1 3) δ: 6.92 (} 1H, d, J = l.8), 7.16-7.25 (2Η, m), .8.37- 8.45 (2Η, m), 8.55 (1Η, d, J = l.8).

[Example 4]

Synthesis of 3 — (2 — methylbenzoyl) isosoxazole

(a) 5—butoxy 3— (2—methylbenzoyl) 1-2—iso Synthesis of Kisazolin

Dissolve 6.71 g (0.05 mol) of 2,1-methyl acetic acid phenone in 15 ml of ethanol, and add 5.6 N hydrochloric acid (dioxane solution) under ice-cooling. 44.6 ml (0.15 monole) was added, and 17.5 ml (0.15 mol) of butyl nitrite was added dropwise over 10 minutes, followed by stirring at room temperature for 23 hours. After the reaction, 25 O ml of ether was added, and the mixture was washed twice with 25 O ml of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure. A crude product of 2,1-methylacetophenone was obtained. To 15.16 g of the obtained crude product, 15 O ml of isopropynole alcoholic alcohol, 19.4 ml of butylvinylinole ether (0.15 mol), and 8.40 g of sodium hydrogen carbonate (0.10 mol) was added and the mixture was stirred at room temperature for 62 hours. After the reaction, add 300 ml of ether, wash twice with 200 ml of saline, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain a crude gel chromatographic chromatograph. Purification by filtration (ethyl acetate / n-hexane) yields 5—butoxy 3— (2—methylbenzoyl) -12-isosoxazoline 10.32 g (79.0%) as a brown color. Obtained as an oil.

- image _{(CDC1 3) δ: 0.93 (} 3H, t, J = 7.3), 1.31-1.41 (2H, m), 1.54 - 1.64 (2Η, m), 2.44 (3H, s), 3.22 (1H, dd, J = 18.3, 2.5), 3.36 (1H, dd, J = 18.3, 6.7), 3.53-3.61 (1H, m), 3.83-3.92 (1H, m), 5.72 (1H, dd, J = 6.7, 2.4 ), 7.25-7.44 (3H, m), 7.75 (1H, dd, J = 7.9, 1.2).

(b) Synthesis of 3— (2—methylbenzoyl) isoxazole 5—butoxy 3— (2—methylbenzoyl) 1-2—isoxoazoline 0.26 g (1 millimol) to toluene 2 ml Then, 0.015 g (0.15 mmol) of concentrated sulfuric acid was added, and the mixture was stirred under heating and reflux for 2 hours. 100 ml of ether was added to the reaction solution, washed with 100 ml of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude gel. Purified by chromatography (ethyl acetate Zn—hexane), and 3— (2—methylbenzoinole) isoxazonole 0.18 g (96.

2%) of crystals were obtained. 33-34 ° C.

-丽_{(CDC1 3) δ: 2.51 (} 3Η, s), 6.90 (1Η, d, J = l.2), 7.28- 7.84 (4Η, m), 8.54 (1Η, d, J = l.8).

[Example 5]

Synthesis of 3 — [2 — (2, 5 — dimethyl phenoxymethyl) benzoyl] isoxazole

(a) Synthesis of 3- (2-bromomethylbenzoinole) isoxazole

0.5-g (3-millimol) of 3- (2-methinobenzoyl) isoxazole in 6 ml of benzene and 0.59 g of N-bromosuccinic acid imid (3.3 mi Mole) and 2,2'-azobisisobutyrolonitrino.

To the mixture was added 0.5 g (0.3 mmol), and the mixture was stirred for 1 hour under heating and reflux. After the reaction, insolubles were removed, and the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl ethyl hexanoate) to give 3-((2-bromoethylbenzoic acid). 0.5 g of isoxazole (62.

6%) as a pale brown oil.

_{'H-NMR (CDC1 3)} δ: 4.80 (2Η, s), 6.95 (1H, d, J = l.02), 7.42- 7.57 (3H, m), 7.93 (1H, d, J = 7.3), 8.56 (1H, d, J = l.8).

(b) Synthesis of 3-[2 — (2, 5 — dimethyl phenoxymethyl) benzoyl] isosoxazole

3 — (2 —Bromomethyl benzoyl) isoxazole 0.27 g (1 mmol) in N, N-dimethylformamide 2 ml, 2,5 —dimethyl phenol 0.1 6 g (1.3 mmol) and 0.21 g (1.5 mmol) of potassium carbonate were added, and the mixture was stirred at room temperature for 14 hours. Anti After the reaction, 100 ml of ether was added, the mixture was washed twice with 80 ml of a saline solution, the ether layer was dried over anhydrous magnesium sulfate, and the residue obtained by concentration under reduced pressure was purified by silica gel chromatography. Purified by chromatography (ethyl acetate / n-hexane) to give 3— [2 (25—dimethyl methoxymethyl benzoyl) benzoyl] isoxazole 026 g (84.6%) Was obtained as colorless crystals.

[Example 6]

2 — Black mouth — 2 '— (25 — Dimethyl thioxymethyl) 2 — Synthesis of hydroxyiminoacetophenone

2 Chloro 2 '— (2,5 — dimethinolephenoxymethyl) Acetophenone 0.58 g (2 mmol) is dissolved in 6 ml of ether and cooled under ice-cooling. To the mixture were added 1.07 ml (6 mmol) of 5.6 N hydrochloric acid (dioxane solution) and 0.47 ml (4 mmol) of butyl nitrite, and the mixture was stirred at room temperature for 21 hours. Then, under ice-cooling, add 5.6 N hydrochloric acid (dioxane solution) 0.36 ml (2 milliliters) and butyl nitrite 0.24 ml (2 milliliters), and add 71.5 at room temperature. Stirred for hours. To the reaction mixture was added 100 ml of ether, washed twice with 80 ml of saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to recrystallize the crude crystals obtained (ethyl ethyl acetate hexane). 2 Chloro 2 '— (2,5 dimethinolephenoxymethyl) 2-Hydroxyiminoacetophenone 0.42 g (66.1%) of light brown color Obtained as crystals. Melting point 126-128 ° C.

'Eta - image _{(CDC1 3) δ: 2.15 (} 3Η, s), 2.30 (3H, s), 6.6-56.70 (2Η, m), 7.01 (1Η, d, J = 3.7), 7.38-7.69 (4Η, in), 8.39 (1Η, s).

[Example 7]

Synthesis of 3— [2— (2,5 dimethylenoxymethyl) α-methoxyiminobenzyl] isoxazole 3-[2-(2, 5-dimethyl ethoxymethyl) benzoyl] 1-5-ethoxy 1-2-isoxazoline 0.35 g (1 millimol) in n-pronono Then, 2 ml of toluene and 0.17 g (2 millimoles) of methoxamicin hydrochloride were added, and the mixture was stirred under heating and reflux for 5 hours. After the reaction, 100 ml of ether was added, the mixture was washed with 80 ml of brine, the ether layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel. Purified with (ethyl acetate / n-hexane), then 3— [2— (2,5—dimethylthiophenoxymethyl) methyl methoxyminobenzyl] isoxazole 0.22 g (6 5.4%) as colorless crystals.

_{lH-NMR (CDC1 3) δ} : 2.13 (2.15) (3Η, s), 2.24 (2.25) (3H, s), 4.01 (4.08) (3H, s), 4.95 (5.01) (2H, s) 6.52- 7.64 (8H, m), 8.39 (8.45) (1H, d, J = l.8).

[Example 8]

Synthesis of 3- (α-methoxyminino 2- 2-methylbenzyl) isoxazole

(a) 5—Ethoxy 3— (2—Methylbenzoinole) 1-2—Synthesis of Isozosazolin

2'-Methyl acetate phenone 1.34 g (0.01 monole) and a dry ether solution (40 ml) and 5 N hydrochloric acid (dioxane solution) 8 ml (0.04 mol) were added to a solution. 2.34 ml (0.02 mol) of butyl nitrate was added over 5 minutes under ice cooling, and the mixture was stirred at room temperature for 18 hours. After the reaction, add 10 Om1 of ether, wash twice with 10 Om1 of saline, dry the ether layer with anhydrous magnesium sulfate, concentrate under reduced pressure, and concentrate under reduced pressure. — A crude product of hydroxyimino-2,1-methylacetophenone was obtained. The obtained crude product was subjected to isoprono. Dissolved in 30 ml of ethanol 2.9 ml (0.03 monole) of 1 ter and 2.52 g (0.03 mol) of sodium hydrogen carbonate were added, and the mixture was stirred at 40 to 45 ° C for 6 hours. After the reaction, 15 O ml of ether was added, and the mixture was washed twice with 15 O ml of a saline solution. The ether layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue obtained by silica gel chromatography. Purified by mattography (Ethynole acetate, Zn-hexane) and purified by 5-ethoxy-3-(2-methylbenzoyl)-2-isoxazoline 1.78 g (76. 3%) as a colorless oil.

_{Ή-NMR (CDC1 3) δ} 1.25 (3Η, t, J = 6.7), 2.44 (3Η, s), 3.22 (1Η, dd, J = 18.9, 2.4), 3.36 (1H, dd, J = 18.3, 6.7 ), 3.59-3.71 (1H, m), 3.87-3.99 (1H, m), 5.73 (1H, dd, J = 6.7, 2.4), 7.25-7.44 (3H, m), 7.76 (1H, dd, J = 6.7, 1.8).

(b) Synthesis of 5-ethoxy-3- (α-methoxymin-2-yl-methylbenzyl) -12-isoxazoline

5-Ethoxy 1 3-(2-Methylbenzoinole) 1-2-Isoxazoline 0.35 g (1.5 milimonole) in ethanol 3 ml, methoxyxamine hydrochloride 0. 19 g (2.25 millimoles) and 0,18 g (2.25 millimoles) of pyridine were added, and the mixture was stirred under heating and reflux for 3 hours. After the reaction, add 10 O ml of ether, wash with 8 O ml of brine, dry the ether layer with anhydrous magnesium sulfate, concentrate under reduced pressure, and concentrate the residue on silica gel chromatography. -(Ethyl acetate Zn-hexane) and refined with 5-ethoxy 3-(methyl methoxy 2-methyl benzyl) 12-isoxazoline 0.37 g (9 4.0%) as a colorless oil.

_{Ή-NMR (CDC1 3) δ} : 1.18-1.27 (3Η, m), 2.26 (2.18) (3Η, s), 3.22- 3.64 (3H, m), 3.80-3.92 (1H, ra), 4.02 (3.94) (3H, s), 5.61-5.67 (1H, m), 7.14-7.31 (4H, m). (c) Synthesis of 3- (α-methoxyminino-2- (methylbenzyl) isooxoazole)

5—Ethoxy 1 3— (α—Methoxyminino 2—Methylbenzyl) —2—Isoxazoline 0.37 g (1.4 mmol) to benzene 28 mL Toluenesulfonate monohydrate (0.03 g, 0.14 mmol) was added, and the mixture was stirred under heating and reflux for 3 hours. After the reaction, the residue obtained by concentration under reduced pressure is purified by silica gel chromatography (ethyl benzene acetate), and 3— (α-methoxyminino-2-methylbenzyl) isoxazole 0 .29 g (95.58%) were obtained as a colorless oil.

_{Ή-NR (CDC1 3) 6} : 2.20 (3Η, s), 4.11 (4.01) (3H, s), 7.01 (6.76) (1H, d, J = l.8), 7.18-7.36 (4H, m) , 8.49 (8.39) (1H, d, J = l.8).

[Example 9]

Synthesis of 3 — [2 — (2, 5 — dimethyl ethoxymethyl) 1 α-methoxyminobenzyl] isoxazole

(a) Synthesis of 3-[2-(2, 5-dimethyl ethoxymethyl) 1-methoxyminobenzyl]-1-5-ethoxy2-isoxoxolin

3— [2— (2,5—dimethyl ethoxymethyl) benzoinole] 1—5—ethoxy 2—isosoxazoline 0.35 g (1 millimol) and ethanol 2 ml , 0.17 g of methoxamine hydrochloride (2 milliliters) and 0.16 ml of pyridine (2 millimoles) were added, and the mixture was stirred under heating and reflux for 7.5 hours. 80 ml of saline was added to the reaction solution, adjusted to pH 2 or less with 1 N hydrochloric acid, and extracted with 100 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography (ethyl acetate / n-hexane) to give 3— [2- (2,5-Dimethyl ethoxymethyl) α-Methoxy methoxy benzene] 15-Ethoxy 2- 2-isoxazoline 0.36 g (941%) of crystals Obtained.

- Anonymous _{(CDC1 3) δ: 1. 14-1.23} (3Η, m), 2.19 (2.18) (3Η, s),

2.28 (2.27) (3H, s), 3.21-3.86 (4H, m), 4.00 (3.94) (3H, s),

5.04 (4.94) (1H, s), 5.56-5.60 (1H, m), 6.58-6.70 (2H, m), 6.99- 7.01 (1H, m) 7.35-7.56 (4H, m).

(b) Synthesis of 3-[2 — (2, 5 — dimethylphenoxymethyl) 1-methoxyethoxyminobenzyl] isoxazole

3 — [2-(2, 5 — dimethyl methoxymethyl) 1 α — methoxyiminobenzyl] 1 5 — ethoxy 1 2 — isoxazoline 0.36 g (0.94 To this solution, 1.9 ml of toluene and 0.009 g of concentrated sulfuric acid (0.092 mmol) were added, and the mixture was stirred with heating under reflux for 30 minutes. 10 O ml of ether was added to the reaction solution, washed twice with 80 ml of a saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product obtained by silica gel chromatography. Purify with (n-hexane / toluene) to obtain 3_ [2— (2.5-dimethylthiophenoxymethyl) -α-methoxymethoxyaminobenzyl] isoxazole crystal 0.25 g (. 7 9 1%) was obtained _{_{(Ή-NMR (CDC1 3)}} δ: 2.15 (2.12) (3Η, s), 2.25 (2.23) (3H, s),

4.08 (4.01) (3H, s), 5.01 (4.95) (2H, s), 6.54 (6.52) (1H, s),

6.64 (1H, d, J = 7.3), 6.93 (6.75) (1H, d, J = l.8), 6.98 (1H, d, J = 7.9), 7.26-7.64 (3H, m), 8.44 (8.39 ) (1H, d, J = l.8).

[Example 10]

Synthesis of 3-[2 — (2, 5 — dimethyl phenyloxymethyl) benzoyl] isoxazole

2 — Chloreau 2,-(2, 5 — dimethyltinolephenoxymethyl) 1 2 — 0.95 g (three millimono) of hydroxyiminoacetophenone was dissolved in 9 ml of isopropanol, and acetylene gas was introduced for 5 minutes with stirring at room temperature. 0.76 g (9 mmol) of sodium hydrogencarbonate was added to the solution, and the mixture was stirred at room temperature while introducing acetylene gas. Nine hours later, the introduction of acetylene gas was stopped, and the mixture was further stirred for 14 hours. After the reaction, 150 ml of ether was added, washed with 200 ml of water, the ether layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product obtained by silica gel chromatography. Purify with toluene (toluene Zn-hexane) to obtain 0.77 g (85.5%) of 3— [2— (2,5—dimethylthiophenoxymethyl) benzoyl] isoxazole as a colorless solid I got it as a thing.

[Example 11]

Synthesis of 3 — (2 —methylbenzoyl) isosoxazole

2 '— Methyl acetate phenone 2.68 g (20 mmol) is dissolved in 40 ml of ether, and 5.6 N hydrochloric acid (dioxane solution) 10 and 71 ml under ice-cooling. (60 millimoles) was added, and 5.85 ml (50 millimoles) of butyl nitrite was added dropwise over 4 minutes, followed by stirring at room temperature for 21 hours. After the reaction, 150 ml of ether was added, washed three times with 120 ml of saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-chloro-2-hydroxyamino. A crude product of 2′-methyl acetate was obtained. The obtained crude product

4.5 g was dissolved in 6 O ml of isopropanol, and acetylene gas was introduced under stirring at room temperature for 30 minutes. To the solution was added 5.04 g (60 mmol) of sodium hydrogen carbonate, and the mixture was stirred at room temperature while introducing acetylene gas. Eight hours later, the introduction of acetylene gas was stopped, and the mixture was further stirred for 63 hours. After the reaction, 200 ml of ether was added, washed with 200 ml of water, and the ether layer was dried over anhydrous magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate n-hexane) and purified to give 3— (2-methylbenzoyl) isosoxazole 2.8 g (7 5.6%) as a colorless solid.

[Example 12]

Synthesis of 3-(2 — black benzoinole) isoxazole

(a) 5—butoxy 1 3— (2—black benzoyl) 1 2—synthesis of sazolin

2 '— Chloroacetophenone 24.74 g (0.16 monole) was dissolved in ether 32 O ml and 5.6 N hydrochloric acid (dioxane solution) was added under ice cooling. 5.7 ml (0.48 mol) was added, and 46.777 ml (0.4 mol) of butyl nitrite was added dropwise over 1 hour, followed by stirring at room temperature for 20 hours. After the reaction, 300 ml of ether was added, and the mixture was washed twice with 600 ml of saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give 2,2,2-dichloro-2-amino. A crude product of acetophenone was obtained. To the obtained crude product, 320 m1 of isopropyl alcohol, 62.1 1 ml of butyl vinyl alcohol (0.48 monole), 26.88 g of sodium hydrogen carbonate (0.08 g) were added. 32 mol) and stirred at room temperature for 3 days. After the reaction, insoluble materials were removed by filtration. The crude product obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate / n-hexane) to give 5-butoxy-. 3— (2-Cross-mouth benzoyl) -12-isosazoline 37.37 g (82.9%) was obtained as a pale brown oil.

_{! H-NMR (CDC1 3)} δ: 0.92 (3Η, t, J = 7.3), 1.30-1.64 (4H, m), 3.22 (1H, dd, J = 18.3, 3.1), 3.33 (1H, dd, J = 18.3, 6.7), 3.53-3.61 (1H, ra), 3.82-3.90 (1H, m), 5.76 (1H, dd, J = 6.7, 2.5), 7.31-7.46 (3H, m), 7.56 (1H, d, J = 7.3).

(b) Synthesis of 3 — (2 — black benzoinole) isoxazole JP 7 4

5—butoxy 3— (2—black benzoinole) 1-2—isoxazoline 36.6 3 g (0.13 monole) in toluene 260 ml, concentrated sulfuric acid 12 8 g (0.013 mol) was added, and the mixture was stirred under heating and reflux for 5 hours. Add 200 ml of tonoren to the reaction solution, wash twice with 400 ml of saline, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain a crude gel chromatograph. Purification by means of graphite (ethyl ethyl n-hexane) yielded 24.65 g (913%) of 3- (2-chlorobenzene) isoxazole. Recrystallization from ethyl acetate and n-hexane gave colorless crystals having a melting point of 63.5 to 64.5 ° C.

_{! H-NMR (CDC1 3)} δ: 6.93 (1Η, d, J = l.8), 7.35 - 7.50 (3H, m), 7.64- 7.67 (1H, m), 8.55 (1H, d, J = l .8).

[Example 13]

3 —Synthesis of Benzoylisoxazole

(a) Synthesis of 3_benzoyl-5-butoxy-2- (isosazozolin) 2-Chloroacetophenone 30.92 g (0.2 mol)

The solution was dissolved in 400 ml, and 3N hydrochloric acid (dioxane solution) 133 ml (0.4 mol) was added under ice-cooling, and butyl nitrite 35.07 ml (0.3 mol) was added. The mixture was added dropwise over 25 minutes, and the mixture was stirred at room temperature for 18 hours. After the reaction, 100 ml of ether was added, and the mixture was washed three times with 400 ml of a saline solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give 2-hydroxy-1-amino. A crude product of acetophenone was obtained. To the obtained crude product, 400 ml of isopropanol alcohol, 77.64 ml (0.6 mol) of butyl vinylinoleether, 33.6 g of sodium hydrogencarbonate (0.4 mol) ) And stirred at room temperature for 5 days. After the reaction, the insolubles were removed by filtration, and the crude product obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate Zn-hexane) to give 3-benzoyl-5. —Butoxy— 2 —Sosoxazoli 44.79 g (90.6%) were obtained as a pale brown oil.

_{! HN R (CDC1 3) δ} : 0.93 (3Η, t, J = 7.3), 1.31-1.45 (2H, m), 1.54 - 1.65 (2Η, m), 3.24 (1Η, dd, J = 18.3, 2.4) , 3.39 (1H, dd, J = 18.3, 6.7), 3.59 (1H, dt, J = 9.8, 6.7), 3.89 (1H, dt, J = 9.2, 6.7), 5.70 (1H, dd, J = 6.7, 2.4), 7.58-7.64 (1H, m), 7.45-7 · 51 (2H, m), 8.20-8.25 (2H, m).

(b) 3 — Synthesis of Benzoi Norei Soxazonole

3—Venzoy Nore 5—butoxy 2—Isoxazoline 44.5 1 g (0.18 monole) to Tonolene 360 ml, concentrated sulfuric acid 1. 8 mol), and the mixture was stirred under heating and reflux for 2 hours. Toluene (200 ml) was added to the reaction solution, washed twice with 400 ml of saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude gel chromatographic product. Purification by chromatography (ethyl acetate Zn—hexane) gave 28.93 g (92.8%) of 3-benzoinoleisoxazole as a pale yellow oil. .

_{! H-NMR (CDC1 3)} δ: 6.92 (1H, d, J = l.8), 7.48-7.56 (2H, m), 7.63- 7.69 (1H, m), 8.30-8.35 (2H, m), 8.55 (1H, d, J = l.8).

Industrial applicability

The process for producing 3-benzoyloxoxazole of the present invention is useful as an industrial process because the number of steps is small and raw materials are easily available as compared with the conventional process.

Claims

Claims I

formula

Wherein, 1¾ ¹ Oyopi 1 ^ ² each independently represent a hydrogen atom, Ryo Norekinore, Anoreko alkoxy, Nono b Gen atoms, Application Benefits off Noreoro main Chizorema other one _n (CH.) - M - R ³ (R ³ is optionally substituted, aryl, M is an oxygen atom or —O—N = C (R ⁴ ) (R ⁴ is a hydrogen atom, alkyl, alkylthio, cyano, or Wherein _n represents 0 or 1.] A compound represented by the general formula (I): wherein acetylene is reacted under basic conditions.

[Wherein the symbols are as defined above].

General formula (II):

[Wherein each symbol is as defined in claim 1], a compound represented by the general formula (I I I):

R ⁵ OCH = CH ₂ III [Wherein, R ⁵ represents alkyl. Is reacted under basic conditions to give a compound of the general formula (IV):

[Wherein each symbol is as defined above], and then reacting the compound with an acid or a base, general formula (I):

[Wherein each symbol is as defined above] General formula (II):

[Wherein each symbol is as defined in claim 1] to the compound represented by the general formula (I I I):

R ⁵ OCH = CH ₂ III

Wherein the compound represented by the formula: wherein R ⁵ is the same as defined in the second aspect of the present invention, is reacted under basic conditions, wherein the general formula (IV):

[Wherein the symbols are as defined above].

4. General formula (II):

[Wherein each symbol has the same meaning as in claim 1], a compound represented by the general formula (I I I):

R ⁵ OCH = CH ₂ III

[Wherein R ⁵ is as defined in claim 2] and reacted under basic conditions to obtain a compound of the general formula (IV):

[Wherein each symbol is as defined above], and

(1) An acid or a base is reacted to form a compound of the general formula (I):

[Wherein each symbol is as defined above], a compound represented by the general formula (V):

NH ₂ OR ⁶ V

(2) — reacting the compound represented by the general formula (V)

(V I):

[Wherein the wavy line (~) indicates an E-form, a Z-form or a mixture thereof, and the other symbols are as defined above].

(3) A general formula (VII) characterized by reacting with a mineral salt of the general formula (V):

[Wherein each symbol is as defined above], a method for producing a 3 — (α-alkoxyminobenzyl) sosoxazole derivative.

5. When the compound represented by the general formula (II) is

(1) General formula (VIII)

[Wherein each symbol has the same meaning as in claim 1], the ability to react an alkyl nitrite with hydrogen chloride on a compound represented by the following formula:

(2) A compound represented by the general formula (VIII) is reacted with alkyl nitrite to form a compound represented by the general formula (IX):

[Wherein each symbol is as defined above], and then the ability to chlorinate it, or

(3) — General formula (X):

The method according to any one of claims 1 to 4, wherein the compound is obtained by reacting a compound represented by the formula: wherein each symbol is as defined above, with alkyl nitrite.

6. General formula (Ia):

A halogenated compound represented by the general formula (XI)

[In the formula, X represents a halogen atom. To obtain a compound represented by the general formula (XII):

R ³ MH XII

[Wherein each symbol has the same meaning as in claim 1], characterized by reacting a compound represented by the following general formula (Ib):

[Wherein each symbol is as defined above] General formula (IIa):

[Wherein R ⁷ and R ⁸ each independently represent a hydrogen atom, an anoalkyl alkoxy, a halogen atom or a trifluoromethyl. ] The compound represented by these.

8. General formula (Ia):

Compound represented by

9. General formula (X I)

[In the formula, X represents a halogen atom. ] The compound represented by