WO1996037463A1

WO1996037463A1 - Process for producing n-methylmethoxyiminoacetamide derivatives and intermediates therefor

Info

Publication number: WO1996037463A1
Application number: PCT/JP1996/001349
Authority: WO
Inventors: Masatsugu Oda; Manabu Katsurada
Original assignee: Mitsubishi Chemical Corporation
Priority date: 1995-05-23
Filing date: 1996-05-22
Publication date: 1996-11-28
Also published as: JPH08319265A

Abstract

A process for producing an N-methyl-methoxyiminoacetamide derivative represented by general formula (III), wherein R2 represents hydrogen, etc., which comprises reacting a novel 1-alkoxy-4-methoxyimino-2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline derivative represented by formula (I), wherein R1 represents C¿1-4? alkyl, with an oxyamine derivative represented by the following general formula (II): H2NO-R?2¿, wherein R2 is as defined above.

Description

Specification

Method for producing N-methyl-methoxyiminoacetic acid amide derivative

Technical field

The present invention relates to a method for producing a methoxyiminoacetic acid amide derivative useful as an agricultural and horticultural fungicide, an intermediate for producing the same, and a method for producing an intermediate.

Background art

Japanese Patent Application Laid-Open No. 07-076464 discloses an N-methyl-methoxyiminoacetic acid amide derivative having excellent bactericidal activity. As a method for producing the same, the publication describes a method for amidating a methoxyiminoacetic acid ester derivative, but this method may involve a side reaction in some cases, and thus the target compound is not necessarily stably obtained. You don't get it.

In addition, W094Z221812 contains 1-hydroxy-14-methoxymino-2-methyl-3-methyl-1, 2,3,4—tetrahydroisoquinoline as a raw material. A method for producing a methyl-methoxyiminoacetic acid amide derivative is described, but according to the examples in the publication, the yield is as low as 38%, which is not industrially satisfactory.

In addition, JP-A-63-323852, JP-A-Heisei 3-4 6268, JP-A-1986-964, JP-A-1981-64, and JP-A-5-435 3, 3, 5-7, 976, 6-, 5-3, 1124, 6-251, 32, etc. also describe biologically active methoxyiminoacetic acid derivatives and their production methods. However, there are problems such as that the yield is low or that they cannot be applied to the production of N-methyl-methoxyiminoacetic acid amide derivative described in the above-mentioned JP-A-7-076564.

Therefore, there is a need for the development of an inexpensive and efficient method for producing methoxyiminoacetic acid amide derivatives useful as agricultural and horticultural fungicides.

As a result of repeated studies, the present inventors have found that a novel compound, a 1-alkoxy-14-methoxyoximino 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoquinone By using a phosphorus derivative as a raw material, the objective product was successfully obtained, and the present invention was completed. Disclosure of the invention

That is, the present invention provides the following general formula (I)

(In the formula, R ¹ represents an alkyl group of d—C _4. ) 1-Alkoxy-14-methoxy-2-amino-2-methyl-13-oxo-1,2,3,4-tetrahedral Droisoquinoline derivative and the following general formula (II)

H ₂ NO -R ² (II)

{Wherein, R ² represents a hydrogen atom or a group represented by the general formula —C (R ³ ) (R ⁴ ) —Ar, wherein R ³ and R ⁴ are each independently a hydrogen atom or C! - represents a § alkyl group of C _4, A r represents a Teroariru group to which may be optionally substituted Ariru group or substituted. }, Characterized by reacting an oxyamidine derivative represented by the following general formula (III):

(Wherein R ² is as defined in formula (II).) A method for producing an N-methyl-methoxyiminoacetic acid amide derivative represented by the formula:

The compound of the general formula (I) is a novel compound, and the present invention also relates to such a novel compound and a method for producing the same.

Hereinafter, the present invention will be described in detail. In the above general formula (I), R ¹ represents a C 1 -C 4 straight or branched alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, .sec-butyl and the like. Of these, it is rather preferably R ¹ is methyl or Echiru, is properly favored by al is methyl.

In the above general formulas (II) and (III), R ² represents a hydrogen atom or a group represented by the general formula C (R ³ ) (R ⁴ ) —Ar. R ³ and R ⁴ each independently represent a hydrogen atom; a C i -C 4 linear or branched alkyl group such as methyl, ethyl, n-propyl, is 0-propyl, n-butyl, sec-butyl and the like. Of these, it is preferred that R ³ and R ⁴ are each independently hydrogen or methyl. C More preferably, R ³ is hydrogen and R ⁴ is methyl.

Ar is an aryl group such as phenyl or naphthyl which may be substituted by the following group; or a heteroaryl group such as pyridyl, phenyl or thiazolyl which may be substituted by the following group. Represent. Preferably, it represents phenyl which may be substituted by the following groups.

Examples of the group substituted by the aryl group represented by Ar include cyano; a halogen atom such as fluorine, chlorine, and bromine; methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like. A C 1 -C s alkyl group; ethenyl, propenyl and the like C ₂ -C 4 alkenyl groups which may be substituted by a halogen atom; trifluoromethyl, difluoromethyl, trichloromethyl or dichlorodifluoroethyl C 1 haloalkyl group such as C 1; C 1 monohalide such as methoxy, ethoxy, iso-propoxy, n-butoxy which may be substituted by a halogen atom or a C ₃ -C 6 cycloalkyl group; an alkoxy group having C 6; methylthio, Echiru Chio, iso - propylthio, alkylthio group of C i one C 6 such as n- Puchiruchio; C i - alkylene of C ₄ An aryl group such as phenyl which may be substituted by a group or a halogen atom; an aryloxy group such as phenyl which may be substituted by a C 4 alkyl group or a halogen atom; C ₂ -C s alkenyloxy group such as good propenyloxy; C z -C e alkynyloxy group such as propargyloxy. The alkyl, alkenyl, and alkynyl chains of these groups It may be a branched chain. 'Among these, preferred substituents on the aryl group include -C

4 is an alkyl group, a halogen atom, a halogen atom, and more preferably a C 1 -C 4 alkoxy group or a trifluoromethyl group which may be substituted by fluorine _(and two adjacent substituents among these substituents) The groups may together form a methylenedioxy group, an ethylenedioxy group or the like to form a condensed ring with the aryl group.

The number of substituents is 1-5, preferably 1-2. When the aryl group has a plurality of substitution groups, they may be the same or different.

Examples of the group which may be substituted with the heteroaryl group represented by Ar include cyano; halogen atoms such as fluorine, chlorine and bromine; methyl, ethyl, n-propyl, iso-propyl, n A C 1 -Cs alkyl group such as —butyl, sec-butyl, etc .; a C 1 -C 4 haloalkyl group such as trifluoromethyl, difluoromethyl, trichloromethyl or dichlorodifluoroethyl; or a halogen atom or C

3 — Methoxy, ethoxy, i S optionally substituted with C 6 cycloalkyl group

Ci-Cs alkoxy groups such as 0-propoxy and n-butoxy are exemplified. The alkyl chains of these groups may be straight or branched. Of these, preferred substituents for the heteroaryl group include C! -An alkyl group of C ₄ ; a halogen atom; or trifluoromethyl.

The number of substituents is the same or different and is 1 or 2.

As shown in the following Scheme 1, the N-methyl-methoxyiminoacetic acid amide derivative represented by the general formula (III) is a compound represented by the general formula (I). By reacting a methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline derivative with an oxyamine derivative of the general formula (II) in the presence or absence of an acid, the compound represented by the formula It can be produced via the compound of (VI). (In the scheme below, R ¹ and R ² are as previously defined.) Scheme 1

The oxamine derivative of the formula (II) may be used as it is or, in some cases, in the form of a salt such as a hydrochloride. The amount to be used is 1 to 3 equivalents, preferably 1 to 3 times, relative to the 1-alkoxy-14-methoxyminnow 2-methyl-3-oxo-1,1,2,3,4-tetrahydridoisoquinoline derivative of the formula (I). 1.5 equivalents. By adding an acid in the above reaction, the desired di-methyl-methoxyimino acetic acid amide derivative represented by the general formula (III) can be obtained in good yield and stably.

Examples of the acid used include organic acids such as acetic acid and trifluoroacetic acid; hydrohalic acids such as hydrochloric acid; hydrogen halides such as hydrogen chloride and hydrogen bromide; methanesulfonic acid, ρ-toluenesulfonic acid or sulfuric acid Sulfonic acids such as pyridine; acid addition salts of organic bases such as pyridin hydrochloride and pyridine sulfate; and Lewis acids such as zinc chloride, iron chloride and aluminum chloride. Of these, sulfonic acids and hydrogen halides are preferred.

The above acid is used in an amount of from a catalytic amount to 5 times equivalent, preferably 1 equivalent, of the 1-alkoxy-14-methoxyimimino 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline derivative of the general formula (I). It is used up to twice the equivalent of the catalyst.

The reaction is usually performed in a solvent.

Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloromethane, and the like; getyl ether, tetrahydrofuran, dioxane Ethers; esters such as ethyl acetate; alcohols such as methanol, ethanol, and propanol Coals; polar solvents such as N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, diacid, and water, and the like, whether a single solvent or a mixed solvent. good. Of these, ethers such as tetrahydrofuran and dioxane; polar solvents such as N, N-dimethylformamide, dimethylsulfoxide and acetic acid are preferred.

The reaction is carried out at a temperature of from 0 ° to the boiling point of the solvent used, preferably from 20 to 120 °. The reaction time is usually about 30 minutes to 24 hours, preferably about 1 to 8 hours.

In this reaction, when no acid was used, the following general formula (VI)

(Wherein, R ² is as defined above.) In some cases. In this case, the desired N-methyl-methoxyiminoacetic acid amide derivative represented by the general formula (III) can be converted by adding an acid and continuing the reaction in the same manner as described above.

The 1-alkoxy-1-methoxyiminor 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline derivative of the general formula (I) is a novel compound, and has the formula (IV) according to the following scheme 2. Can be produced by reacting a benzal halide derivative with an alcohol of the formula (V) in the presence of a base. (In the scheme below, X represents a chlorine atom or a bromine atom, and R ¹ is as defined above.) Scheme 2

The alcohol of the formula (V) is used in an amount of 1 equivalent to a large excess, preferably 2 equivalents to an amount of a solvent, based on the benzol halide derivative of the formula (IV).

The base used may be either an inorganic base or an organic base. Examples of the inorganic base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate and calcium carbonate. Alkali metal hydrides such as sodium bicarbonate and potassium hydrogen carbonate; alkali metal hydrides such as sodium hydride

An alkali metal such as metallic sodium; Examples of the organic base include tertiary amines such as triethylamine; aromatic bases such as pyridine and picoline; alkali metal alcoholates such as sodium methethylate and potassium t-butoxy. Preferable examples include alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides and alkali metal alcoholates.

The above base is used in an amount of 1 equivalent to 10 equivalents, preferably 2 equivalents to 5 equivalents, based on the benzol halide derivative of the general formula (IV). The reaction is usually performed in a solvent.

Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, and the like; getyl ether, tetrahydrofuran, dioxane, and the like. Ethers; esters such as ethyl acetate; ketones such as acetone and methylethyl ketone; alcohols such as methanol, ethanol, propanol and butanol; -triles such as acetonitrile; N-dimethylformamide, N-methylpyrrolide And a polar solvent such as dimethyl sulfoxide, acetic acid, and water. The solvent may be a single solvent or a mixed solvent. Preferable examples include ethers, alcohols, and polar solvents such as N, N-dimethylformamide and dimethylsulfoxide.

The reaction is carried out at a temperature from room temperature to the boiling point of the solvent used, preferably at 20 to 150 ° C. The reaction time is usually about 30 minutes to 48 hours, preferably about 1 to 10 hours.

The benzal halide derivative of the formula (used as a starting material can be produced, for example, by the method shown in the following scheme 3 or a method analogous thereto. (In the following scheme, X is as defined above. )

Scheme 3

(X) (IV)

That is, the glyoxylic acid ethyl ester of the formula (VI I) is oxidized by a method known per se (for example, described in JP-A-5-977768) or a method analogous thereto, thereby obtaining the compound of the formula (VI II) Or a methoxyiminoacetic acid derivative of the formula (IX). The hydroxyiminoacetic acid derivative of the formula (VIII) can be easily converted to a methoxyiminoacetic acid derivative of the formula (IX) by treating with a methylating agent such as dimethyl sulfate or methyl iodide.

Next, an inert solvent (eg, halogenated hydrocarbons such as carbon tetrachloride, In the presence of a catalyst such as perbenzoic acid, 2,2'-azobis (isobutyrate), or light in the presence of methoxyimino diacid of the above formula (IX). The derivative is treated with a halogenating agent such as chlorine, bromine, N-bromosuccinic acid imide, N-chlorosuccinic acid imide or sulfuryl chloride to give the benzal halide acetate derivative of formula (X). I can guide you. At that time, a halogenating agent is required at least twice equivalent to the methoxyiminoacetic acid derivative of the formula (IX). Next, the acetate derivative of benzal halide of the formula (X) can be reacted with methylamine in an inert solvent to lead to the desired benzal halide derivative of the formula (IV). Methylamine can be used in an amount ranging from 1 equivalent to a large excess with respect to the acetic acid ester derivative of benzylhalide of the formula (X), but is preferably used in an amount equivalent to 13 equivalents. Solvents used include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloromethane, and the like; getyl ether, tetrahydrofuran Ethers, such as dioxane; dioxane; ketones, such as acetone and methylethyl ketone; alcohols, such as methanol, ethanol, and propanol; N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, Examples thereof include polar solvents such as acetonitrile and water, which may be a single solvent or a mixed solvent. Preferred solvents include toluene, tetrahydrofuran, ethanol or water. The reaction is carried out at a temperature of from 178 C to the boiling point of the solvent, preferably from 0 to 60.

The glyoxylic acid ester derivative of the formula (VII) used as a starting material in Scheme 3 can be prepared by a known method {for example, a method described in Synthetic Communication, 11, 943 (1981)}, Alternatively, it is manufactured by a method according to it.

Compounds (IX), (X) and (IV) described in Scheme 3 have isomers (E, Z) due to the asymmetric carbon to which the methoxyimino group is bonded, but in an inert solvent, All can be converted to the E-form by treating with an appropriate acid. When the E-form is used as a raw material, the E-form of a biologically active N-methyl-methoxyiminoacetic acid amide derivative of the formula (ΠΙ) can be produced. Examples of the acid used for the isomerization reaction include organic acids such as acetic acid and trifluoroacetic acid; hydrohalic acids such as hydrochloric acid; hydrogen halides such as hydrogen chloride; methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid and the like. Sulfonic acids; acid addition salts of organic bases such as pyridine hydrochloride and pyridine sulfate; and Lewis acids such as zinc chloride, iron chloride and aluminum chloride. Preferred are organic acids, hydrogen halides and sulfonic acids. The acid used is used in an amount of from the catalytic amount to the solvent amount, preferably from the catalytic amount to 1 equivalent.

Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; and hydrocarbons such as getyl ether, tetrahydrofuran and dioxane. Ethers; esters such as ethyl acetate; ketones such as acetone and methyl ethyl ketone; alcohols such as methanol, ethanol and propanol; nitriles such as acetonitrile; N, N-dimethylform Examples thereof include polar solvents such as amide, N-methylpyrrolidone, dimethyl sulfoxide, acetic acid, and water, which may be a single solvent or a mixed solvent. Preferred are ethers such as tetrahydrofuran and dioxane, alcohols, polar solvents such as N, N-dimethylformamide and acetic acid.

The reaction is carried out at a temperature ranging from room temperature to the boiling point of the solvent used, preferably at a temperature of 20 to 120.

The 1-alkoxy-1-methoxyminnow 2-methyl-3-oxo-1,1,2,3,4-tetrahydroisoquinoline derivative of the formula (I) can also be produced according to Scheme 4 below. (In the scheme below, X or R ¹ is as defined above.) Scheme 4

That is, the 1-alkoxy-1-methoxyoximino 2-methyl-3-oxo-1,1,2,3,4-tetrahydroisoquinoline derivative of the formula (I) is converted to the 4-methyoxyisoquinoline of the formula (XII) Toximinino 2-methyl-3-oxo-1,2,3,4-tetrahydroquinoline is converted to HO—R ¹ of the above formula (V) in the presence of a base, wherein R ¹ is already defined. The compound can be produced by reacting with an alcohol represented by the formula and a halogenating agent.

The alcohol of the formula (V) is a one-fold equivalent to a large excess of the 4-methoxymino 2-methyl-3-oxo-1,1,2,3,4-tetrahydroisoquinoline of the formula (XII) Preferably, it is used in an amount from 2 equivalents to the amount of solvent.

Examples of the base to be used include sodium hydroxide, alkali metal hydroxides such as sodium hydroxide, sodium carbonate, sodium carbonate, calcium carbonate and the like. Alkali metal or alkaline earth metal carbonates; Alkali metal bicarbonates such as sodium bicarbonate and hydrogen bicarbonate realms; Alkali metal bicarbonates such as sodium acetate Metal acetates; Tertiary amines such as triethylamine; Aromatic bases such as pyridine and picolin; Polyvinylpyrrolidone (cr0ss-1 inked), polyvinylpyridine, etc. Bases: alkali metal alcoholates such as sodium ethylate and t-butoxy potassium. Of these, alkali metal carbonates, alkali metal bicarbonates, or alkali metal acetates are preferred. New

The above base is used in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (XII).

Examples of halogenating agents used include chlorine, bromine, sulfuryl chloride, sulfuryl bromide, N-chlorosuccinic acid imid, N-bromosuccinic acid imid, and 1,3-dibromobutane. , 5-dimethylhydantoin and the like. Preferably, N-bromosuccinic acid imide or bromine is used. The halogenating agent used is used in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (XII).

The reaction is usually performed in a solvent.

Examples of the solvent used include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, and the like; getyl ether, tetrahydrofuran, Ethers such as dioxane; esters such as ethyl acetate; ketones such as acetone and methyl ethyl ketone; alcohols such as methanol, ethanol, propanol and butanol; and nitriles such as acetate-tolyl. A polar solvent such as N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetic acid, and water may be used, and a single solvent or a mixed solvent thereof may be used. Of these, aromatic hydrocarbons and alcohols are preferred.

The reaction is carried out at a temperature from room temperature to the boiling point of the solvent used, preferably from 20 to 150. The reaction time is usually 30 minutes to 24 hours, preferably 1 to 8 hours. The 4-methoxyminnow 2-methyl-3-oxo- 1,2,3,4-tetrahydroquinoline of the formula (XII) is a novel compound, and it comprises a benzyl halide derivative of the formula (XI) and methylamine. In the presence or absence of a base (eg, triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc.), and in an inert solvent (eg, ethanol, toluene, tetrahydrofuran, etc.). Can be produced by reacting in The 4-methoxymino-2-methyl-3-oxo-1,1,2,3,4-tetrahydroisoquinoline of the formula (XII) is a compound of N-benzylmethylamine (XIII) and oxalic acid derivative. free 2-Methyl-3,4-dioxo-1,2,3,4-tetrahydroisoquinoline (XIV) obtained by a Delkraft reaction or the like can be produced by a method known per se (for example, described in JP-A-5-977768). It can also be manufactured by oxidation.

In any of the above reactions, the compound obtained in any of the above reactions can be easily separated and purified from the reaction mixture by a method known per se, for example, extraction, recrystallization, or column chromatography. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist.

Example 1

Synthesis of 1-Methoxy 4-Methoxymino 2-Methyl-3-oxo-1 1,2,3,4-tetrahydroisoquinoline

0.5 g (1.82 mmo1) of N-methyl-2- (2-dichloromethylphenol) -1-2-methoxyiminodic acid amide and 0.53 g (3.8 g) of lithium carbonate A solution of 4 mmo 1) in 2 ml of methanol was heated and stirred at 50 ^ for 17 hours. After cooling, 20 ml of ethyl acetate was added to the reaction mixture, which was washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate Z hexane = 2: 3) to obtain 0.28 g of the title compound (yield: 65.8%).

Melting point: 1 24.5-1 25.5 ° C

XH-NMR (CD CI s); 2.97 (3H, s), 3.24 (3H, s), 4.23 (3H, s), 5.62 (1H, s) s), 7, 4—7.5 (3H, m), 7.46 (1H, dd)

Example 2

1-Methoxy 4-Methoxyimino 1-2-Methyl-3-oxo-1 1,2,3,4-te Synthesis of trahydroisoquinoline 0.5 g (1.37 mmol) of N-methyl-1- (2-dibromomethylphenol) -12-methoxyiminoacetic acid amide and 0.18 g of sodium methoxide

A solution of (3.33 mmol) in 2 ml of methanol was stirred at room temperature for 8 hours. To the reaction mixture was added 20 ml of ethyl acetate, washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate Z hexane = 2: 3) to obtain 0.23 g of the title compound (yield: 71.5%). . NMR spectrum measurement confirmed that the compound was the same as that in Example 1.

Example 3

Synthesis of 1-ethoxy-1-methoxy-2-amino-2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline

N-methyl-2- (2-dibromomethylphenyl) -1-2-methoxyiminoacetic acid amide 0.5 g (1.37 mmol) and sodium ethoxide 0.19 g

A solution of (2.79 mmo 1) in ethanol (2 ml) was stirred at room temperature for 8 hours. Ethyl acetate (20 ml) was added to the reaction mixture, and the mixture was washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate Z hexane = 2: 3) to obtain 0.21 g of the title compound (yield: 61.8%).

Melting point: 93.6-95.2 ° C

XH-NMR (CDC 1 a); 1.11 (3H, t), 3.15 (1H, m), 3.24 (3H, s), 3.30 (1H, m), 4.23 (3H, s), 5.64 (1H, s), 7.4-7.5 (3H, m), 7.46 (1H, dd)

Example 4

4-Methoxyii minnow 2-Methyl-3-oxo-1-synthesis of 1,2,3,4-tetrahydrosoquinolin

2- (2-bromomethylphenyl) -1-2-methoxyethyl acetate 1.0 g (3.33 mmol), 1 ml of pyridine and 1 ml of methanol were added to 1 ml of a 40% methanol solution of methanol, and the mixture was stirred at room temperature for 1.5 hours. After the solvent was distilled off from the reaction mixture, 20 ml of toluene was added, and the mixture was washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to obtain 0.26 g of the title compound (yield: 38.2. %).

Melting point: 1 20.0-1 2 2. O

"• H-NMR (CDC1a); 3.20 (3H, s), 4.18 (3H, s), 4.55 (3H, s), 7.18 (1 H, d), 7.37 (1H, dd), 7.41 (1H, dd), 8.39 (1H, d)

Example 5

Synthesis of 1-Methoxy 4-Methoxy-2-amino-1,2-Methoxy-3-oxo-1,2,3,4-tetrahydroisoquinoline

4-Methoxyiminnow 2-Methyl-3-oxo-1,2,3,4-tetrahydroquinone 0.81 g (4.0 mmo 1), sodium nitrate 0.3 0.71 g (4.0 mmol) of N-bromosuccinic acid was added to a mixture of 3 g (4.0 mmo1) and 8 ml of methanol, and the mixture was stirred at 50 ° C for 1.5 hours. did. Further, 0.71 g (4.0 mmo1) of N-bromosuccinic acid imide and 0.33 g (4.0 mmol) of sodium acetate were added, and the mixture was stirred at 50¾ for 2.5 hours. Stirred. Further, 0.71 g (4.0 mmo1) of N-bromosuccinic acid imide and 0.33 g (4.0 mmo1) of sodium acetate were added, and the mixture was stirred at room temperature for 24 hours. did. Saturated aqueous sodium bicarbonate was added to the reaction mixture, extracted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 0.65 g of the title compound (yield 69.4%). ). It was confirmed by NMR spectrum measurement that the compound was the same as that of Example 1.

Example 6

1-Methoxy 4-Methoxyiminor 2-Methyl-3-oxo-1 1,2,3, Synthesis of 4-tetrahydroisoquinoline

4-methoxyminnow 2-methyl-3-oxo-1,1,2,3,4-tetrahydroquinone 0.8 1 g (4.0 mm o 1), sodium carbonate 0.85 To a mixture of g (8.0 mmo 1) and 4 ml of methanol was added 1.28 g (8.0 mmo 1) of bromine, and the mixture was stirred at 50-6 for 3 hours. Further, 1.28 g (8. Ommo1) of bromine and 0.85 g (8.0 mmo1) of sodium carbonate were added, and the mixture was stirred at 50-6 Ot for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, extracted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate Z hexane = 1: 2) to obtain 0.46 g of the title compound (yield 49. 1%). ). It was confirmed by NMR spectrum measurement that the compound was the same as in Example 1. Example 7

N-Methyl-2- [2- (1- (4-difluoromethyoxy-3-methoxyphenyl) ethyloxyminomethyl} phenyl] Synthesis of 1-2-Methoxyiminoacetic acid amide

1-Ethoxy 1- 4-methoxymino 2- 2-Methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline 0.5 g (2.02mm o 1), 1- (4-difluoromethoxine 3) —Methoxyphenyl) A solution of 0.52 g (2.23 mmo 1) of ethylethylamine and 15 mg of methanesulfonic acid in 1 ml of acetic acid was heated and stirred at 80 ^ for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate Z hexane = 1: 2) to obtain 0.52 g of the title compound (yield: 57.3%). .

^X H-NMR (CDC 1 a); 1.57 (3 H, d), 2.88 (3 H, d), 3.88 (3 H, s), 3.89 (3 H , s), 5.23 (1H, q), 6.54 (1H, t), 6.65 (1H, br), 6.91 (1H, dd), 6. 9 7 (1 H, d), 7.1-7.2 (2 H, m), 7.35-7.4 (2 H, m), 7.70 (1H, m), 7.96 (1H, s)

Example 8

N-methyl-2- [2- [1- (3-trifluoromethinorefle) ethinoleoxyiminomethyl} phenyl] Synthesis of 1-2-methoximinoacetic acid amide

1-Methoxy 4-minoximino 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline 0.5 g (2.14 mmo 1) in 1 ml of acetic acid —Trifluoromethylphenyl) ethyloxyamine 0.48 g (2.34 mmo 1) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was recrystallized (ethyl acetate / hexane = 1: 5), and 0.8 g of 4-methoxyethoxyminoh 2-methyl-3-oxo-1-1- (1-trifluoro) was added. 1,1,2,3,4-Tetrahydroisoquinoline was obtained as a diastereomer mixture (89% yield).

^{X H-NMR (CD C 1} 3); 1. 20 (3 H, d), 1. 3 1 (3 H, d), 3. 2 1 (3 H, s), 3. 2 3 (3 H , s), 4.15 (3H, s), 4.17 (3H, s), 4.25 (1H, q), 4.54 (lH, q), 5.12 (2H, br), 5.56 (1H, br), 5.65 (1H, br), 7.2-7.6 (14H, m), 8.35 (2 H, m)

4-Methoxyxy Minnow 2-Methyl-3-oxo-1- 1- {1- (3-trifluoromethylphenyl) ethyloxyamino} -1-Diastereoisomeric mixture of 1,2,3,4-tetrahydroisoquinoline 1 ml of acetic acid and 0.01 g of p-toluenesulfonic acid were added to 0.45 g (1.1 mmo 1), and the mixture was stirred at 80 for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated saline solution, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl ethyl hexane-1: 2) to obtain 0.35 g of the title compound (yield: 7.78%).

Melting point: 88.5—89.0 ° C

^{X H- NMR (CD CI s)} ; 1. 5 8 (3 H, d), 2. 8 8 (3 H, d), 3.86 (3H, s), 5.30 (1H, q), 6.67 (1H, br), 7.15 (1H, dd), 7.35-7. 5 5 (5 H, m), 7.60 (1 H, s), 7.68 (1 H, dd), 7.96 (1 H, s)

Example 9

N-Methyl-2- (2- (1- (4-chlorophenyl) ethyloxyiminomethyl} File) Synthesis of 12-Methoxyiminoacetamide Hydroxidium 1.4 g ( 22.5 mm o 1) of methanolic water (10 m 1 Z 2 ml) solution in N-methyl-2- (2-dibromomethylphenol) -12-methoxyaminoacetic acid amide 2 g (5.5 mmol) and stirred at 45 ° C for 2 hours. Ethyl acetate (20 ml) was added, and the mixture was washed sequentially with water and saturated saline, and dried over anhydrous sodium sulfate. 2 ml of acetic acid was added to the residue obtained by distilling off the solvent, and 0.84 g (4.9 mmo 1) of 1- (4-phenylphenyl) ethyloxyamine was added at room temperature. did. After stirring at room temperature for 3 hours, 0.1 g of p-toluenesulfonic acid was added, and the mixture was heated and stirred at 80 ° C for 1 hour. After cooling, 20 ml of ethyl acetate was added, and the mixture was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 1.0 g of the title compound (yield: 49%).

Example 10

N-Methyl-2— [2- (1- (3-Trifluoromethylphenyl) ethyloxyminomethyl} phenyl) Synthesis of 1-2-methoxyminodiamide amide sodium carbonate 2.36 g (22.3 mmol) in a solution of methanol (8 ml Z 2 ml) in N-methyl-2- (2-dibromomethylphenyl) -12-methoxyamino amide 2 g (5.5 mmol) Was added and the mixture was stirred at 80 ° C for 7 hours. Ethyl acetate (20 ml) was added, and the mixture was washed with water, 1N hydrochloric acid and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated, 2 ml of acetic acid and 0.1 ml of water were added to the residue, and 1- (3-trifluoromethylphenyl) ethyloxamine 1.13 g (5. 5 mm o 1) was added. After stirring at room temperature for 3 hours, 0.05 _g of p-toluenesulfonic acid was added and heated and stirred at 80 ° C for 1 hour. After cooling, 20 ml of ethyl sulphate was added, washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate hexane = 1: 2) to obtain 1.42 g of the title compound (yield: 63.4%).

In the same manner as in Examples 8 to 10, the compounds described in Tables 11 and 12 can be produced.

table

Compound R ⁴ R ³ (, Y) _n

Object α

1 Η H 3-CF ₃ mp 93-97

2 Η H 4-CF ₃ n D 1.5505 no 25)

3 Η H 3-CI m.p. 90-93 ° C

4 Η H 4-Cl m.p. 119-123

5 Η H 3-CHs m.p. 90-93

6 Η H 4-CH3 m.p. 148-150

7 Η H 2, 5- (CH ₃ ) ₂ mp 106.5-107t

8 Η H 3-OCH3 viscous

9 Η H 4-OCHs viscous

10 Η H 3-OCF3 viscous

11 Η H 4-OCF3 m.p. 96-97 ° C

12 Η H 2, 5-C m.p. 148.5-150.5

13 Η H 3,5- (CF ₃ ) ₂ mp 102.5—105 ^

14 CH ₃ H mp 107.5-110.2¾

15 CH ₃ H 2-C1 viscous

16 CH ₃ H 3-C1 mp 82.5-83

17 CH ₃ H 4-Cl mp 87.5-90.5 ^

18 CH ₃ H 4-Cl viscous

19 CH ₃ H 3-Br viscous

20 CH ₃ H 4-Br amorphous solid

_{21 CH 3 H 3, 4-} Cl 2 mp110.9-111.7. C Table I (continued)

Compound R ⁴ R ³ (Y) _n Property QL

22 CH ₃ H 2, 5-Clz viscous

23 CH ₃ H 3-CF ₃ mp 88.5-89 ^

24 CH ₃ H 4-CF ₃ mp 70.5-71.5

25 CH ₃ H 4-CF3 viscous

26 CH ₃ H 2-CH3 viscous

27 CH ₃ H 3-CHs viscous

28 CH ₃ H 4-CH3 viscous

29 CH ₃ H 2, 4- (CH ₃ ) ₂ viscous

30 CH ₃ H 2,5-(CH ₃ ) ₂ viscous

31 CH ₃ H 3, 4- (CH ₃ ) ₂ viscous

32 CH ₃ H 4-C ₂ H ₅ amorphous solid

33 CH ₃ H 4-C ₃ H n) viscous

34 CH ₃ H 4-C ₃ H ₇ (iso) viscous

35 CH ₃ H 4-C ₄ H ₉ (tert) viscous

36 CH ₃ H 2-OCH3 viscous

37 CH ₃ H 3-OCH3 viscous

38 CH ₃ H 4-OCH3 amorphous solid

39 CH ₃ H 4-0C ₂ H _s Amorphous solid

40 CH ₃ H 4-OCaHr (n) Amorphous solid

41 CH ₃ H 3-0C ₃ Hr (iso) Amorphous solid

42 CH ₃ H 4-0C ₃ H ₇ (iso) Amorphous solid

43 CH ₃ H 3 Aprono-reginoleoxy Amorphous solid

44 CH ₃ H 4 1-propargyloxy Amorphous solid

45 CH ₃ H 4-0CH ₂ CH = CC1 ₂ Viscosity

46 CH ₃ H 3-OPh Amorphous solid

47 CH ₃ H 4-OPh Amorphous solid Table I (continued)

* Compounds Nos. 18, 25 and 62 are isomers in the benzyloxyimino moiety of compounds Nos. 17, 24 and 61, respectively.

** Isomers in the methoxyimino moiety include E-form and Z-isomer, but only physical properties of E-form are shown in Tables 1 and 2 unless otherwise specified. Table 1 2

Industrial applicability

According to the present invention, a novel intermediate, a 1-alkoxy-14-methoxyimimino 2-methyl-3-oxo-1 1,2,3,4-tetrahydroisoquinoline derivative, By passing through, the methoxyiminoacetic acid amide derivative of the general formula (II) can be efficiently produced. According to the method of the present invention, it is possible to obtain a methoxyiminoacetic acid amide derivative in a high yield of about 80%.

The methoxyiminoacetic acid amide derivative obtained according to the present invention has a high control effect on, for example, wheat powder rust, leaf rust and the like of barley as described in JP-A-7-076464. It is an excellent agricultural and horticultural fungicide.

Claims

Scope of request General formula (I) below

(Wherein, R ¹ represents an alkyl group of d—C _4. ) 1-alkoxy-14-methoxyiminor 2-methyl-3-oxo-1 1,2,3,4-tetrahydroisoquinoline derivative The following general formula (II)

H ₂ NO— R ² (II)

(Wherein, R ² represents a hydrogen atom or a group represented by the general formula C (R ³ ) (R ⁴ ) A Ar, wherein R ³ and R ⁴ each independently represent a hydrogen atom or d—C ₄ Ar represents an aryl group which may be substituted or an aryl group which may be substituted.} An oxamine derivative represented by the formula: (III)

(Wherein R ² is as defined in formula (II).) A method for producing an N-methyl-methoxyimino acetic acid amide derivative represented by the formula:

2. The following general formula (VI)

(VI)

b-one

(Wherein R ² is as defined in claim 1). 1-oxyamino-4-methoxyminino 2-methyl-3-oxo-11,2,3,41-tetrahydroisoquinoline A method for producing an N-methyl-methoxyiminoacetic acid amide derivative of the general formula (III), comprising treating the derivative with an acid.

3. —wherein R ^{2 in} general formula (II) or general formula (IV) is a hydrogen atom or general formula — C (R ³ ) (R ⁴ ) -A r (wherein R ³ and R ⁴ are each independently hydrogen Ar is —C ₄ alkyl group, halogen atom, Ci which may be substituted by halogen atom, C 1 -C ₄ alkoxy group or trifluoromethyl group which may be substituted by halogen atom. 3. The method according to claim 1, wherein the group is a group.

4. General formula (I)

(Wherein R ¹ is as defined in claim 1). 1-Alkoxy-14-methoxyminino 2-methyl-3-oxo-1 1,2,3,4-tetrahydroisoquinoline derivative .

5. —A monoalkoxy-14-methoxyiminor 2-methyl-3-oxo-1,1 according to claim 4, wherein R ^{1 in the} general formula (I) is methyl or ethyl. 2,3,4-Tetrahydroisoquinoline derivative.

6. The following general formula (IV)

(In the formula, X represents a chlorine atom or a bromine atom.) Conductor and the following general formula (V)

HO-R ¹ (V)

(Wherein R ¹ is as defined in claim 1). The alcohol represented by the general formula (I) is reacted with an alcohol represented by the general formula (I). Method for producing methoxyiminot 2-methyl-3-oxo- 1,2,3,4-tetrahydroisoquinoline derivative.

7. The following formula (XII)

4-Methoxyiminot 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline represented by the following general formula (V)

HO-R ¹ (V)

Wherein R ¹ is as defined in claim ^1. A monoalkoxy represented by the general formula (I) characterized by reacting with an alcohol represented by the formula: A method for producing a 1,4-methoxymino 2-methyl-3-oxo-1,1,2,3,4-tetrahydroisoquinoline derivative.

8 The following formula (XII)

4-Methoxymino 2-methyl-3-oxo-1,2,3,4'-trahydroisoquinoline represented by