CN1315780C - Process for producing n-(1-(2,4-dichlorophenyl)ethyl)-2- cyano-3,3-dimethylbutanamide - Google Patents

Abstract

A method for producing N-formyl-1-arylmethylamines represented by the general formula [VI]: RArCH-NH-CHO [VI] In the formula, R represents a C ₁ -C ₄ alkyl group, and Ar represents the following group Group: in the formula, R _represents hydrogen or chlorine; the method includes injecting the aryl ketone represented by the general formula [V] and formic acid into formamide and/or ammonium formate simultaneously: RArC=O [V] in the formula, R and Ar has the same meaning as above.

Description

Process for producing N-formyl-1-arylmethylamines

The application date is October 27, 1995, and the invention name is "N-[1-(2,4-dichlorophenyl) ethyl]-2-cyano-3,3-dimethylbutane The manufacturing method of amide” and the divisional application of the invention patent application with application number 200310120789.6.

technical field

The present invention relates to a method for producing N-formyl-1-arylmethylamines useful as plant disease control agents.

Background technique

As a method for producing N-[-1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide, it is known that 2-cyano- 3,3-Dimethylbutyrate is hydrolyzed into carboxylic acid in the presence of alkali, and thionyl chloride acts on the carboxylic acid to obtain reactive carboxylic acid chloride and 1-(2,4-dichloro A method in which phenyl)ethylamine reacts in the presence of a base.

However, because in this method there must be a process of hydrolysis and turning the acid into chloride, and reagents such as thionyl chloride are necessary, so people are looking for a simpler method.

Contents of the invention

The present inventor has studied the method for easily obtaining N-[1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutaneamide, and found There is no need for hydrolysis and the process of turning the acid into chloride, and there is no need for reagents such as thionyl chloride, but by making 2-cyano-3,3-dimethylbutyrate and 1-(2, The direct reaction of 4-dichlorophenyl) ethylamine obtains N-[1-(2,4-dichlorophenyl) ethyl]-2-cyano-3 , the method of 3-dimethylbutanamide, and found the method of 2-cyano-3,3-dimethylbutyrate and 1-(2,4-dichlorophenyl)ethylamine as its raw materials Improved manufacturing method, thus completing the present invention.

First, it is explained about the C ₂ -C ₄ alkyl (such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.) esters of α-cyano-tert-butylacetic acid and 1-(2, 4-dichlorophenyl)ethylamine, N-[1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethyl characterized by reaction at 130～250°C The production method (hereinafter referred to as the production method 1 of the present invention) of butane amide (hereinafter referred to as compound 1), and

A N characterized by the reaction of C ₂ -C ₄ alkyl esters of α-cyano-tert-butyl acetic acid and (R)-1-(2,4-dichlorophenyl)ethylamine at 130-250°C - the production method of [(R)-1-(2,4-dichlorophenyl) ethyl]-2-cyano-3,3-dimethylbutanamide (hereinafter referred to as compound 1a) (hereinafter referred to as The production method 2) of the present invention is performed.

First, Production Method 1 of the present invention will be described.

This reaction can make the C ₂ -C ₄ alkyl ester of α-cyano-tert-butyl acetic acid (either racemic or optically active) and 1-(2,4-dichlorophenyl)ethylamine (Whether it is a racemate or an optically active substance), in the absence of a solvent or in a solvent, at a reaction temperature of 130-250°C, preferably at a reaction temperature of 130-220°C, the reaction is usually carried out for 0.5-24 hours . The amount of reactant used _is usually in _the ratio of 0.9- 1.2 moles. The solvent used as necessary is not particularly limited as long as it is inert during the reaction and has a boiling point of 130 to 250° C., for example, xylene, cumene, 1,3,5-trimethyl Hydrocarbon solvents such as benzene, halogenated aromatic hydrocarbon solvents such as chlorobenzene and dichlorobenzene, ether solvents such as diglyme and triglyme, or mixtures thereof.

The reaction solution after the reaction is finished is usually cooled to room temperature and other crystallization operations, and the crystals generated are filtered, and then washed with an appropriate solvent (organic solvents such as methanol, ethanol, Virahol, hexane, chlorobenzene, water or Their mixed solvents) are washed, dried, and if necessary, further purified by recrystallization or the like to isolate the desired compound 1. Next, Production Method 2 of the present invention will be described.

This reaction can make the C ₂ -C ₄ alkyl ester of α-cyano-tert-butyl acetic acid (no matter it is racemic or optically active) and (R)-1-(2,4-dichlorobenzene base) ethylamine (the optical purity does not have to be 100% ee (enantiomeric excess), for example, it can be an optically active substance that is rich in (R) with an optical purity of 75% ee or more), in solvent-free or solvent, at 130～ The reaction is usually carried out for 0.5-24 hours at 250°C, preferably at a reaction temperature of 130-220°C. Amounts of reactants used, ratio of (R)-1-(2,4-dichlorophenyl)ethylamine to 1 mole of _C2 - _C4 alkyl ester of α-cyano-tert-butylacetic acid Usually 0.9-1.2 moles. The solvent used as necessary is not particularly limited as long as it is inert during the reaction and has a boiling point of 130 to 250° C., for example, xylene, cumene, 1,3,5-trimethyl Hydrocarbon solvents such as benzene, halogenated aromatic hydrocarbon solvents such as chlorobenzene and dichlorobenzene, ether solvents such as diglyme and triglyme, or mixtures thereof.

After the reaction, the reaction solution is usually cooled to room temperature and other crystallization operations, and the crystals generated by filtration are washed with suitable solvents (organic solvents such as methanol, ethanol, isopropanol, hexane, chlorobenzene, water or their mixture) solvent (solvent) and then dried to obtain the desired compound 1a.

In addition, in order to improve the characteristics of crystals, crystals can also be taken out by the following crystallization operation.

That is, the reaction solution after the reaction of distilling off the organic solvent is added as needed, while keeping it warm at 130-170 ° C, while injecting an organic solvent such as monochlorobenzene, dichlorobenzene, etc. that is azeotropic with water, and dissolves the solution. Cool to 70-100°C and keep warm at the same temperature. On the other hand, add water, a small amount of acid (hydrochloric acid, sulfuric acid, etc.) , At the same temperature, the solution dissolved in the above organic solvent (kept at 70-100°C) is slowly injected into it. Crystals of compound 1a are precipitated while substantially azeotroping the organic solvent and water and distilling off. The compound 1a slurry obtained in this way was slowly cooled to 20-40°C, and the crystals were collected by filtration, washed with water, and dried to obtain compound 1a as a crystalline powder with good filterability.

The usefulness of Production Method 2 of the present invention will be described below.

In compound 1, since there is an asymmetric carbon on the acid side and the amine side, there are a total of 4 optical isomers, that is, the X1 form (R, R) and the X2 form are present in the order (acid side, amine side) (S, S), Y1 body (R, S) and Y2 body (S, R), there are two diastereoisomers, namely X body (racemate: X1 body and X2 body) and Y body (racemate: Y1 body and Y2 body), but as shown in the reference examples mentioned later, the inventors found that the plant disease control activity is concentrated in the Y2 body and X1 body, and found that the plant disease of the Y2 body The control activity is much stronger than that of the X1 body, that is to say, the plant disease control activity of the Y body is much stronger than that of the X body.

However, when compound 1 derived from a racemate amine is obtained on an industrial scale, if crystallization is performed, the X form with weak plant disease control activity among the above two diastereomers is preferentially crystallized, and its diastereomer The ratio of isomers is easily affected by various factors such as heat, so it is known that there is a problem of not necessarily being stable (difficult to control). Therefore, a variety of studies have been carried out, and it has been unexpectedly found that in optically active amines (for example, at an optical purity of 75% ee or more) In the compound 1a (optical isomer) derived from the enriched optical isomer in the R form), the X1 form and the Y2 form are crystallized in approximately equal amounts, and the ratio of the diastereoisomers is within the usual operating conditions. It is not affected by factors such as heat and does not change, thereby obtaining the manufacturing method 2 of the present invention.

The C ₂ -C ₄ alkyl ester of α-cyano-tert-butyl acetic acid used as a raw material compound in the present invention can also be produced, for example, by a method described in J.Am.Chem.Soc.Vol.4791 (1950) or the like , but can be efficiently obtained by the following raw material production method.

1-(2,4-Dichlorophenyl)ethylamine can be produced, for example, by methods described in Organic Reaction, Vol 5, 301-330 (1949) and JP-A-2-306942.

A method for producing a C ₂ -C ₄ alkyl ester of α-cyano-tert-butylacetic acid as a raw material of Production Method 1 will be described below.

C ₂ -C ₄ alkyl esters of α-cyano-tert-butylacetic acid, via C ₂ -C ₄ alkyl esters of 2-cyano-3-methyl-2-butenoic acid and methylmagnesium halide, Obtained by reacting in the presence of a copper catalyst.

Examples of C ₂ -C ₄ alkyl esters of 2-cyano-3-methyl-2-butenoic acid used include ethyl 2-cyano-3-methyl-2-butenoate , 2-cyano-3-methyl-2-butenoic acid n-propyl ester, 2-cyano-3-methyl-2-butenoic acid isopropyl ester, 2-cyano-3-methyl-2 -n-butyl crotonate, isobutyl 2-cyano-3-methyl-2-butenoate, and the like.

As the methylmagnesium halide used, methylmagnesium chloride (CH ₃ MgCl), methylmagnesium bromide (CH ₃ MgBr), methylmagnesium iodide (CH ₃ MgI) can be mentioned, all of which are commercially available, or It can be modulated by reacting magnesium and methyl halide in a usual way.

As a copper catalyst, a monovalent or divalent copper salt is usually used, and examples thereof include copper (I) chloride [CuCl], copper (I) bromide [CuBr], and copper (I) iodide [CuI]. The reaction is usually carried out in an organic solvent. As the organic solvent used, for example, ether solvents such as tetrahydrofuran (hereinafter referred to as THF), diethyl ether, and dibutyl ether, aromatic hydrocarbon solvents such as toluene, xylene, and benzene, and ether solvents are mentioned. Mixed solvents with aromatic hydrocarbon solvents, etc.

The reaction temperature is usually 10-60°C, the reaction time is usually 0.5-10 hours, and the amount of reactant used in the reaction is C ₂ -C ₄ alkane for 1 mole of 2-cyano-3-methyl-2-butenoic acid base ester, the ratio of methyl halide magnesium is usually 1-2 moles, for 1 weight part of C ₂ -C ₄ alkyl ester of 2-cyano-3-methyl-2-butenoic acid, copper catalyst The proportion is usually 0.0005-0.1 parts by weight.

The reaction solution after the reaction is usually treated with water, ammonium chloride water, dilute sulfuric acid water, etc., and then the organic layer is concentrated, and if necessary, it is subjected to purification operations such as distillation to isolate the target α-cyano-tert-butyl group. C ₂ -C ₄ alkyl esters of acetic acid.

The C ₂ -C ₄ alkyl ester of 2-cyano-3-methyl-2-butenoic acid, which is the raw material used here, can be efficiently produced by the following production method.

Specific embodiments

The following describes in detail the production method of C ₂ -C ₄ alkyl esters of 2-cyano-3-methyl-2-butenoic acid, which is characterized in that, in the presence of a catalyst, using hexane as the main solvent, making acetone Reaction with C ₂ -C ₄ alkyl esters of cyanoacetic acid.

Examples of C ₂ -C ₄ alkyl esters of cyanoacetic acid used include ethyl cyanoacetate, n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate, cyano Isobutyl acetate and the like can be commercially available or can be produced by a usual method.

As a catalyst, substitutable aniline and carboxylic acid are usually used. As the substituent in the substitutable aniline, for example, hydroxyl, methyl, methoxy, etc. can be mentioned. As an example of substitutable aniline, aminophenol can be mentioned. (p-aminophenol, o-aminophenol, m-aminophenol, etc.), toluidine (p-toluidine, o-toluidine, m-toluidine).

Examples of carboxylic acids include lower (eg, C ₁ -C ₃ ) fatty acids (eg, acetic acid, formic acid, propionic acid, etc.) and benzoic acid.

Examples of the copper catalyst include copper (II) chloride (CuCl ₂ ), copper (II) bromide (CuBr ₂ ), and copper (II) iodide (CuI ₂ ).

As a reaction solvent, a solvent based on n-hexane is used. More specifically, the ratio of n-hexane to all solvents is usually 50-100% by weight. As a reaction solvent that can be mixed with n-hexane, for example, Aromatic hydrocarbon solvents, such as toluene and xylene, etc. are mentioned.

The reaction temperature is usually 50-100° C., the reaction time is usually 5-20 hours, and the water generated during the reaction is usually removed while the reaction is being carried out.

The amount of reactant used in the reaction, relative to the C ₂ -C ₄ alkyl ester of 1 mole of cyanoacetic acid, the acetone ratio is usually 1-4 moles, and the catalyst ratio is usually 0.001-0.2 moles (the ratio of aniline that can be substituted is usually 0.001-0.1 mol, the carboxylic acid ratio is usually 0.1-0.2 mol).

The reaction solution after the reaction is usually concentrated under reduced pressure or normal pressure, or distilled intact, or dissolved in ethyl acetate, toluene, xylene and other solvents, washed with water, and then the solution is concentrated under reduced pressure to remove the solvent. If necessary, purification operations such as distillation are performed to isolate the target C ₂ -C ₄ alkyl ester of 2-cyano-3-methyl-2-butenoic acid.

According to the method of the present invention, lower alkyl esters of 2-cyano-3-methyl-2-butenoic acid can be produced in high yield.

The optically active 1-(2,4-dichlorophenyl)ethylamine used as the raw material of the present invention can conveniently use cheap optically active aspartic acid in the implementation on an industrial scale, by optical resolution (RS)-1 -(2,4-Dichlorophenyl)ethylamine was obtained.

The following describes the production method of optically active 1-(2,4-dichlorophenyl)ethylamine, which is characterized in that, using optically active aspartic acid, optically separates (RS)-1-(2,4-dichloro phenyl) ethylamine.

In this optical separation method, it usually proceeds through three processes, (process a) mixing optically active aspartic acid and (RS)-1-(2,4-dichlorophenyl)ethylamine to generate a salt, and then , (process b) crystallize the optically active diastereoisomeric salt in a solvent, isolate the salt by filtration etc., (process c) treat the salt with a base. Processes a, b and c are described in more detail below.

(process a)

Optically active (L- or D-) aspartic acid can be obtained on an industrial scale, usually with an optical purity of 90% ee or higher. (RS)-1-(2,4-dichlorophenyl)ethylamine, for example, 2,4-dichloroacetophenone can be used as starting material, by carrying out Leuckert described in Organic Reaction Vol.5, 301-330 (1949) produced in response.

The amount of the reactant used is, for 1 mole of (RS)-1-(2,4-dichlorophenyl)ethylamine, the ratio of optically active aspartic acid is usually 0.1-1.2 moles, preferably 0.3-1 moles . The mixing may be performed in a solvent, and examples of the solvent used as necessary include water, lower alcohols such as methanol and ethanol, or mixtures thereof.

(process b)

The obtained salt is dissolved in a solvent by heating usually at a temperature ranging from 50 to 120°C, and the solution is usually cooled to a temperature ranging from 0 to 40°C to precipitate the optically active diastereoisomer salt. As the solvent, water, lower alcohols such as methanol and ethanol, or a mixture thereof are usually used.

The precipitated salt is isolated by filtration or the like, but if necessary, it can be recrystallized from lower alcohols such as water, methanol, ethanol, or a mixture thereof, and then purified.

(process c)

Usually at a temperature in the range of 0-40°C, for 1 mole of the salt, a base such as sodium hydroxide is usually used in a ratio of 1-10 moles to make the salt alkaline, and the free amine is extracted with an organic solvent such as toluene , after operations such as concentration, the optically active 1-(2,4-dichlorophenyl)ethylamine as the target object can be isolated.

The stereo configuration-optical activity of the optically active 1-(2,4-dichlorophenyl)ethylamine obtained by the production method of the present invention is R-(+) when L-aspartic acid is used as the separating agent. , where D-aspartic acid is used as the separating agent is (S)-(-).

Furthermore, in the production method of the present invention, unreacted (RS)-1-(2,4-dichlorophenyl)ethylamine can be recovered from the filtrate after filtering the salt, and the used optically active natural Aspartic acid can be easily recovered from the filtrate and the aqueous layer after amine extraction, and the recovered optically active aspartic acid can be reused.

In addition, as an optical separation method for 1-phenylethylamines, a method using mandelic acid in a water solvent (JP-A-56-26848) and a method using tartaric acid and malic acid in a water solvent (Org .Synthesis, Coll, Vol.2, 506(1943)), but even if the optical separation method of these 1-phenylethylamines is applied to 1-(2,4-dichlorophenyl)ethylamine, but due to the Due to the substituent at the ortho position of the phenyl group, there is a problem that optical resolution may not be possible, or only 1-(2,4-dichlorophenyl)ethylamine whose optical purity is significantly lowered may be obtained.

As a result of repeated research on this, it was found that using an organic solvent as the separation solvent and using optically active mandelic acid as the optical separation agent enables the industrially advantageous production of the target product with high optical purity and high efficiency. Optically active 1-(2,4-dichlorophenyl)ethylamine.

The method for industrially producing 1-(2,4-dichlorophenyl)ethylamine with excellent optical activity is described in detail below, which is characterized in that, in an organic solvent, optical separation of mandelic acid with optical activity (RS) is used. -1-(2,4-Dichlorophenyl)ethanamine.

(RS)-1-(2,4-dichlorophenyl)ethylamine is a racemic mixture containing R-isomer and S-isomer in equal amounts, but even a mixture containing one optical isomer in excess can also be used.

The optically active mandelic acid, which is the optical separating agent of the present invention, can be used regardless of its D-form or L-form.

The usage amount thereof is 0.1-1.2 times, preferably 0.3-1 times that of (RS)-1-(2,4-dichlorophenyl)ethylamine by mole.

Examples of organic solvents used as the isolation solvent include alcohol-based solvents such as methanol, ethanol, and n-propanol, ketone-based solvents such as acetone and methyl isobutyl ketone, ester-based solvents such as ethyl acetate, and methyl tert-butyl ether. , dioxane, diethyl ether and other ether solvents, toluene, xylene, chlorobenzene and other aromatic solvents, acetonitrile and other nitrile solvents, and mixtures thereof. Water may also be contained in organic solvents.

The amount of solvent used varies depending on the solvent used, but for (RS)-1-(2,4-dichlorophenyl)ethylamine, it is usually 2-100 times (by weight), preferably 2-10 times (weight).

When performing optical resolution, for example, in the above-mentioned solvent, (RS)-1-(2,4-dichlorophenyl)ethylamine and optically active mandelic acid are reacted to form diastereoisomeric salts, Alternatively, after dissolving the pre-prepared diastereomeric salt, one diastereomeric salt is precipitated by standing or stirring. Cooling and concentration can also be carried out as required. The temperature range is usually -20°C to the boiling point of the solvent.

The precipitated salt is then isolated. The resulting salt may also be recrystallized if desired. Next, the salt is decomposed with a base, and the resulting organic layer is separated or extracted with an organic solvent to obtain the optically active 1-(2,4-dichlorophenyl)ethylamine as the target object.

Optically active mandelic acid can be recovered by separating the organic layer or extracting the remaining aqueous layer, converting it to acidic with an acid, and then extracting it with an organic solvent.

On the other hand, optically active 1-(2,4-dichlorophenyl)ethylamine and optically active mandelic acid can be recovered by performing the same operation as above on the mother liquor from which diastereomers have been separated. .

As the base used for decomposing diastereoisomeric salts, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like are generally used. Its amount is usually 1-5 times (moles) relative to the salt.

In addition, in the case of extracting the amine produced by decomposing the salt, as the extraction solvent, for example, ester solvents such as ethyl acetate, ether solvents such as methyl tert-butyl ether, tetrahydrofuran, and diethyl ether, toluene, xylene, chlorobenzene, etc., are generally used. and other aromatic solvents, etc. Its amount is usually 0.1-5 times (by weight) relative to the salt.

Examples of acids used for recovering optically active mandelic acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid. An acid is used so that the pH of the water layer becomes 0.5-2. In this case, salts such as sodium chloride can also be added, usually in an amount of 0.1-0.2 times the weight of the water layer.

Examples of the extraction solvent for optically active mandelic acid include ether solvents such as methyl tert-butyl ether, ester solvents such as ethyl acetate, and alcohol solvents obtained by forming a two-layer system with water, such as n-propanol. Its usage amount is 0.1-10 times relative to the weight of the water layer.

According to this method, an organic solvent is used as a solvent, and optically active mandelic acid, which is a specific carboxylic acid, is used as an optical isolating agent, thereby making it possible to easily and efficiently produce the desired optically active mandelic acid with high optical purity. -(2,4-Dichlorophenyl)ethanamine. In addition, optically active mandelic acid, which is an optical separating agent, can also be recovered easily, and since it can be recycled, it is industrially advantageous.

Furthermore, the optically active 1-(2,4-dichlorophenyl)ethylamine as the target object can also be obtained by an industrially superior method, which is characterized in that, in an organic solvent, the optically active diphenyl Optical separation of acyl tartaric acid (RS)-1-(2,4-dichlorophenyl)ethylamine. This method is described in detail below.

(RS)-1-(2,4-dichlorophenyl)ethylamine is a racemic mixture containing R-isomer and S-isomer in equal amounts, but even if one of the optical isomers is contained in excess be usable.

Optically active dibenzoyl tartaric acid, which is the optical separating agent of the present invention, can be used regardless of its D-form or L-form.

The amount used is usually 0.3-1.2 times (mol) relative to (RS)-1-(2,4-dichlorophenyl)ethylamine, preferably 0.5-1 times (mol).

As the organic solvent used as the separating agent, for example, alcohol solvents such as methanol, ethanol and n-propanol, ketone solvents such as acetone and methyl isobutyl ketone, ester solvents such as ethyl acetate, methyl tert-butyl Ether-based solvents such as ether, dioxane, and diethyl ether; aromatic-based solvents such as toluene, xylene, and chlorobenzene; nitrile-based solvents such as acetonitrile; and mixtures thereof. The organic solvent may also contain water.

The amount of solvent used varies with the solvent used, but for (RS)-1-(2,4-dichlorophenyl) ethylamine, it is usually 2-100 times (weight), preferably 2-20 times (weight) ).

For optical resolution, for example, after reacting (RS)-1-(2,4-dichlorophenyl)ethylamine and optically active dibenzoyl tartaric acid in the above solvent to form diastereoisomeric salts , or after dissolving the pre-prepared diastereomeric salt, one diastereomeric salt is precipitated by standing or stirring. It can also be cooled and concentrated as needed. The temperature range is usually -20°C to the boiling point of the solvent.

The precipitated salt is then isolated. The salt obtained can also be recrystallized if desired. Next, the salt is decomposed with an alkali, and the resulting organic layer is separated or extracted with an organic solvent to obtain optically active 1-(2,4-dichlorophenyl)ethylamine as the target product.

Optically active dibenzoyl tartaric acid can be easily recovered by separating the organic layer or extracting the remaining aqueous layer, making it acidic with an acid, and then extracting it with an organic solvent.

On the other hand, optically active 1-(2,4-dichlorophenyl)ethylamine and optically active dibenzoyltartaric acid can be recovered by performing the same operation as above on the mother liquor from which diastereomer salts have been separated.

Here, as the base used for decomposing the diastereoisopine salt, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like are generally used. Its dosage is usually 1-5 times (moles) relative to the salt.

In addition, when extracting the amine generated by decomposing the salt, as the extraction solvent, for example, an ester solvent such as ethyl acetate, an ether solvent such as methyl-tert-butyl ether, tetrahydrofuran, diethyl ether, etc., toluene, xylene, chlorobenzene, etc. are generally used. and other aromatic solvents. The amount used is usually 0.1-5 times (by weight) relative to the salt.

Examples of acids used when recovering optically active dibenzoyltartaric acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid. Usually, the acid is used so that the pH of the water layer becomes 0.5-2. In addition, salts such as sodium chloride can also be added in this case, and the amount is usually 0.1-0.2 times of the weight of the water layer.

In addition, examples of extraction solvents for optically active dibenzoyltartaric acid include ether-based solvents such as methyl tert-butyl ether, ester-based solvents such as ethyl acetate, and alcohol-based solvents obtained by forming a two-layer system with water, such as n-butanol. . Its usage amount is 0.1-10 times relative to the weight of the water layer.

According to the present invention, the optically active 1- (2,4-Dichlorophenyl)ethylamine.

In addition, optically active dibenzoyltartaric acid as an optical separating agent can also be easily recovered and recycled, so it is industrially advantageous.

The S form of phenylethylamine remaining in the filtrate after the above-mentioned optical separation method can be used as the R form by racemization. As such a method, for example, sodium naphthalene has been known to act on it. The manufacture method of the racemic α-phenylethylamine that forms (patent open No. 50-49235), make sodium hydroxide effect and form the manufacture method of α-naphthylethylamine (patent open No. 54-5967), make The production method of α-phenylethylamine formed by the action of sodium supported on alumina (JP-A-50-50328), the racemic 1-( A method for producing 4-chlorophenyl)ethylamine (JP-A-4-275258) and the like.

However, when the above-mentioned known method is applied to optically active 1-(2,4-dichlorophenyl)ethylamine, there arises a problem that the racemization reaction does not proceed completely.

Therefore, a method has been found to condense optically active 1-(2,4-dichlorophenyl)ethylamine with 2,4-dichloroacetophenone to produce a new type of optically active compound N-(α-methyl -2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine, when alkali metal alkoxide acts on it in dimethyl sulfoxide, it will be racemic The reaction proceeds efficiently, and at the same time, it was found that the target racemic 1-(2,4-dichlorophenyl)ethylamine can be easily obtained by hydrolyzing the racemic imine.

The following details racemic 1-(2,4-dichlorophenyl)ethylamine, after optically active N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4- The manufacture method of dichlorophenyl) ethylamine.

The optically active N-(α-methyl-2,4-dichlorophenylidene)-α-(2,4-dichlorophenyl)ethylamine of the present invention can undergo dehydration condensation of optically active 1-(2, 4-dichlorophenyl) ethylamine and 2,4-dichloroacetophenone to manufacture. Here, the optically active 1-(2,4-dichlorophenyl)ethylamine may be any one of the R form and the S form, or a mixture in which one of them is in excess.

The dehydration condensation can be carried out by a known method, for example, the method of J. Chem. Soc, 14, 2624 (1984). The consumption of 2,4-dichloroacetophenone is usually 0.5-2 times, preferably 0.95-1.05 times (mol) with respect to optically active 1-(2,4-dichlorophenyl)ethylamine.

The reaction is usually carried out with a solvent or a catalyst, but it can also be carried out without a solvent or a catalyst. When a solvent is used, as long as the solvent does not interfere with the reaction, for example, aromatic solvents such as toluene, benzene, xylene, and chlorobenzene, and ether solvents such as dioxane and methyl tert-butyl ether are mentioned. , Aliphatic solvents such as hexane and heptane, halogen solvents such as dichloroethane and chloroform, etc. It is preferable to remove the water produced by the dehydration condensation out of the system during the reaction.

The amount of the solvent used is usually 0-20 times (by weight), preferably 3-10 times (by weight) relative to the optically active 1-(2,4-dichlorophenyl)amine.

Examples of the dehydration condensation catalyst include zinc chloride, zinc bromide, zinc fluoride, titanium tetrachloride, boron trifluoride, boron tribromide, phosphorus trichloride, magnesium bromide, iron chloride, chlorine Lewis acids such as aluminum chloride, tin tetrachloride, alkoxytitanium, copper (II) triflate, sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, and sulfonic acid-based ion exchange resins, 12 phosphotungsten (IV) acid, heteropolyacids such as 12 silicotungstic (IV) acid, etc.

Among them, zinc chloride, titanium alkoxide, titanium tetrachloride, boron trifluoride, p-toluenesulfonic acid and the like are preferably used. Zinc chloride, titanium alkoxide and the like are preferable.

The usage amount of catalyst is usually 0.001-0.1 times, preferably 0.005-0.05 times (mol) with respect to optically active 1-(2,4-dichlorophenyl)ethylamine.

The reaction temperature of condensation is usually 70-180°C, and it is better to remove the water generated by dehydration condensation out of the system while reacting. The reaction time is usually 1-20 hours.

The resulting optically active N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine can also be obtained as it is after removing the catalyst from the reaction mass. It can be used in the subsequent process, and can also be separated by methods such as distillation to remove low-boiling components, and can also be refined by means of distillation, recrystallization, and various chromatography after separation.

When racemate-forming optically active N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine to produce a racemate, in It is carried out by allowing an alkali metal alkoxide to act in the coexistence of dimethyl sulfoxide.

As the alkali metal alkoxide, metal alkoxides of tertiary alcohols such as potassium t-butoxide, sodium t-butoxide, potassium t-amylate, and sodium t-amylate are preferably used, for example.

The amount used is usually 0.01-2 times that of the optically active N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine, which is higher than Preferably it is 0.03-0.2 times (mol).

In addition, the amount of dimethyl sulfoxide used is generally 0.1-10 times, preferably 0.5-5 times (mole). Of course it can also be used as a solvent.

The racemization reaction is usually carried out in the presence of a solvent. As such a solvent, as long as it does not interfere with the reaction, for example, aromatic solvents such as toluene, benzene, xylene, and chlorobenzene; ether solvents such as diethyl ether, methyl tert-butyl ether, and dioxane; , Heptane and other aliphatic solvents, dimethyl sulfoxide, etc. The amount of solvent used varies depending on the type of solvent used, but relative to the optically active N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine , usually 0.3-100 times (weight), preferably 0.5-10 times (weight).

The reaction temperature and reaction time of the racemization reaction vary depending on the type and amount of the alkali metal alkoxide, but the temperature is usually from 0°C to the boiling point of the solvent, preferably from 0°C to 100°C, more preferably from 10°C to 50°C. °C, the reaction time is usually 1-48 hours.

The progress of the reaction can be traced by the following methods: take a part of the reaction substance to measure the optical rotation, or analyze it by high-speed liquid chromatography with an optical active column after hydrolysis.

The resulting optically active N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethanamine is washed from the reaction mass with, for example, an aqueous solution containing inorganic salts such as common salt. After the net removal of dimethyl sulfoxide, alkali metal alkoxide, etc., it is usually used in the subsequent process as it is, but it can be separated by distillation to remove low boiling point components, or it can be separated by distillation, recrystallization, various Refined by chromatography and other means.

Racemic N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine, for example, can be decomposed into racemic 1-(2,4-dichlorophenyl)ethylamine and 2,4-dichloroacetophenone.

The hydrolysis is carried out, for example, in the presence of acids such as dilute hydrochloric acid and sulfuric acid without or using a solvent. At this time, the amount of acid used is usually based on equivalents relative to racemic N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine 1-10 times, preferably 1.05-1.5 times.

The amount of water used is generally 1-1000 in moles relative to racemic N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine Times, preferably 20-100 times.

In the case of using a solvent, the usual amount used is 0.1- 5 times (weight). As the solvent, as long as it does not inhibit the reaction, for example, alcohol solvents such as methanol and ethanol, aliphatic solvents such as hexane and heptane, halogen solvents such as dichloroethane and chloroform, ethyl acetate, etc. Ester solvents, ether solvents such as dioxane and diethyl ether, aromatic solvents such as toluene, xylene, and chlorobenzene, etc.

The hydrolysis reaction temperature and reaction time also depend on the type and amount of acids used, the temperature is usually 0°C to the boiling point of the solvent, preferably 30-70°C, and the reaction time is usually 10 minutes to 5 hours.

Usually hydrolyzed to generate water-soluble 1-(2,4-dichlorophenyl)ethylamine and acid salts, and 2,4-dichloroacetophenone. In the case of carrying out without a solvent, for example, a non-water-miscible solvent can be added to the reaction substance, and 2,4-dichloroacetophenone can be extracted and separated in the organic layer, and then the aqueous layer can be decomposed with an aqueous alkali solution such as sodium hydroxide aqueous solution. It becomes alkaline, and then it is extracted with a water-insoluble solvent, and the obtained organic layer is usually concentrated under reduced pressure, and 1-(2,4-dichlorophenyl)ethylamine can be taken out.

When using a water-soluble solvent such as an alcoholic solvent for hydrolysis, after distilling off the alcohol, the same treatment as above can be carried out. When using a non-water-soluble solvent, separate the reaction substance as it is, and extract it in the organic layer. 2,4 -Except for dichloroacetophenone, the same treatment as above can be performed.

In addition, after subjecting the reaction substance to steam distillation to separate 2,4-dichloroacetophenone by distillation, the aqueous solution of alkali such as sodium hydroxide aqueous solution is used to make it alkaline, and then extracted with a non-water-soluble solvent, and the resulting The organic layer was concentrated under reduced pressure to obtain 1-(2,4-dichlorophenyl)ethylamine.

In addition, the reaction substance is made alkaline with an aqueous alkali solution such as sodium hydroxide aqueous solution, and then extracted with a water-insoluble solvent to obtain 2,4-dichloroacetophenone and 1-(2,4-dichlorophenyl)ethane A mixture of amines can be separated by using a usual separation means, such as chromatography. The separated and recovered 2,4-dichloroacetophenone can be recycled.

According to the present invention, the useless optically active 1-(2,4-dichlorophenyl)ethylamine, via the optically active N-(α-methyl-2,4-dichlorobenzylidene)-α-(2, 4-dichlorophenyl)ethylamine, whereby the useful racemic 1-(2,4-dichlorophenyl)ethylamine can be easily and efficiently produced.

As a method for producing chlorosubstituted phenylalkylamines [II], among the corresponding chlorosubstituted phenylalkyl ketones, it is known that ammonia and hydrogen are reacted at 120 atmospheres under a Raney nickel catalyst poisoned by a sulfur compound. The method (Japanese patent open Zhao 2-73042).

However, in this method, in addition to the equipment problems caused by the necessity of high pressure, there is also the problem that the raw material ketone is incidentally formed into a reduced alcohol body.

The present inventors have obtained the following results after research: In order to make the chlorine-substituted phenylalkylamines [II] used in the present invention more advantageously produced industrially, using their oxime acetates, if in a specific solvent, catalyst, i.e. organic carboxyl Catalytic hydrogenation in the presence of an acid solvent or a platinum catalyst can efficiently produce chloro-substituted phenylalkylamines [II] with a high yield even at low pressure and with little incidental generation of alcohols.

The following description is by using the general formula [I]

(wherein R ₁ represents a lower alkyl group, R ₂ represents a hydrogen atom or a chlorine atom.) Chlorine-substituted phenylalkyl ketoxime acetic acids represented by catalytic hydrogenation under an organic carboxylic acid solvent and a platinum catalyst, the general formula for production [II]

(where R ₁ and R ₂ represent the same meaning as above)

Representation of chlorine-substituted phenylalkylamines.

In this process, examples of R ₁ in the chlorosubstituted phenylalkylketoxime acetates [I] include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Lower alkyl groups such as butyl, sec-butyl, and pentyl.

As _R2 , a hydrogen atom and a chlorine atom are mentioned, for example.

Specific examples of acetate salts [I] include 2'-chloroacetophenone, 3'-chloroacetophenone, 4'-chloroacetophenone, 2',3'-dichloroacetophenone, 2'- , 4'-dichloroacetophenone, 2',5'-dichloroacetophenone, 3',4'-dichloroacetophenone, 3',5'-dichloroacetophenone, 2'-chloroacetophenone , 3'-chloroacetophenone, 4'-chloroacetophenone, 2',3'-dichloroacetophenone, 2',4'-dichloroacetophenone, 2',5' -Dichloroacetophenone, 3′,4′-dichloroacetophenone, 3′,5′-dichloroacetophenone, 2′-chlorophenyl-isopropylketone, 3′-chloro Phenyl-isopropyl ketone, 4'-chlorophenyl-isopropyl ketone, 2',3'-dichlorophenyl-isopropyl ketone, 2',4'-dichlorophenyl-isopropyl ketone Ketone, 2′,5′-dichlorophenyl-isopropyl ketone, 3′,4′-dichlorophenyl-isopropyl ketone, 3′,5′-dichlorophenyl-isopropyl ketone, 2'-chlorophenyl-n-propyl ketone, 3'-chlorophenyl-n-propyl ketone, 4'-chlorophenyl-n-propyl ketone, 2',3'-dichlorophenyl-n-propyl Ketone, 2', 4'-dichlorophenyl-n-propyl ketone, 2', 5'-dichlorophenyl-n-propyl ketone, 3', 4'-dichlorophenyl-n-propyl ketone, 3',5'-dichlorophenyl-n-propyl ketone, 2'-chlorophenylamyl ketone, 3'-chlorophenylamyl ketone, 4'-chlorophenylamylketone, 2',3 '-Dichlorophenylpentyl ketone, 2',4'-dichlorophenylpentyl ketone, 2',5'-dichlorophenylpentyl ketone, 3',4'-dichlorophenylpentyl Ketones, 3',5'-dichlorophenylamyl ketone and other oxime acetates.

Acetate salts [I] can be easily produced, for example, according to the method described in Organic Synthesis Collective Vol.6, 278, that is, hydroxylamine and acid and salt act on the corresponding ketones, that is, chloro-substituted benzenes represented by the general formula [IV] base ketones,

Thereby deriving into ketoximes, i.e. chlorine-substituted phenylalkyl ketoximes represented by the general formula [III],

Acylating is then effected by the action of an acylating agent.

Among them, when a salt of hydroxylamine and an acid acts on the ketone [IV], examples of the salt of hydroxylamine and an acid used include hydrochloride, sulfate, phosphate, etc., and salts of inorganic acids. The amount used is usually 1-1.1 times that of ketones [IV] in moles.

The reaction is usually carried out under a solvent. As such a solvent, for example, a mixture of water and a water-miscible alcoholic solvent such as methanol or ethanol, a mixture of water and hexane, pentane, toluene, dichloromethane, dichloroethane, methyl tert-butyl ether Mixtures of solvents that are immiscible with water, etc. In the latter case, the reaction can be carried out more smoothly by interphase transfer and the use of a catalyst. The solvent is used in an amount of 1 to 10 times (by weight) relative to the ketones [IV].

The reaction also proceeds at room temperature, but the reaction can also be accelerated by heating to 50-60°C. As the reaction proceeds, the inorganic acid will be free, but it can be neutralized with an aqueous alkali solution such as sodium hydroxide, sodium carbonate, ammonia, etc. during or after the reaction. The produced ketoximes [III], for example, when obtained in the form of crystals, can be isolated by distilling off the solvent, washing the obtained crystals with water, etc., drying and isolating; The organic layer was separated, washed with water, and the solvent was distilled off for isolation.

When the acylating agent acts on the ketoxime [III] for acetic acidification, examples of the acylating agent include acetic anhydride, acetic acid halides such as acetic acid chloride and acetic acid bromide, and the like. The amount of acylating agent is usually 1-1.1 times in moles relative to ketoximes [III], but in the case of catalytic hydrogenation without isolating acetates [I] as it is, the preferred range of use in moles is 1-1.05 times, thereby inhibiting the by-product amide of the target substance.

The reaction is usually carried out under a solvent. Examples of such solvents include organic carboxylic acids such as formic acid, acetic acid, and propionic acid; hexane, pentane, toluene, methylene chloride, ethylene dichloride, and methyl tert-butyl ether. The amount used is usually 1 to 10 times (by weight) relative to the ketoxime [III]. The reaction temperature is usually from 20°C to the boiling point of the solvent, preferably from 50°C to the boiling point of the solvent.

After the reaction, the acetate [I] can be obtained, for example, by distilling off the solvent, excess acylating agent, and the like. In addition, when organic carboxylic acids are used as the solvent, the catalytic hydrogenation reaction may be carried out as it is.

The present invention is characterized by the catalytic hydrogenation of acetates [I] in an organic carboxylic acid solvent and a platinum catalyst. Although the platinum catalyst is not particularly limited, platinum supported on a carrier such as carbon, silica gel, or alumina is usually used. catalyst.

The amount of the platinum catalyst used is usually 0.05-1% by weight, or 0.1-0.2% by weight in terms of metal, relative to the acetates [I].

Examples of organic carboxyls used as solvents include lower carboxylic acids such as formic acid, acetic acid, propionic acid, and mixtures thereof. Among them, acetic acid is preferably used.

The amount of the organic carboxylic acid is 1-100 times (weight), preferably 5-10 times (weight) relative to the acetate salts [I].

The catalytic hydrogenation reaction is usually carried out at 10-50°C, preferably at 20-40°C. When the temperature exceeds 50°C, the formation of by-products such as dimers and ketone bodies tends to increase, so it is better to carry out at a temperature below 50°C.

The pressure of hydrogen is usually 5 kg/cm ² ·G or more, preferably 5-50 kg/cm ² ·G, but the reaction can sufficiently proceed even at 5-30 kg/cm ² ·G. When it is less than 5 kg/cm ² ·G, the reaction becomes slow and the formation of by-products such as dimers and amides tends to increase, so it is preferable to carry out at 5 kg/cm ² ·G or more.

In this way, amines [II] are produced as the target object, but after the reaction is completed, for example, the catalyst can be separated, and then the organic carboxylic acid can be distilled off, then neutralized with an aqueous alkali solution such as caustic soda, extracted with an organic solvent, and then extracted with an organic solvent. The organic solvent was distilled off, whereby the target product was taken out. Purification can also be carried out by applying purification means such as distillation and recrystallization as necessary.

In addition, the separated and recovered catalyst can also be recycled.

According to the method of the present invention, the target 1-chloro-substituted phenylalkylamines [II] can be efficiently produced in a high yield even under low pressure with almost no by-production of alcohols.

The raw material 1-phenylethylamine of the present invention can be obtained by making N-formyl-1-arylmethylamines [VI]

                                                                                                 

(In the formula, R represents an aryl group which may also have a substituent or an aralkyl group which may also have a substituent, and Ar represents an aryl group which may also have a substituent.)

It is obtained by hydrolysis. It is also known in the past to manufacture N-formyl-1-phenylethylamine and the like by heating a mixture consisting of acetophenone, ammonium formate and formic acid (such as J.AM.Chem.Soc.Vol.58, 1808 (1936)). However, this method cannot meet the yield of the target object.

Accordingly, research was carried out and it was found that N-formyl-1-arylmethylamines [VI] can be produced in high yield by simultaneously injecting formamide and/or ammonium formate Formula [V] (wherein, R and Ar represent the same meaning as above)

RArC=0 [V]

Represented aryl ketones and formic acid.

This process is detailed below.

In the aryl ketones used here, R represents a lower alkyl group, an aryl group that may also have a substituent, or an aralkyl group that may also have a substituent. Examples of the lower alkyl group include methyl, ethyl, and , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, etc.

As the aryl group which may have a substituent, for example, in addition to phenyl and naphthyl, halogen atoms such as fluorine, chlorine, bromine, nitro, the same lower alkyl as above, difluoro Substituted methyl, trifluoromethyl and other lower halogenated groups, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butyl lower alkoxy such as oxy and pentyloxy; phenyl, naphthyl and the like substituted with lower haloalkoxy such as difluoromethoxy and trifluoromethoxy. Examples of aralkyl groups that may have substituents include, for example, benzyl and naphthylmethyl, halogen atoms such as fluorine, chlorine, and bromine, nitro, and lower alkyl groups similar to those described above. , lower halo groups such as difluoromethyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy , tert-butoxy, pentyloxy and other lower alkoxy groups, difluoromethoxy, trifluoromethoxy and other lower haloalkoxy and other substituted benzyl groups, naphthylmethyl groups and the like.

Examples of Ar include an aryl group having a substituent such as a halogen atom, a nitro group, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, etc. as described above.

Representative compounds of aryl ketones [V] include, for example, acetophenone, 2-chloroacetophenone, 3'-chloroacetophenone, 4'-chloroacetophenone, 4'-fluoroacetophenone Ketone, 4'-bromoacetophenone, 2',3'-dichloroacetophenone, 2',4'-dichloroacetophenone, 2',5'-dichloroacetophenone, 2', 6'-dichloroacetophenone, 3',4'-dichloroacetophenone, 3',5'-dichloroacetophenone, 3',4'-dibromoacetophenone, 2'-nitrate Acetophenone, 3'-nitroacetophenone, 4'-nitroacetophenone, 2'-trifluoromethylacetophenone, 3'-trifluoromethylacetophenone, 4'-trifluoromethylacetophenone Methylacetophenone, 2'-methoxyacetophenone, 3'-methoxyacetophenone, 4'-methoxyacetophenone, 2'-trifluoromethoxyacetophenone, 3' -Trifluoromethoxyacetophenone, 4'-trifluoromethoxyacetophenone, 2',4'-dimethoxyacetophenone, propiophenone, 2'-chlorophenylethylketone, 3 '-Chlorophenyl ethyl ketone, 4'-chlorophenyl ethyl ketone, phenyl propyl ketone, 2'-chlorophenyl-isopropanone, 3'-chlorophenyl-isopropanone, 4'-chloro Phenyl-isopropanone, 2'-chlorophenyl-n-acetone, 3'-chlorophenylpentanone, 2'-methylacetophenone, 2'-chloro-4'-trifluoroacetophenone, 2 '-Methoxy-4'-bromoacetophenone, 2'-nitrophenyl-isobutyl ketone, 4'-tolylacetone, benzophenone, 4'-chlorobenzophenone, benzyl Phenyl phenone, 4'-methylbenzyl phenyl ketone, 1-methylnaphthone, 2-methylnaphthone, etc.

In addition, as the raw material formamide and ammonium formate of the present invention, commercially available products may be used, and products obtained by reacting formic acid with ammonia water or ammonia gas may be used. The amount used is usually 1 to 10 times, preferably 2 to 4 times, in terms of nitrogen conversion, relative to the aryl ketones [V].

The amount of formic acid used is usually 0.1-10 times, preferably 0.5-5 times, and more preferably 0.7-4 times the molar amount of the aryl ketones [V]. Formic acid can be used even if it contains water or ammonium formate.

The present invention is characterized by simultaneously injecting aryl ketones [V] and formic acid into formamide and/or ammonium formate, but it is also possible to separately add aryl ketones [V] and formic acid to formamide and/or ammonium formate , it is also possible to mix the two.

The reaction temperature is usually 150-200°C, preferably 155-175°C, depending on the scale of production, etc., but the aryl ketone [V] and formic acid are usually injected simultaneously within 0.5-10 hours. After simultaneous injection, stirring is usually continued for 1-10 hours in order to fully proceed the reaction.

Wherein the ammonia gas generated by the reaction system is captured with formic acid, and recycled to the reaction system as ammonium formate and/or used in the next reaction is preferred. Thereby, the effective utilization of by-product ammonia can be achieved, and the amount of ammonium formate used can also be reduced.

For example, as formic acid injected at the same time, when formic acid containing ammonium formate generated by formic acid absorbing ammonia gas is recycled to the reaction system and used, the amount of aryl ketones [V] injected per unit time is expressed as The amount of formic acid to the ammonia recovery tower is usually 10-100 times by mole, and the amount of formic acid recycled to the recovery liquid reaction system is usually 0.1-10 times by mole, preferably 0.5-5 times , more preferably 0.7-4 times.

In addition, the piping leading to the ammonia gas recovery tower is usually preferably kept at 80-120 °C, so as to prevent ammonium carbonate from adhering to the wall and improve the recovery rate of ammonia gas.

In this way, N-formyl-1-arylmethylamines [IV] as the target product are produced, but after the reaction is completed, the low boiling point components are distilled off from the reaction material to obtain the target product.

Purification can also be carried out by applying purification means such as distillation and recrystallization as necessary. The recovered low boiling point components contain formamide and the like and can be reused.

The obtained N-formyl-1-arylmethylamines [IV] are hydrolyzed with hydrochloric acid, sulfuric acid, etc., whereby 1-arylmethylamines can be easily derived.

According to the method of the present invention, the N-formyl- 1-Arylmethylamines.

Hereinafter, the present invention will be described more specifically based on examples, etc., but the present invention is not limited to these

Example.

Examples 1-9

(Method A)

In a four-necked flask equipped with a ビクリエ type rectification tower, a thermometer and a mechanical stirrer, add a prescribed amount of C ₂ -C ₄ alkyl esters of (RS)-α-cyano-tert-butyl acetic acid and 1-(2 , 4-dichlorophenyl) ethylamine. After raising the temperature to 180°C, the reaction was carried out for 5-10 hours while distilling off the produced alcohol at 180-190°C. After the reaction was completed, it was cooled to room temperature, and the resulting crystals were collected by filtration and washed twice with n-hexane. The desired compound 1 was obtained by drying the obtained crystals under reduced pressure.

(Method B)

Add a specified amount of C ₂ -C ₄ alkyl esters of (RS)-α-cyano-tert-butylacetic acid to a four-necked flask equipped with a rectification column (20cm) filled with spirals, a thermometer and a mechanical stirrer and 1-(2,4-dichlorophenyl)ethylamine, and then add 50ml of the prescribed solvent. The solution was heated and refluxed (about 30 ml) for 8-20 hours while distilling off the generated alcohol together with the solvent. After the reaction was finished, cool to room temperature, add 50ml of n-hexane, filter the resulting crystals, and wash twice with n-hexane. The obtained crystals were dried under reduced pressure to obtain the desired compound 1.

The yield of compound 1 (racemate) is shown in Table 1, and the yield of compound 1a (optical form) is listed in Table 2, respectively.

In addition, as a reference comparative example, in the above method A or method B, the methyl ester of α-cyano-tert-butyl acetic acid is used to replace the C ₂ -C ₄ alkyl ester of α-cyano-tert-butyl acetic acid, here Examples of the occasions are also shown in Table 1.

[Table 1]

Example method R ^*1 CYBR ^* 2(g) DCEA ^*3 (g) Solvent (g) Amount obtained (g) Yield rate (relative to CYBR) Diastereomer ratio X/Y ^*4 1 A Et 20.0 23.6 none 34.6 93.5% 88/22 2 B Et 20.0 27.0 Xylene 35.8 96.7% 67/33 3 A Bu 19.7 20.0 none 28.8 90.8% 63/37 B Et 20.0 27.7 Cumene 34.3 92.7% 52/48 Reference Comparative Example A A Me 20.0 28.2 none 22.6 56.0% 79/21 Reference Comparative Example B B Me 20.0 36.8 Xylene 26.3 65.2% 71/29

*1. Alkyl group of (RS)-α-cyano-tert-butyl acetate (Me.Et.Bu represent methyl, ethyl, n-butyl, respectively).

*2. Alkyl (RS)-α-cyano-tert-acetate.

*3. (RS)-1-(2,4-dichlorophenyl)ethylamine.

*4. The ratio was calculated by the area comparison method analyzed by high-speed liquid chromatography.

[The analytical conditions of high-speed liquid chromatography (HPLC) are as follows:

Device: Hitachi L-6200

Column: SUMIPAX YMC-GEL SIL 120A

(5μm, diameter 4mm x length 25cm)

Mobile phase: n-hexane/ethanol/trifluoroacetic acid=240:10:1

Detection: UV254nm]

[Table 2]

Example method R ^*1 CYBR ^* 2(g) DCEA ^*3 (g) Solvent Yield (g) Yield rate (relative to CBR) Diastereomer ratio X1/Y2 ^*4 5 ^*13 B Et 20.0 27.0 ^*5 Xylene 35.3 95.4% 50/50 ^*8 6 A Et 20.0 23.6 ^*5 none 33.6 90.8% 49/51 ^*9 7 A Bu 19.7 20.2 ^*5 Et 28.6 90.0% 50/50 ^*10 8 A Et 20.0 23.6 ^*6 none 33.8 91.3% 46/46 ^*11 9 A Et 17.0 20.0 ^*7 none 27.2 86.7% 44/44 ^*12

*1. Alkyl group of (RS)-α-cyano-tert-butyl acetate (Et.Bu stands for ethyl group and n-butyl group respectively)

*2. Alkyl (RS)-α-cyano-tert-butyl acetate.

*3. Optically active 1-(2,4-dichlorophenyl)ethylamine enriched in (R)-body

*4. The ratio is calculated by the area comparison method analyzed by high-speed liquid chromatography

[The analytical conditions of high-speed liquid chromatography (HPLC) are as follows:

Device: Hitachi L-6200

Column: SUMIPAX YMC-GEL SIL120A+SUMICHIRAL OA-4700 (5μm, diameter 4mm×length 25cm) (5μm, diameter 4.6mm×length 25cm)

Mobile phase: n-hexane/ethanol/trifluoroacetic acid=240:10:1

Detection: UV254nm

*5. Use (R)-1-(2,4-dichlorophenyl)ethylamine with an optical purity of 99.8%ee or higher

*6. Use (R)-1-(2,4-dichlorophenyl)ethylamine with an optical purity of 84%ee

*7. Use (R)-1-(2,4-dichlorophenyl)ethylamine with an optical purity of 76%ee or higher

*8.X2/Y1＝＜0.1/＜0.1

*9.X2/Y1＝＜0.1/＜0.1

*10.X2/Y1＝＜0.1/＜0.1

*11.X2/Y1=4/4

*12.X2/Y1=6/6

*13. the physical property value of the compound of the present invention obtained by embodiment 5 is as follows:

mp.160-161°C, [α]D ²⁰ =+18.0° (C=1.01, CH ₂ Cl ₂ )

Example 10

17.95 g (0.105 mol) of (RS)-α-cyano-tert-butyl ethyl acetate was charged into a four-necked flask equipped with a Vikryu rectification column, a thermometer, and a mechanical stirrer, and the temperature was raised to 190°C. 20.0 g (0.105 mol) of (R)-1-(2,4-dichlorophenyl)ethylamine (optical purity: 92.4% ee) was added dropwise thereto at the same temperature over 2 hours. Further, the reaction was carried out for 17 hours while distilling off the produced alcohol at the same temperature. After the reaction was completed, the reaction substance was cooled to 140-150° C., and 91.9 g of monochlorobenzene was added thereto. The solution was then cooled to 80-90°C and kept at the same temperature. On the other hand, 215 g of water, 1.14 g of 35% aqueous hydrochloric acid solution and 0.03 g of seed crystals were charged into another four-necked flask equipped with a thermometer, a coil condenser for condensing the distillate, and a mechanical stirrer, and the temperature was raised to After 97-100°C, the above-mentioned monochlorobenzene solution was added dropwise thereto at the same temperature over a period of 2 hours and 15 minutes (kept at 80°C). Water and monochlorobenzene were azeotroped, and the crystals of Compound 1a were precipitated almost at the same time as monochlorobenzene was distilled off to obtain an aqueous slurry of Compound 1a. After cooling this aqueous slurry to 25 degreeC over 2 hours, it stirred at the same temperature for 30 minutes. The crystals were collected by filtration and washed once with 100ml of water. The obtained crystals were dried under reduced pressure to obtain 30.0 g of compound 1a. (Yield 91, 2%, ratio of optical isomers X1:X2:Y1:Y2=47.2:1.9:1.8:49.1)

Test example 1

Each optical isomer (X1 body, X2 body, Y1 body and Y2 body) of racemic compound 1 is separated and purified by high-speed liquid chromatography by the following method, and its activity of preventing and controlling plant diseases (fusarium wilt) The survey results are summarized in Table 3.

(1) HPLC separation conditions are as follows:

Device: Hitachi L-6200

Column: SUMIPAX YMC-GEL SIL 120A+SUMICHIRAL OA-4700 (5μm, diameter 4mm×length 25cm) (5μm, diameter 4.6mm×length 25cm)

Mobile layer: n-hexane/ethanol/trifluoroacetic acid=240:10:1

Detection: UV254nm]

Dissolve X1, X2, Y1, Y2 in sequence. In addition, the absolute structure of each is determined by analyzing the X-ray structure of the X1 body and the Y body (Y1+Y2)

(2) Test example

Sandy loam soil was put into a plastic box, Oryza genus (Kinki No. 33) was sown, and cultivated in a greenhouse for 20 days. Then prepare the test agent of wettable powder (50 parts of compound, 3 parts of calcium lignosulfonate, 2 parts of sodium lauryl sulfate and 45 parts of synthetic hydrous silicon oxide are well pulverized and mixed to obtain), the test agent Dilute it with water to a prescribed concentration, and spread it on the stems and leaves so as to fully adhere to the leaves of the Oryza plant. After spreading, the plants are air-dried, sprayed with a spore suspension of Magnaporthe grisea, and inoculated. After inoculation, it was left to stand for 4 days under dark and humid conditions at 28°C, and then its control efficacy was investigated.

The evaluation method of the control effect is: observe the disease state of the tested plants with naked eyes during the investigation, that is, the degree of flora and disease spots on leaves, stems, etc., and divide them into 6 grades: It is determined as "5", the degree of recognition of 10% is determined as "4", the degree of recognition of 30% is designated as "3", the degree of recognition of 50% is designated as "2", and the degree of recognition of 70% is designated as "2". "1", below which no difference from the onset state in the case of no test compound could be discerned was defined as "0", represented by 5, 4, 3, 2, 1, 0, respectively.

[table 3]

Concentration (ppm) Control Efficacy X1(R,R) ^* X2(S,S) ^* Y1(R,S) ^* Y2(S,R) ^* X1+Y2(1:1) Racemate (1:1:1:1) Furacet (commercially available drug) 100 4 0 0 5 5 5 5 50 4 0 0 5 5 4 4 25 4 0 0 5 4 4 4 12.5 3 0 0 4 4 4 4 6.3 3 0 0 4 4 4 1 3.1 2 0 0 4 4 3 0 1.6 2 0 0 4 3 3 0 0.8 1 0 0 3 3 2 0 0.4 0 0 0 3 2 1 0 0.2 0 0 0 1 0 0 0

*The absolute structure of each asymmetric carbon is shown in the order of (acid side, amine side).

The manufacture of embodiment 11α-cyano-tert-butyl ethyl acetate

Prepare a methylmagnesium chloride solution from 119 g of methyl chloride, 49.6 g of magnesium, and 509 g of THF, add 6.0 g of copper (I) iodide to the solution at 35 to 40°C, and then drop it there for about 1 hour at the same temperature Add 240 g of ethyl 2-cyano-3-methyl-2-butenoate dissolved in 480 g of toluene to form a solution. After the dropwise addition was completed, the reaction was carried out at the same temperature for regeneration for 1 hour. The reaction mixture was cooled to 20-30°C, and then poured into 1742g of 20% ammonium chloride water at 10-20°C. After standing at room temperature and separating the layers, the aqueous layer was extracted twice with 480 ml of ethyl acetate, and the organic layers were combined and washed twice with 480 g of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was distilled as it was (boiling point of the main fraction: 80-86° C./12-15 mmHg) to obtain the desired product. The recovered amount of ethyl α-cyano-tert-butyl acetate after distillation was 249 g, and the yield was 94%.

In the above-mentioned production examples, the reaction was carried out in the same manner except for changing the type or amount of the catalyst, and the results are summarized in Table 4. In addition, the yield in the table shows the ratio with respect to the alkyl ester of 2-cyano-3-methyl-2-butenoic acid.

[Table 4]

Example Reaction solvent THF: toluene Catalyst (parts by weight) ^*2 Raw material alkyl ^*3 Response time (hr) Yield ^*4 (%) 11 1:1 ^*1 Gui(0.025) Ethyl 1 94 12 1:1 ^*1 CuCl(0.025) Ethyl 1 91 13 1:1 ^*1 CuCl(0.013) Ethyl 1 91 14 1:1 ^*1 CuCl(0.006) Ethyl 1 91 15 1:1 ^*1 CuCl(0.002) Ethyl 1 89 16 1:1 ^*1 CuCl(0.001) Ethyl 1 89 Reference Comparative Example 1 1:1 ^*1 none Ethyl 1 60 Reference Comparative Example 2 THF only none Methyl 2.5 35

*1. Weight ratio

*2. Catalyst amount (parts by weight) relative to 1 part by weight of lower alkyl ester of raw material 2-cyano-3-methyl-2-butenoic acid.

*3. The alkyl group of the lower alkyl ester of raw material 2-cyano-3-methyl-2-butenoic acid.

*4. Yield after distillation.

Production examples of raw materials are shown below. In addition, the reaction rate is a value calculated|required by the following formula.

Reaction rate=100-the area ratio (%) of the alkyl ester of residual cyanoacetic acid

Analysis conditions of gas chromatography (GC): Shimazawa GC-7A,

Column: 10% DEXSIL 300GC Diameter 3mm x Length 1m UNIPORTHP100～200 mesh

Column temperature: from 70° to 150°C at 5°C/min

Production of Example 17 2-cyano-3-methyl-2-butenoic acid ethyl ester

50.0 g of ethyl cyanoacetate, 51.34 g of acetone, 1.99 g of acetic acid, 0.24 g of p-aminophenol and 41 ml of n-hexane were charged, and heated under reflux for 9 hours while azeotropically removing water generated during the reaction. When analyzed by gas chromatography, the reaction rate of ethyl cyanoacetate was 99%. After the reaction, the reaction solution was concentrated under reduced pressure to remove hexane, acetic acid and unreacted acetone, and then the residue was distilled under a reduced pressure of 20mmHg using a 30cm rectification column filled with spirals, and 110-113 ℃ fraction. The recovered amount of ethyl 2-cyano-3-methyl-2-butenoate after distillation was 63.6 g, and the yield was 94%.

In the above-mentioned production examples, except for replacing the type of reaction solvent, the type of catalyst, the type of the alkyl group of the alkyl cyanoacetate, or the reaction time, the reaction was carried out in the same manner, and the results are summarized in Table 5. In addition, the yield in the table shows the ratio with respect to the alkyl ester of cyanoacetic acid.

[table 5]

Example Reaction solvent Hexane: Toluene catalyst R ^*1 Response time (hr) Response rate (%) Yield ^*2 (%) 17 Hexane only A ^*4 Et 9 99 94 18 Hexane only A ^*4 Bu 9 99 93 19 Hexane only B ^*5 Et 12 96 87 20 Hexane only Et 9 99 95 twenty one Hexane only D ^*7 Et 10 99 95 twenty two 2:1 Et 10 99 92 Reference Comparative Example Toluene only A ^*4 Et 30 80 63

*1. The alkyl group of the lower alkyl ester of raw material cyanoacetic acid. (Et, Me, and Bu represent ethyl, methyl, and n-butyl respectively.)

*2. Yield after distillation

*3. Weight ratio

*4.A: p-aminophenol and acetic acid

*5.B: p-toluidine and acetic acid

*6.C: p-aminophenol and benzoic acid

*7.D: p-aminophenol and propionic acid

Examples of optical resolution of 1-(2,4-dichlorophenyl)ethylamine are described below. In addition, the following % all represent weight%.

In addition, the optical purity (ee: enautomericexcess) of 1-(2,4-dichlorophenyl)ethylamine was determined by high-speed liquid chromatography (HPLC) under the following conditions using an optically active column.

HPLC conditions: Column: SUMICHIRAL OA-4100

(diameter 6μm x length 25cm)

Developing solvent: hexane: ethanol: trifluoroacetic acid = 240: 10: 1

Detection: UV254nm

In addition, the absolute configuration (R or S) of optically active 1-(2,4-dichlorophenyl)ethylamine is determined by the method described in JP-A-2-76846, making R obtained by the method of the present invention -(+)-1-(2,4-dichlorophenyl)ethylamine (99.9%ee) reacted with (RS)-α-cyano-tert-butylacetic acid, and the obtained diastereomer mixture Separation, and then a stereoisomer obtained ((R)-N-[1-(2,4-dichlorophenyl) ethyl]-(R)-2-cyano-3,3-butane Amide]) for X-ray structure analysis.

Example 23

53.24 g of L-aspartic acid (a special grade reagent product of Wako Pure Chemical Industries, Ltd.: chemical purity > 99.0%, [α] D=+24.9～+25.8°) and (RS)-1-(2, Add 76.5 g of 4-dichlorophenyl)ethylamine into a mixture of 1.2 liters of water and 2.8 liters of 95% ethanol, and heat to reflux for 1 hour while stirring. While stirring the solution, it was air-cooled to 40°C, and then water-cooled to 20°C. Stir at 20°C for 30 minutes, take out the resulting crystals, and wash with 100 ml of cold ethanol. The resulting crystals were dried to obtain 27.8 g of white (+)-1-(2,4-dichlorophenyl)ethylamine·L-aspartic acid salt. This crystal was dissolved in 100ml 20% NaOH aqueous solution, and the free amine was extracted with 100ml toluene. The obtained toluene layer was dried over anhydrous magnesium sulfate, and concentrated by an evaporator to obtain 19.2 g of the desired (R)-(+)-1-(2,4-dichlorophenyl)ethanamine. The optical purity was 87% ee.

Example 24

13.31 g of L-aspartic acid (special grade reagent product manufactured by Wako Pure Chemical Industries, Ltd.: chemical purity>99.0%, [α] _n =+24.9～+25.8°) and (RS)-1-(2 , 38.14 g of 4-dichlorophenyl) ethylamine was added to a mixture of 150 ml of water and 200 ml of 95% ethanol, and heated to reflux for 1 hour while stirring. The solution was air-cooled to 40°C while stirring, and then water-cooled to 20°C. Keep at 20°C for 30 minutes, take out the generated crystals, and wash with 50 ml of cold ethanol. After drying the obtained crystals, 14.2 g of white (+)-1-(2,4-dichlorophenyl)ethylamine·L-aspartic acid salt were obtained. This crystal was dissolved in 50 ml of 20% NaOH aqueous solution, and the free amine was extracted with 100 ml of toluene. The obtained toluene layer was dried over anhydrous magnesium sulfate, and then concentrated by an evaporator to obtain 8.3 g of the desired (R)-(+)-1-(2,4-dichlorophenyl)ethanamine. The optical purity is 91% ee.

Example 25

66.6 g of L-aspartic acid (special grade reagent produced by Wako Pure Chemical Industries, Ltd.: chemical purity>99.0%, [α] _D =+24.9～+25.8°) and (RS)-1-(2, Add 190.07 g of 4-dichlorophenyl)ethylamine into a mixture of 1 liter of water and 1 liter of methanol, and heat to reflux for 1 hour while stirring. The solution was air-cooled to 40°C while stirring, and then water-cooled to 20°C. Stir at 20°C for 30 minutes, remove the resulting crystals, and wash with 100 ml of cold methanol. The resulting crystals were dried to obtain 67.35 g of white (+)-1-(2,4-dichlorophenyl)ethylamine·L-aspartic acid salt. The crystals were dissolved in 200 ml of 20% NaOH aqueous solution, and the free amine was extracted with 200 ml of toluene. The obtained toluene layer was fresh-dried with anhydrous sulfuric acid, and then concentrated with an evaporator to obtain 39.6 g of the desired (R)-(+)-1-(2,4-dichlorophenyl)ethylamine. The optical purity is 92% ee.

Example 26

10.7 g of L-aspartic acid (special grade reagent produced by Wako Pure Chemical Industries, Ltd.: chemical purity > 99.0%, [α] _D = +24.9 to 25.8°) and (RS)-1-(2,4 - 15.0 g of dichlorophenyl) ethylamine was added into 200 ml of water, and stirred and heated to reflux for 1 hour. While stirring this solution, it was air-cooled to 45°C, and then cooled approximately uniformly to 5°C over 3 hours. The obtained crystals were taken out and washed twice with 30 ml of cold water. The obtained crystals were dried to obtain 3.7 g of white (+)-1-(2,4-dichlorophenyl)ethylamine·L-aspartic acid salt. The crystals were dissolved in 10 ml of 20% NaOH aqueous solution, and the free amine was extracted with 50 ml of toluene. The obtained toluene layer was dried over anhydrous magnesium sulfate, and then concentrated by an evaporator to obtain 2.15 g of the desired (R)-(+)-1-(2,4-dichlorophenyl)ethylamine. The optical purity was 87% ee.

Example 27

53.24 g of L-aspartic acid (special grade reagent product manufactured by Wako Pure Chemical Industries, Ltd.: chemical purity > 99.0%, [α] _D = +24.9～+25.8°) and (RS)-1-(2 , 76.5 g of 4-dichlorophenyl) ethylamine was added to a mixture of 1.2 liters of water and 2.8 liters of 95% ethanol, and heated to reflux for 1 hour while stirring. The solution was air-cooled to 40°C while stirring, and then water-cooled to 20°C. Stir at 23°C for 30 minutes, take out the resulting crystals, and wash with 100 ml of cold ethanol. The obtained crystals were dried to obtain 25.6 g of white (+)-1-(2,4-dichlorophenyl)ethylamine·L-aspartic acid salt. The crystals were recrystallized with 200 ml of a 50% ethanol aqueous solution to obtain 20.4 g of (+)-1-(2,4-dichlorophenyl)ethylamine·L-aspartate. Then the crystals were dissolved in 100 ml of 20% NaOH aqueous solution, and the free amine was extracted with 100 ml of toluene. The obtained toluene layer was dried over anhydrous magnesium sulfate, and then concentrated by an evaporator to obtain 11.9 g of the desired (R)-(+)-1-(2,4-dichlorophenyl)ethanamine. The optical purity is 99.9% ee. The specific rotation is [α] _D ²⁵ =+44.86° (C=1.114).

Example 28

53.24 g of D-aspartic acid (special grade reagent product manufactured by Wako Pure Chemical Industries, Ltd.: chemical purity>99.0%, [α] _D =-24.0～-26.0°) and (RS)-1-(2 , 76.5 g of 4-dichlorophenyl) ethylamine was added to a mixture of 1.2 liters of water and 2.8 liters of 95% ethanol, and heated to reflux for 1 hour while stirring. The solution was air-cooled to 40°C while stirring, and then water-cooled to 20°C. After stirring at 20°C for 80 minutes, the resulting crystals were taken out and washed with 100 ml of cold ethanol. The obtained crystals were dried to obtain 27.1 g of white (-)-1-(2,4-dichlorophenyl)ethylamine·D-ascosine salt. The crystals were recrystallized from 200 ml of 50% ethanol aqueous solution to obtain 22.1 g of (-)-1-(2,4-dichlorophenyl)ethylamine·D-aspartic acid salt. The crystals were then dissolved in 100 ml of 20% NaOH aqueous solution, and the free amine was extracted with 100 ml of toluene. The obtained toluene layer was dried over anhydrous magnesium sulfate and then concentrated by an evaporator to obtain 11.9 g of the desired (S)-(-)-1-(2,4-dichlorophenyl)ethanamine. The optical purity is 99.6% ee. Specific rotation [α] _D ²⁴ = -43.87° (C = 1.082).

Example 29

Stir and heat a solution consisting of (RS)-1-(2,4-dichlorophenyl)ethylamine 2g and ethanol 12ml to 70°C, and add 1.6g of D-mandelic acid and 12ml of ethanol to it in 1 minute The formed solution was then stirred and naturally cooled to 25° C., and then stirred at the same temperature for 12 hours. The precipitated crystals were filtered off and dried to obtain 1.4 g of diastereoisomeric salts. 1 g of 20% aqueous sodium hydroxide solution was added to the crystals, followed by extraction twice with 2 ml of toluene, the resulting toluene layer was dried over magnesium sulfate, and the solvent was distilled off to obtain (S)-1-(2,3-dichlorophenyl ) ethylamine 0.77g.

Its optical purity was analyzed by high-speed liquid chromatography using an optical column, and the result was 91% ee.

Example 30

(1) Heat a solution composed of (RS)-1-(2,4-dichlorophenyl)ethylamine 16g and ethanol 10ml to 70°C, stir, and add L-mandelic acid to it for about 30 minutes. 12.8 g and 40 ml of ethanol, then heated up to 75° C. and stirred at the same temperature for 30 minutes. Then, it was cooled to 20° C. over 5 hours, and the precipitated crystals were filtered off and dried to obtain 13.2 g of diastereoisomeric salts. 10 g of a 20% aqueous sodium hydroxide solution was added to the crystals, followed by extraction twice with 20 ml of toluene, and the resulting organic layer was dried over magnesium sulfate and the solvent was distilled off to obtain (R)-1-(2,4-dichlorobenzene base) ethylamine 7.3g. Its optical purity is 82% ee.

(2) 15.6 g of a residue were obtained by distilling off low-boiling point components from the mother liquor after diastereoisomer filtration. Add 13 g of 20% aqueous sodium hydroxide solution thereto, then extract twice with 30 ml of toluene, dry the resulting toluene layer with magnesium sulfate and distill off the solvent to obtain (S)-1-(2,4-dichlorophenyl) ethyl Amine 12.7g. Its optical purity is 70% ee.

(3) After mixing the residual water layer extracted with toluene in (1) and (2), add 36% hydrochloric acid to adjust its pH value to 0.7. Subsequently, extraction was performed three times with 50 ml of ethyl acetate, and the solvent was distilled off after drying over magnesium sulfate to obtain 12.3 g of L-mandelic acid.

Example 31

Stir and heat a solution consisting of (RS)-1-(2,4-dichlorophenyl)ethylamine 16g and ethyl acetate 17ml to 70°C, and add 6.4g of L-mandelic acid dropwise therein for about 30 minutes and ethyl acetate 80ml, then warmed up to 75°C and continued stirring at the same temperature for 30 minutes. After cooling to 20° C. over 5 hours, the precipitated crystals were filtered off and dried to obtain 12.9 g of diastereoisomeric salts. After treating a part of it as in Example 29, the optical purity was determined to be 81.2% ee.

Example 32

A mixture consisting of 19 g of (RS)-1-(2,4-dichlorophenyl)ethylamine, 120 ml of 95% ethanol, and 15.2 g of L-mandelic acid was heated to reflux, and allowed to cool overnight. The precipitated crystals were filtered off and dried to obtain 10.8 g of diastereomer salts. After treating a part of it as in Example 29, the measured optical purity was 64% ee.

Example 33

(1) Heat a solution consisting of 90 g of (RS)-1-(2,4-dichlorophenyl)ethylamine and 167 g of methyl tert-butyl ether to 45°C, stir, and then add A solution consisting of 32 g of L-mandelic acid and 197 g of methyl tert-butyl ether was stirred at the same temperature for 30 minutes. Then, it was cooled to 20° C. for 6 hours, and the precipitated crystals were filtered off, washed twice with 42 g of methyl tert-butyl ether, and dried to obtain 84 g of diastereoisomeric salts. 185 g of a 5% aqueous sodium hydroxide solution was added to the crystals, followed by extraction twice with 42 g of methyl tert-butyl ether, and the resulting organic layer was dried over magnesium sulfate and the solvent was distilled off to obtain (R)-1-(2,4 -Dichlorophenyl)ethylamine 39.9 g. Its optical purity is 95.2% ee.

(2) The filtrate after filtering off the diastereomer salt was combined with the washing liquid, and 18 g of a 5% sodium hydroxide aqueous solution was added thereto for washing. Low-boiling components in the organic layer were distilled off to obtain 50.1 g of (S)-1-(2,4-dichlorophenyl)ethylamine. Its optical purity is 77.6%ee.

(3) In (1) and (2), the salt was decomposed using 5% aqueous sodium hydroxide solution, and the remaining aqueous layer after separation of the organic layer was mixed, and then 36% hydrochloric acid was added to adjust the pH to 1.4. Subsequently, extraction was performed three times with 150 g of methyl tert-butyl ether, dried over magnesium sulfate, and the solvent was distilled off to obtain 31.7 g of L-mandelic acid.

Comparative example 1

In Example 32, 15 g of L-tartaric acid was used instead of L-mandelic acid, but when 120 ml of 95% ethanol was used, 1080 ml of 9% ethanol was added because there were many remaining crystals of L-tartaric acid. Except this, it was carried out as in Example 32, whereby 10.8 g of diastereoisomeric salts were obtained.

After treating a portion of it as in Example 29, the optical purity was determined to be 36% ee.

Comparative example 2

In Example 32, 13.4 g of malic acid was used instead of L-mandelic acid, but when 120 ml of 95% ethanol was used, 360 ml of 95% ethanol was added because the result of L-malic acid remained. In addition, according to the example of Example 32, 14.5 g of diastereoisomeric salts were obtained thereby.

After treating a part of it as in Example 29, its optical purity was determined to be 0.8% ee.

Comparative example 3

In Example 29, except that 120 ml of water was used instead of ethanol, the implementation was carried out as in Example 29. As a result, a water layer and an oil layer were separated, and no crystals were precipitated.

Example 34

(1) A solution consisting of 3.95 g of D-dibenzoyl tartaric acid and 60 ml of 95% ethanol was warmed up to 60° C., and 2 g of (RS)-1-(2,4-dichlorophenyl) ethylamine and 95 % ethanol 20ml solution, and stirred at the same temperature for 5 minutes. Then, it was stirred and cooled naturally to 25° C., and then stirred and left at the same temperature for 12 hours.

The precipitated crystals were filtered off, and the obtained crude diastereomeric salt was recrystallized from 500 ml of 95% ethanol, followed by drying to obtain 1.6 g of diastereomeric salt. 1.2 g of 20% aqueous sodium hydroxide solution was added to the crystals, and then extracted three times with chloroform, and the obtained chloroform layer was dried over magnesium sulfate, and the solvent was distilled off to obtain (S)-1-(2, 0.66 g of 4-dichlorophenyl)ethylamine.

Its optical purity was analyzed by high-speed liquid chromatography using an optical active column, and the result was 92% ee.

(2) Distill off the low boiling point components from the mother liquor of the crude diastereomer salts by filtration, add 2.4g 20% sodium hydroxide aqueous solution to the resulting residue, and extract 3 times with 7.5ml chloroform , and the obtained chloroform layer was dried with magnesium sulfate, and the solvent was distilled off to obtain 1.15 g of (R)-1-(2,4-dichlorophenyl)ethylamine.

Its optical purity was 79% ee as analyzed by high-speed liquid chromatography using an optically active column.

Example 35

(1) Heat a solution consisting of 4 g of (RS)-1-(2,4-dichlorophenyl)ethylamine and 10 ml of 95% ethanol to 70° C., stir, and add D-2 A solution consisting of 7.88 g of benzoyl tartaric acid and 25 ml of 95% ethanol was then heated to 80° C. and stirred at the same temperature for 30 minutes. It was then cooled to 20° C. over 5 hours, and stirring was continued at the same temperature for 30 minutes. The precipitated crystals were filtered off, recrystallized from 500 ml of 95% ethanol, and dried to obtain 3.2 g of diastereoisomeric salts. After adding 5 g of 20% sodium hydroxide aqueous solution to this crystal, it was extracted twice with 20 ml of toluene, and the obtained organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain (S)-(2,4-dichlorophenyl)ethane Amine 1.32g. Its optical purity is 91% ee.

(2) Distill off low-boiling components from the mother liquor after filtering out the crude diastereomers, add 7 g of 20% aqueous sodium hydroxide solution to 6.58 g of the resulting residue, then extract with 20 ml of toluene, and use magnesium sulfate The toluene layer was dried, and the solvent was distilled off to obtain 2.3 g of (R)-1-(2,4-dichlorophenyl)ethylamine. Its optical purity is 91% ee.

(3) Mix the remaining aqueous layers after extracting toluene in (2), and then adjust the pH value to 0.7 with 36% hydrochloric acid. Next, 7 g of common salt was added thereto, and the salt was precipitated at 40 to 60° C., then extracted five times with 80 ml of ethyl acetate, and the solvent was distilled off to obtain 6.82 g of D-dibenzoyl tartaric acid.

Example 36

(1) Prepare (S)-1-(2,4-dichlorophenyl)ethylamine (optical isomer ratio S body/R body=80.3/19.7) 62g and 2,4-dichloroacetophenone 62g 0.28 g of zinc chloride was added to a mixture composed of 130 g of toluene, and then refluxed for 20 hours while removing generated water to the outside of the system.

Next, this was washed with 10 g of a 5% aqueous sodium hydroxide solution at 25° C., and after liquid separation, the obtained toluene layer was azeotropically dehydrated for 4 hours to remove water.

Get its part, use gas chromatography to analyze, calculate N-(alpha-methyl-2,4-dichlorobenzylidene)-alpha-(2,4-dichlorophenyl)ethylamine content is 116g, unreacted The content of 1-(2,4-dichlorophenyl)ethylamine was 1 g, and the content of 2,4-dichloroacetophenone was 0.5 g.

(2) Next, at 30°C, a solution consisting of 1.2 g of potassium tert-butoxide and 10.1 g of dimethyl sulfoxide was added to the above-mentioned toluene solution after water removal, and after stirring at the same temperature for 10 hours, a 10% Wash once with 233 g of saline and twice with saturated saline.

(3) 285 g of 5% hydrochloric acid was added to the obtained toluene solution, stirred at 60° C. for 1 hour, and then allowed to stand at the same temperature for 3 minutes for liquid separation to obtain an aqueous layer and a toluene layer.

194 g of toluene was added to the water layer, and extraction was performed at 60°C. The toluene layer thus obtained and the toluene layer obtained above were combined, and the solvent was distilled off to obtain 60.7 g of 2,4-dichloroacetophenone.

72 g of 27% aqueous sodium hydroxide solution was added to the aqueous layer extracted with toluene, followed by extraction with 580 g of toluene, and toluene was removed by distillation to obtain 61.7 g of 1-(2,4-dichlorophenyl)ethylamine.

A part of the latter was collected and analyzed by high-speed liquid chromatography using an optical column, and the optical isomer ratio of S-form/R-form=52.3/47.7.

Example 37

In Example 36, except that (R)-1-(2,4-dichlorophenyl)ethylamine (optical isomer ratio S body/R body=1/99) was used instead of (S)-1-( Except for 2,4-dichlorophenyl)ethanamine, the procedure was carried out according to Example 36 to obtain 59.7 g of 2,4-dichloroacetophenone and 61 g of 1-(2,4-dichlorophenyl)ethanamine. The latter optical isomer ratio S body/R body=45.1/54.9.

Example 38

By implementing the reaction according to Example 36-(1), N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine containing optical activity was obtained of toluene solution.

Next, toluene and unreacted raw materials were distilled off to obtain 111 g of white crystals of optically active N-(α-methyl-2,4-dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine . E/Z＝8/92, melting point＝77～85℃

H-NMR: 1.32(2d, 3H), 1.51(d, 3H), 2.23(s, 3H), 2.29(2s, 3H), 4.56(m, 1H), 6.6-7.8(m, 6H)

Example 39

In Example 36-(2), it was carried out according to Example 36-(2) except that a solution composed of 111 g of crystals obtained in Example 38 and 130 g of dried toluene was used as the toluene solution. Next, after concentrating the obtained toluene solution under reduced pressure, the low boiling point components were distilled off at 100°C and 20 mmHg for 5 hours to obtain racemic N-(α-methyl-2,4- 110 g of dichlorobenzylidene)-α-(2,4-dichlorophenyl)ethylamine. E/z = 8/92.

Example 40

In Example 36-(3), except that the solution composed of 110 g of the oil obtained in Example 39 and 130 g of toluene was used as the toluene solution, the implementation was carried out according to Example 36-(3), to obtain 2,4-di 56.9 g of chloroacetophenone and 57.8 g of 1-(2,4-dichlorophenyl)ethylamine.

The optical isomer ratio of the latter was S body/R body=51.9/48.1.

Example 41

In Example 36, except that 0.45 g of titanium tetraisopropoxide was used instead of zinc chloride, the implementation was carried out as in Example 36 to obtain 59.2 g of 2,4-dichloroacetophenone and 1-(2,4-bis Chlorophenyl) ethylamine 60.8g. The latter optical isomer ratio S body/R body=53.3/46.7.

Example 42

In Example 36, except that 0.62 g of p-toluenesulfonic acid was used instead of zinc chloride, and xylene was used instead of toluene, all were implemented according to Example 36 to obtain 59.1 g of 2,4-dichloroacetophenone and 1-(2 , 4-dichlorophenyl) ethylamine 60.1g. The optical isomer ratio of the latter is S body/R body=53/47.

Comparative example 4

In Example 36, except that 20 g of tert-butanol was used instead of dimethyl sulfoxide, the implementation was carried out according to Example 36, thereby obtaining 60.3 g of 2,4-dichloroacetophenone and 1-(2,4-dichloroacetophenone Chlorophenyl) ethylamine 61.5g. The optical isomer ratio of the latter is S body/R body=80.3/19.7.

Comparative Example 5

1.8 g of potassium tert-butoxide was added to a mixture consisting of 6 g of (S)-1-(2,4-dichlorophenyl)ethylamine and 9 g of dimethyl sulfoxide as used in Example 36 at 80°C, Stirring was continued for 10 hours at the same temperature. After cooling to room temperature, a part thereof was collected, and the ratio of optical isomers was analyzed by high-speed liquid chromatography using an optical column. Its optical isomer ratio S body/R body=80.3/19.7.

Example 43

(1) Manufacture of Chlorine-Substituted Phenyl Ketoximes

Add 122 g of hydroxylamine hydrochloride and 400 g of water to a mixture of 300 g of 2′,4′-dichloroacetophenone and 1,200 g of methanol. After the temperature is raised to 60° C., at the same temperature, 27% aqueous sodium hydroxide solution is added to adjust the pH. Stirring was continued for 3 hours while the value became 4-5. Next, 27% sodium hydroxide aqueous solution was added to make the pH 8, and a total of 1200 g of water and methanol were distilled off under reduced pressure. 1200 g of water was added to the residue, cooled to 25° C., and the precipitated crystals were filtered and washed with 1200 g of water. Drying was performed to obtain 322 g of white crystals of 2',4'-dichloroacetophenoxime (99% yield).

The purity is 99.5%.

(2) Manufacture of chlorinated phenylalkyl ketoxime acetates

36.4 g of acetic anhydride was added to a mixture of 70 g of 2',4'-dichloroacetophenoxime and 70 g of n-heptane, followed by stirring at 70°C for 2 hours. A small amount of the reaction substance was sampled and analyzed by gas chromatography, and it was found that the raw material had disappeared.

The reaction mass was cooled to 25°C, and the precipitated crystals were filtered to obtain 60.2 g of white needle crystals of 2',4'-dichloroacetophenoxime acetate. The filtrate with a purity of 100% was concentrated under reduced pressure, and the obtained residue (crystal) was washed with 10 g of ice-cold n-heptane to obtain 22.5 g of white needle crystals with a purity of 99%.

Example 44

2',4'-dichloroacetoxime acetate (purity 100%) 2g, acetic acid 20g, 5% platinum-carbon (50% water-containing product) obtained in Example 43-(2) were charged into 100ml In the autoclave, after replacing with nitrogen, the temperature was raised to 30°C, and the pressure was increased to 20 kg/cm ² ·G with hydrogen. At the same temperature, the reaction was carried out for 5 hours while supplying hydrogen to maintain the pressure at 20 kg/cm ² ·G.

After the reaction, the catalyst was filtered, the acetic acid in the filtrate was distilled off under reduced pressure, 5 g of toluene was added to the residue, and after washing with 18 g of 5% aqueous sodium hydroxide solution, the solvent of the organic layer was distilled off to obtain 1.54 g of an oily substance. It was analyzed by gas chromatography.

1-(2′,4′-dichlorophenyl)ethylamine is 94.5%, N-1-(2′,4′-dichlorophenyl)ethyl-α-(2′,4′-dichloro Phenyl)ethylamine was 0.97%, N-acetyl-α-(2',4'-dichlorophenyl)acetamide was 0.56%, and 2',4'-dichloroacetophenone was 1%. Dechlorinated compounds and carbonyl-reduced alcohols were below the detection range.

Example 45

In Example 44, except that 2', 4'-dichloroacetylbenzoxime acetate was replaced with 2 g of 4'-chloroacetylbenzoxime acetate, it was implemented according to Example 44, thereby obtaining 1.47 g of Oil.

1-(4'-chlorophenyl)ethylamine 98.8%, N-acetyl-α-(4'-chlorophenyl)acetamide 0.91%, dechlorinated compounds and carbonyl-reduced alcohols were not detected out.

Example 46

In Example 44, except that 2 g of 3', 4'-dichloroacetoxime acetate was used instead of 2', 4'-dichloroacetoxime acetate, it was implemented as in Example 44, whereby 1.53 g of an oil were obtained.

1-(3′,4′-dichlorophenyl)ethylamine is 89.8%, 1-(4′-chlorophenyl)ethylamine is 1.4%, N-1-(3′,4′-dichlorobenzene Base) ethyl-α-(3′,4′-dichlorophenyl)ethylamine is 2.9%, N-acetyl-α-(2′,4′-dichlorophenyl)acetamide is 1.9%, Carbonyl-reduced alcohols were not detected.

Example 47

In Example 44, except that 2', 4'-dichloroacetoxime acetate was replaced with 2 g of 3', 5'-dichloroacetoxime acetate, it was implemented as in Example 44, so that 1.54 g of an oil were obtained.

1-(3′,5′-dichlorophenyl)ethylamine is 88.7%, 1-(3′-chlorophenyl)ethylamine is 2%, N-1-(3′,5′-dichlorophenyl Base) ethyl-α-(3′,5′-dichlorophenyl)ethylamine is 2.9%, N-acetyl-α-(3′,5′-dichlorophenyl)acetamide is 2.9%, Carbonyl-reduced alcohols were not detected.

Example 48

36.4 g of acetic anhydride was added to a mixture of 70 g of 2',4'-dichloroacetophenoxime and 210 g of acetic acid, followed by stirring at 100°C for 2 hours. A small amount of reaction material was taken as a sample and analyzed by gas chromatography, and it was found that the raw material disappeared. Put all the above-mentioned reaction substances, 210g of acetic acid, and 3.9g of 5% platinum-carbon (50% water-containing product) into a 1000ml autoclave, replace with nitrogen, heat up to 30°C, and pressurize to 20kg/cm ² ·G with hydrogen . The reaction was carried out for 10 hours at the same temperature while supplying hydrogen to maintain the pressure at 20 kg/cm ² ·G.

After the reaction, the catalyst was filtered, the acetic acid in the filtrate was distilled off under reduced pressure, 100 g of toluene was added to the residue, and then washed with 180 g of 5% aqueous sodium hydroxide solution, and the solvent of the organic layer was distilled off to obtain 65 g of oil, which was subjected to gas phase Chromatographic analysis.

1-(2′,4′-dichlorophenyl)ethylamine is 91%, 1-(4′-chlorophenyl)ethylamine is 2.9%, N-1-(2′,4′-dichlorobenzene 1.1% of ethyl) ethyl-α-(2′,4′-dichlorophenyl)ethylamine and 1.5% of N-acetyl-α-(2′,4′-dichlorophenyl)acetamide. Carbonyl-reduced alcohols were not detected. By distilling this, 58.5 g of 1-(2',4'-dichlorophenyl)ethanamine with a purity of 99% was obtained. The boiling point is 130-132°C/20mmHg.

Example 49

In Example 48, except for using 0.57 g of 5% platinum-carbon (50% water-containing product) and all the catalysts recovered in Example 48, it was carried out according to Example 48, thereby obtaining 64 g of an oily substance.

1-(2′,4′-dichlorophenyl)ethylamine is 89.9%, 1-(4′-chlorophenyl)ethylamine is 1.8%, N-1-(2′,4′-dichloro Phenyl)ethyl-α-(2′,4′-dichlorophenyl)ethanamine 3.4%, N-acetyl-α-(2′,4′-dichlorophenyl)acetamide 1.6% , no carbonyl-reduced alcohol was detected.

Example 50

In Example 44, 1.52 g of an oily substance was obtained by following the same procedures as in Example 44 except that the pressure was maintained at 5 kg/cm ² ·G.

1-(2′,4′-dichlorophenyl)ethylamine is 78.2%, 1-(4′-chlorophenyl)ethylamine is 4.6%, N-1-(2′,4′-dichlorophenyl Base) ethyl-α-(2′,4′-dichlorophenyl)ethylamine is 6.1%, N-acetyl-α-(2′,4′-dichlorophenyl)acetamide is 1.9%, 0.4% of 2',4'-dichloroacetophenone. Carbonyl-reduced alcohols were not detected.

Example 51

In Example 44, 1.54 g of an oily substance was obtained by carrying out the same procedure as in Example 44 except that the pressure was maintained at 10 kg/cm ² ·G.

1-(2′,4′-dichlorophenyl)ethylamine is 87.2%, 1-(4′-chlorophenyl)ethylamine is 3.7%, N-(2′,4′-dichlorophenyl) Ethyl-α-(2′,4′-dichlorophenyl)ethylamine is 1.1%, N-acetyl-α-(2′,4′-dichlorophenyl)acetamide is 0.5%, 2′ , 4'-dichloroacetophenone was 1.3%, and no carbonyl-reduced alcohol was detected.

Comparative example 6

In Example 44, except that 5% palladium-carbon (50% water-containing product) was used instead of platinum-carbon as a catalyst, and the pressure was kept at 10 kg/cm ² ·G while reacting for 5 hours, all according to Example 44 Implementation, thus obtaining 1.49 g of oil.

1-(2′,4′-dichlorophenyl)ethylamine is 53.8%, phenylethylamine is 31%, 1-(4′-chlorophenyl)ethylamine is 16.9%, 1-(2′- Chlorophenyl) ethylamine is 13.1%, N-1-(2′, 4′-dichlorophenyl) ethyl-α-(2′, 4′-dichlorophenyl) ethylamine is 6.2%, N -Acetyl-α-(2',4'-dichlorophenyl)acetamide 4.7%, 2',4'-dichloroacetophenone 0.5%.

Comparative Example 7

In Example 48, except that 40.6 g of acetic anhydride was used and the reduction reaction was carried out while maintaining the pressure at 10 kg/cm ² ·G, 68 g of an oily substance was obtained by carrying out the same procedure as in Example 48.

1-(2′,4′-dichlorophenyl)ethylamine is 51%, 1-(4′-chlorophenyl)ethylamine is 1%, N-1-(2′,4′-dichlorophenyl Base) ethyl-α-(2′,4′-dichlorophenyl)ethylamine is 1.3%, N-acetyl-α-(2′,4′-dichlorophenyl)acetamide is 42.1%, 0.5% of 2',4'-dichloroacetophenone.

Comparative Example 8

In Example 44, except that 20 g of methanol was used as a solvent, and the pressure was maintained at 10 kg/cm ² ·G, it was carried out as in Example 44, thereby obtaining 1.52 g of an oily substance. 1-(2′,4′-dichlorophenyl)ethylamine is 12%, N-1-(2′,4′-dichlorophenyl)ethyl-α-(2′,4′-dichloro 63% of phenyl)ethylamine and 15% of N-acetyl-α-(2',4'-dichlorophenyl)acetamide.

Comparative Example 9

Add 18.9 g of 2′,4′-dichloroacetophenone, 35 g of methanol, 0.15 g of bis(2-hydroxyethyl) sulfide, 0.1 g of ammonium acetate, and 1.0 g of Raney nickel catalyst (50% aqueous product) into the autoclave Inside, after nitrogen substitution, 4.6 g of ammonia water was added, and the pressure was increased to 50 kg/cm ² ·G with hydrogen.

Next, after raising the temperature to 130°C, the pressure was increased to 80 kg/cm ² ·G with hydrogen, and the reaction was carried out at the same temperature for 4 hours while supplying hydrogen to maintain the pressure at 80 kg/cm ² ·G. After the reaction, the catalyst was filtered, and low-boiling components in the filtrate were distilled off under reduced pressure to obtain 19.5 g of an oil, which was analyzed by gas chromatography.

1-(2',4'-dichlorophenyl)ethanamine accounted for 24.8%, 1-(4'-chlorophenyl)ethanamine accounted for 53.4%, and unknown components accounted for 15.9%.

Example 52

Add 155.1 g of ammonium formate to a reactor equipped with a Dean-Stark separator, and after heating to 155° C., add 98.5 g of acetophenone and 49.6 g of 76% formic acid to it under stirring for 3 hours each, at 160 Stirring was continued for 3 hours at °C. During the reaction, the effluent was separated, and the operation of returning the acetophenone layer (upper layer) to the reactor was repeated as appropriate.

After cooling to room temperature, low boiling point components were distilled off from the reactant under reduced pressure to obtain 116.1 g of crude N-formyl-1-phenylethylamine.

It was analyzed by gas chromatography and the purity was 87.5%.

Example 53

In Example 52, except that 139.6 g of 1′-acetylnaphthalene was used instead of acetophenone, the same implementation was carried out as in Example 52 to obtain 164.5 g of crude N-formyl-1-naphthylethylamine. The purity is 82.3%.

Example 54

In Example 52, except that 110.7 g of formamide was used instead of ammonium formate, and 126.7 g of 4'-chloroacetophenone was used instead of acetophenone, the implementation was carried out as in Example 52 to obtain crude N-formyl-1-(4- Chlorophenyl) ethylamine 150g. The purity is 87.4%.

Example 55

In Example 52, except that 155 g of 2',4'-dichloroacetophenone was used instead of acetophenone, the implementation was carried out as in Example 52 to obtain crude N-formyl-1-(2,4-dichlorophenyl ) ethylamine 170.8g. The purity is 78.9%.

Example 56

The ammonia absorption tower was connected to the reactor, and 206 g of ammonium formate was added to the reactor. Add 76% formic acid 233g in the groove of ammonia absorbing tower, circulate in the tower with 20g/min, keep the connecting part of absorbing tower and reactor at 80 ℃ of insulations simultaneously.

Stir and heat the reactor to 155°C, drop 2',4'-dichloroacetophenone into it at 0.68g/min, drop into the tank liquid of the ammonia absorption tower at 0.48g/min for 3 hours, and then Stirring was continued at -160°C for 7 hours during which time the formic acid continued to circulate.

After the reaction, low boiling point components were distilled off under reduced pressure to obtain 162.2 g of crude N-formyl-1-(2,4-dichlorophenyl)ethylamine with a purity of 86%.

The distillate obtained by distilling off low-boiling components was 137.9 g, which was analyzed by gas chromatography and contained 69.8% of formamide, 12.9% of formic acid and 1.7% of 2',4'-dichloroacetophenone.

After the reaction, the tank liquid of the ammonia absorption tower was 229.2 g, containing 4.7% of formamide, 36.7% of formic acid, 0.2% of ammonium formate, and 1.7% of 2',4'-dichloroacetophenone.

Example 57

By 27% ammoniacal liquor 56.8g and the distillate 137g that embodiment 56 reclaims and the groove liquid 113g of ammonia absorption tower form mixture decompression distillate water 166g, add this concentrate in the reactor, add in the groove of ammonia absorption tower The tank liquid 116g of the ammonia absorption tower that 90% formic acid 130g and embodiment 56 reclaim, except above, implement according to embodiment 56. 165.4 g of crude N-formyl-1-(2,4-dichlorophenyl)ethylamine with a purity of 83.7% was obtained. The distillate obtained by distilling off the low-boiling components was 112.5%, which contained 80.1% of formamide, 15.7% of formic acid and 1.2% of 2',4'-dichloroacetophenone. After the reaction, the tank liquid of the ammonia absorption tower is 265g, which contains formamide 6%, formic acid 31.5%, ammonium formate 0.2%, 2', 4'-dichloroacetophenone 3%.

Example 58

In Example 52, except that 123.2 g of 2'-methoxyacetophenone was used instead of acetophenone, the implementation was carried out as in Example 52 to obtain crude N-formyl-1-(2-methoxyphenyl)ethane Amine 143.7 g. The purity is 90%.

Comparative Example 10

In Example 52, benzene acetate and formic acid were added to ammonium formate in 3 hours, and then kept stirring for 3 hours. Outside all implement by this embodiment 52. 112 g of crude N-formyl-1-phenylethylamine with a purity of 82.7% was obtained.

Comparative Example 11

In Example 55, 2′, 4′-dichloroacetophenone and formic acid were added to ammonium formate in 3 hours, and then kept stirring for 3 hours. Instead, formic acid, ammonium formate and 2′, 4′-dichloroacetate The mixture composed of acetophenone was heated and stirred at 160°C for 6 hours, except that it was carried out as in Example 55. 178.6 g of crude N-formyl-1-(2,4-dichlorophenyl)ethylamine with a purity of 70.4% was obtained.

Comparative Example 12

In Example 54, 4'-chloroacetophenone and formic acid were added to formamide in 3 hours, and then kept stirring for 3 hours. As an alternative, the mixture composed of formamide, formic acid and 4'-chloroacetophenone It was heated and stirred for 6 hours, except that it was carried out according to Example 54. 144.2 g of crude N-formyl-1-(2,4-dichlorophenyl)ethylamine with a purity of 84.6% was obtained.

Example 59

A mixture of 162 g of the crude N-formyl-1-(2,4-dichlorophenyl)ethylamine obtained in Example 56, 96 g of water and 121 g of 36% hydrochloric acid was refluxed for 1 hour with stirring.

Then add 224g of water, then extract twice with 80g of toluene at 70°C, then add 173g of 8% caustic soda aqueous solution to the water layer, extract twice with 100g of toluene at 60°C, then wash the obtained toluene layer with 80g of water After 2 times, toluene was distilled off to obtain 128.8 g of crude 1-(2,4-dichlorophenyl)ethylamine with a purity of 93.4%. It was distilled under reduced pressure to obtain 118 g of a refined product with a purity of 99.5%.

Example 60

Add 0.6 g of copper (II) chloride to a methylmagnesium chloride solution prepared from 24.2 g of methyl chloride, 11.7 g of magnesium and 121 g of tetrahydrofuran at 15-25 ° C, and then add 61.3 g of 2 - A solution of ethyl cyano-3-methyl-2-butenoate in 61 g of toluene. After the addition was complete, the reaction was further carried out at the same temperature for 2 hours. The reaction mixture was cooled and poured into 173 g of 15% aqueous sulfuric acid at 5-15°C. The mixture was heated to 50-60° C., then allowed to stand at the same temperature and phase-separated, the aqueous layer was extracted once with 31 g of toluene, and the organic layers were combined and washed with 67 g of 5% aqueous sodium bicarbonate and 31 g of water. The combined organic layers were analyzed by gas chromatography using n-dipropylphthalate as internal standard. The recovered amount of ethyl 2-cyano-3,3-dimethylbutenoate was calculated to be 65 g (96%).

Example 61

The reaction was carried out in a manner similar to that of Example 60 above, except that 3.0 g of copper(II) chloride was used instead of 0.6 g of copper(II) chloride. The yield of ethyl 2-cyano-3,3-dimethylbutenoate was 95%.

Compound N-[(R)-1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide of the present invention can be used as an effective agent for controlling Fusarium wilt The ingredients are used, and the control agent and the fusarium wilt control method characterized by treating Oryza seeds with the control agent will be described below.

The compound of the present invention, that is, N-[(R)-1-(2,4-dichlorophenyl) ethyl]-2-cyano- 3,3-Dimethylbutanamide not only has superior control efficacy in foliage dispersal and the like for Fusarium wilt, but also has excellent control efficacy over a long period of time in seed treatment.

The absolute stereo configuration of the benzyl position on the amine side is (R), but the optical purity related to this position does not have to be 100% ee (enantiomeric excess). In the present invention, the optical purity related to this position is, for example, 75% ee [i.e. (R): (S) = 87.5: 12.5] or more (R) is rich in optical active body, but preferably the optical purity of the relevant part is 85% ee [i.e. (R): ( S) = 92.5:7.5] and above (R) isoforms are rich in optically active forms. In addition, the α-position on the acid side of the compound of the present invention is easy to undergo racemization (epimerization), and in practical applications for the control of Fusarium wilt, the stereo configuration of such a position does not have a great impact on the control effect, so in this Regardless of whether the part is the (R) body or the (S) body, the mixture may be used in any ratio, but the (RS) body is usually used from an industrial point of view.

The compound of the present invention shows a particularly good control effect on the important disease Fusarium wilt (Pyriculariaoryzae) of the Oryza genus, and then by mixing with other suitable plant disease control agents, due to the synergistic effect, not only the control becomes more effective, Moreover, it also shows a more effective effect on the control of rice bakanae disease (Gibberella fujikuroi), which is another important disease of Oryza genus.

When the compound of the present invention is used as an active ingredient of a fusarium wilt control agent, it can also be used as if adding other ingredients, but usually it is mixed with a solid carrier, a liquid carrier, a surfactant and other preparation adjuvants to prepare an emulsion, water And agent, suspension agent, granule, powder etc. use. The compound of the present invention as an active ingredient in these preparations contains 0.1 to 99%, preferably 0.2 to 95%, by weight.

Examples of pharmaceutical carriers include kaolin clay, atumaru yaitokure-, bentonite, acid clay, pyrophyllite, talc, diatomaceous earth, calcite, corn cob powder, walnut shell powder, urea, ammonium sulfate, synthetic hydrous Silicon oxide and other loose powders or granules, as the liquid carrier, aromatic hydrocarbons such as xylene and methylnaphthalene, alcohols such as isopropanol, ethylene glycol and cellosolve, acetone, cyclohexanone, iso Ketones such as phorone, vegetable oils such as soybean oil and cottonseed oil, dimethyl sulfoxide, acetonitrile, water, etc.

Examples of surfactants used for the purposes of emulsification, dispersion, wet spreading, etc. include alkyl sulfate ester salts, alkyl (aryl) sulfonates, dialkyl sulfosuccinates, polyoxyethyl alkanes Anionic surfactants such as aryl ether phosphate ester salt, naphthalenesulfonic acid formaldehyde condensate, polyoxyethylene alkyl ether, polyethylene oxide polyoxypropylene block copolymer, sorbitan fatty acid ester, poly Nonionic surfactants such as oxyethylene sorbitan fatty acid ester, etc.

Examples of auxiliary agents for formulations include lignosulfonate, alginate, polyvinyl alcohol, gum arabic, CMC (hydroxymethyl cellulose), PAP (acid isopropyl phosphate), and the like.

These preparations can be used as they are, or diluted with water and spread on stems and leaves, or scattered powder and granular on the soil surface and water surface, or mixed with loose powder and granular on the soil surface, or treated in seedling boxes, or treated with seeds.

As the method of seed treatment, there are seed dipping treatment, seed spraying treatment, seed coating treatment, etc. When performing seed treatment, it can also be coated with calcium peroxide or the like for direct seeding.

In addition, it can also be used in combination with other plant disease control agents, insecticides, parasiticides, nematicides, herbicides, plant growth regulators, fertilizers, and soil conditioners.

The implementation of other plant disease control agents that can be mixed is shown below together with the compound symbols.

(A) 1,3-dithiolane-2-ylidene diisopropyl dipropionate

[General name isoprothiolane],

(B) 6-methyl-1,2,4-triazolo[3,4-b]benzothiazole

[generic name tricyclazole],

(C) 3-aryloxy-1,2-benzothiazole-1,1-dioxide

[generic name probenazole],

(D) 1,2,5,6-tetrahydro-4H-pyrrole (3,2,1-i j)quinolin-4-one

[common name pyroquilon],

(E)(2)-2′-methylacetophenone 4,6-dimethylpyrimidin-2-ylhydrazone

[General name ferimzone],

(F) S, S-o-ethyl diphenylphosphodisulfate

[common name edifenphos],

(G) 4,5,6,7-tetrachlorophthalketone

[common name phthalide],

(H) Kasugamycin

[common name kasugamycin]

(I) α, α, α-Trifluoro-3-isopropoxy-o-toluanilide

[common name flutolanil],

(J) 1-(4-chlorobenzyl)-1-cyclopentyl-3-phenylurea

[common name pencycuron],

(K) Validamycin

[General name validamycin],

(L) 3′-Isopropoxy-o-toluanilide

[common name mepronil],

(M) 6-(3,5-dichloro-4-methylphenyl)-3(2H)-pyridazinone

[common name diclomezine],

(N) N-(1,3-dihydro-1,1,3-trimethylisophenylfuran-4-yl)-5-chloro-1,3-dimethylpyrazole-4-carboxylic acid Amide

[common name furametpyr],

(O)methyl(E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate, [ICIA5504]

(P) 5-Ethyl-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylic acid

[General name oxolinic acid],

(Q)(E)-4-Chloro-α,α,α-trifluoro-N-(1-imidazol-1-yl-2-propoxyethylene)-o-toluidine

[generic name triflumizole],

(R) N-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide

[common name prochloraz],

(S) 2-[(4-Dichlorophenyl)-methyl]-5-(1-methylethyl)-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopenta alcohol

[generic name ipconazole],

(T) N-Furfuryl-N-imidazol-1-ylcarbonyl-DL-homoalanine pent-4-enyl ester

[common name pefurazoate],

(U) Methyl-1-butylcarbamoyl-benzopyrazol-2-ylcarbamate

[common name benomyl]

(V) 4,4'-(O-phenylene) bis(3-dimethyl thiourethanate)

[common name thiophanate-methyl],

(W)2-(thiazol-4-yl)benzimidazole

[generic name thiobenzonzimidazole],

(X) Bis(dimethylcarbamoyl) disulfide

[common name thiram],

(Y) 4-cyclopropyl-6-methyl-N-phenylpyridazin-2-amine

[CGA219417, Proposed Generic Name. cyprodinil],

(Z) 4-(2,2-difluoro-1,3-benzodioxol-4-yl)pyrrole-3-carbonitrile

[common name fludioxonil],

When the compound of the present invention is mixed with the active ingredients of the above-mentioned other plant disease control agents, the mixing ratio varies depending on the type of plant disease control agent to be mixed, but relative to 1 part by weight of the compound of the present invention, the plant The disease control agent is usually 0.001-100 by weight, preferably 0.2-20.

Examples of insecticides obtained by mixing are shown together with the compound symbol as follows,

(a) 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethyl)sulfinyl-1H-pyrazole-3-carbonitrile

[general name fiproni1],

(b) 1-(6-Chloro-3-pyridylmethyl-N-nitroimidazolin-2-ylideneamine

[general name imidacloprid],

(c) N-[2,3-dihydro-2,2-dimethylphenylfuran-7-yl-oxycarbonyl (methyl)aminothio]-N-isopropyl-β-alanine ethyl ester

[common name benfuracarb],

(d) S, S'-(2-dimethylaminotrimethylene) bisthiocarbamate

[general name cartap]

(e) 4-(methylthio)phenyl dipropylphosphate

[common name propaphos]

(f) 2,3-dihydro-2,2-dimethylphenylfuran-7-yl(dibutylaminothio)methylcarbamate

[common name carbosulfan],

(g) (E)-N-(6-chloro-3-pyridylmethyl)-N-ethyl-N'-methyl-2-nitrovinylidenediamine

[common name nitenpyram],

(h) (E)-4,5-dihydro-6-methyl-4-(3-pyridinemethyleneamino)-1,2,4-triazin-3(2H)-one

[common name pymetrozine],

(i) O-4-nitro-m-tolylphosphoryl sulfate O, O-dimethyl ester

[common name fenitrothion],

etc.

When the compound of the present invention and the active ingredients of the above-mentioned insecticides are used in combination, the mixing ratio varies depending on the type of insecticide to be mixed, but for 1 part by weight of the compound 1 of the present invention, the weight ratio of the insecticide Usually, it is 0.01-100, Preferably it is 0.2-20.

When the compound of the present invention is used as an active ingredient of a fusarium wilt control agent, the treatment amount varies depending on weather conditions, preparation form, treatment period, treatment method, treatment site, etc., but it is usually 0.05 to 200 g per 1 hectare, preferably 0.1-100g. When diluting emulsions, water preparations, suspensions, etc. with water, the application concentration is 0.00005-0.5%, preferably 0.0001-0.2%. Granules, powders, etc. are not diluted. apply. When treating in a nursery box, as the active ingredient amount, about 0.1 to about 100 g, preferably about 0.5 to about 10 g can generally be used per box for a commonly used large nursery box (30cm×60cm×3cm).

When carrying out seed treatment, as the active ingredient amount, per 1kg of seeds usually can use about 0.001～about 50g, preferably can use about 0.01～about 10g, but when carrying out seed dipping treatment, per 1kg of seeds is generally in the proportion of 1～3kg Usually about 5,000 to about 50,000 ppm of high-concentration liquid immersion for a short time, usually about 5-30 minutes. Or generally immerse in a low-concentration liquid medicine of about 20 to about 4000 ppm in a ratio of 1 to 3 kg for a long time, and the time is about 6 hours to about 48 hours. Common preparation examples are listed below. In addition, parts represent parts by weight, and the compound (1) of the present invention was obtained by using the above-mentioned Example 5.

Preparation Example 1

50 parts of the compound (1) of the present invention, 3 parts of calcium lignosulfonate, 2 parts of sodium lauryl sulfate and 45 parts of synthetic hydrous silicon oxide were thoroughly pulverized and mixed to obtain a water neutralizer.

Preparation example 2

25 parts of the compound of the present invention (1), 3 parts of polyoxyethylene sorbitan monooleate, 3 parts of CMC and 69 parts of water are mixed, and the particle size of the active ingredient is wet pulverized to below the micron to obtain a suspending agent.

Preparation example 3

2 parts of the compound (1) of the present invention, 8 parts of kaolin clay and 10 parts of talc were thoroughly pulverized and mixed to obtain a powder.

Preparation Example 4

20 parts of the compound (1) of the present invention, 14 parts of polyoxyethylene styryl phenyl ether, 6 parts of calcium dodecylbenzenesulfonate and 60 parts of xylene were thoroughly mixed to prepare an emulsion.

Preparation Example 5

10 parts of compound (1) of the present invention, 1 part of synthetic hydrous silicon oxide, 2 parts of calcium lignosulfonate, 30 parts of bentonite and 73 parts of kaolin were thoroughly pulverized and mixed, added water and fully mixed, granulated and dried to obtain granules.

Each of the compounds (A) to (Z) and (a) to (h), and a mixture of each of these compounds and the compound (1) of the present invention can also be formulated as in the above formulation examples 1 to 5.

Test examples of the effectiveness of the compound of the present invention as a fusarium wilt control agent and the like will be described below. The compound (1) of the present invention is obtained according to the above-mentioned Example 5, and other plant disease control agents and insecticides are represented by the above-mentioned compound symbols. In addition, the compounds used for comparative control are represented by the following compound symbols. That is (2) N-[(RS)-1-(2,4-dichlorophenyl)ethyl]-(RS)-2-cyano-3,3-dimethylbutaneamide [JP-P2 - Compound (6) specifically described in Publication No. 76846].

Test example 2 fusarium wilt control test (seed dipping treatment)

The test medicament of the water and agent prepared by formulation example 1 was diluted with water to a specified concentration, and Oryza seeds (Nipponbare) were dipped therein for 10 minutes at a ratio of 2kg of liquid medicine/1kg of seeds. After the treated rice was air-dried, it was sown at a rate of 160g seeds/case, and the seedlings were raised for 20 days. Transplant 5 Oryza seedlings into 1/5000 arena Wagner pots covered with soil and filled with water. Cultivation was continued in the greenhouse while continuously performing water leakage treatment at a rate of 3 cm per day from the lower part of the Wagner pot. Six weeks after transplantation, they were moved together with other Oryza seedlings with Fusarium wilt into a vinyl plastic room, and were infected with Fusarium wilt while maintaining a humidified state. After 11 days of bacterial inoculation, investigate the incidence index of Fusarium wilt of leaves according to the following standard, and obtain the control value by the following formula. In addition, the incidence rate in the untreated area was 58%

Incidence Index Lesion Area Ratio

0 0

1 1～5%

2 6～25%

4 26～50%

8 51% or more

N: number of leaves to investigate

n1～n4=the number of leaves of each disease index 1, 2, 4, 8

The results are shown in Table 6.

Table 6

Test drug Active ingredient treatment concentration (ppm) Control value (%) (1) 10000 86 5000 74 2500 65 (2) 10000 61 5000 41 (B) 10000 0 (T) 10000 0 (U) 10000 0

As mentioned above, the compound (1) of the present invention showed excellent control efficacy even under harsh conditions, and surprisingly, the compound of the present invention showed approximately equal control efficacy.

Test example 3 fusarium wilt control test (seed spraying treatment)

The water and agent prepared by embodiment 1 are diluted with water to the specified concentration, and the rice seed (Nipponbare) is sprayed with the dose of 30ml/1kg seed. The treated rice is air-dried. Then sow the seeds in plastic troughs filled with sandy loam, and cultivate them in the greenhouse for 20 days. Then move it into the vinyl plastic room together with other rice seedlings that have fallen ill with Fusarium wilt, and keep it in a humidified state to infect it with Fusarium wilt. After 10 days of inoculation, investigate the disease index of leaves according to Test Example 2, and obtain the control value. Incidence in the untreated area was 100%.

The results are shown in Table 7.

Table 7

Test drug Active ingredient treatment concentration (ppm) Prevention value (%) (1) 2000 86 (1)+(Q) 2000+2000 100 (1)+(R) 2000+2000 100 (1)+(S) 2000+2000 100 (1)+(T) 2000+2000 100 (1)+(V) 2000+2000 100 (2) 2000 48 (Q) 2000 0 (R) 2000 0 (S) 2000 15 (T) 2000 0 (V) 2000 0

Test example 4 rice bakanae disease control test (seed blowing coating treatment)

Rice seed (Nihonbare) is infected with rice bakanae disease (Gibberella fujikuroi) earlier, the test agent made into water and agent by preparation 1 is diluted to the prescribed concentration with water, and it is used as the medicine of 30ml/1kg seed to the rice seed. Quantitative blow coating treatment. After the treated rice seeds were air-dried, the sandy loam soil was filled into plastic troughs, and each trough was sown at a ratio of 50 grains, and cultivated in the greenhouse for 21 days. The disease state was investigated, and the healthy seedling rate was obtained from the following formula.

The results are shown in Table 8.

Table 8

Test drug Active ingredient treatment concentration (ppm) Control value (%) (1)+(Q) 10000+10000 100 (1)+(R) 10000+10000 100 (1)+(S) 10000+10000 100 (1)+(T) 10000+10000 100 (1)+(V) 10000+10000 100 (1) 10000 10 (Q) 10000 78 (R) 10000 88 (S) 10000 93 (T) 10000 84 (V) 10000 70 Bacterial inoculation · Untreated 0 Not inoculated, not treated 100

Test Example 5 Fusarium wilt control test (scattering of stems and leaves)

Sandy loam soil was filled in plastic tanks, rice seeds (Nipponbare) were sown, and they were grown in a greenhouse for 20 days. The test agent made into a suspension according to formulation 2 was diluted with water to a prescribed concentration, and for each rice seedling, the amount of the drug solution (30 liters/10 ares) that was slightly moistened on the leaf surface was spread on the stem and leaf. After spreading, the plants are air-dried and inoculated by spraying with a spore suspension of Fusarium wilt. After inoculation, cultivate for 4 days at 28°C in darkness and high humidity, investigate the incidence index of Fusarium wilt of leaves according to Test Example 2, and obtain the control value. In addition, the disease degree of the untreated area was 100%.

The results are shown in Table 9

Table 9

Drugs to be tested Active ingredient treatment concentration (ppm) Prevention value (%) (1) 100 100 50 99 25 94

Test Example 6 Fusarium wilt control test (scattering of stems and leaves)

Put the sandy loam into a plastic tank, sow rice seeds (Nipponbare), grow in the greenhouse for 20 days, and dilute the test agent made into water and agent according to Preparation Example 1 to the specified concentration with water, and spread it in a fully attached manner onto the leaves of the rice seedlings. The preventive effect test was carried out and the residual effect test was carried out after the medicinal liquid was air-dried. After being kept in the greenhouse for 7 days, the spore suspension of Fusarium wilt was sprayed and inoculated respectively. After inoculation, it was kept at 24°C under high humidity for 10 days, and the control effect was investigated according to the following index.

Prevention index Control effect 5 sound 4 The control effect is more than 90% 3 The control effect is 70-89% 2 The control effect is 41-69% 1 Control effect 1～40% 0 Control effect 0%

Table 9

Test drug Active ingredient treatment concentration (ppm)   Prevention index residual effect Preventive effect (1) 2.50.5 42 42 (1)+(E) 2.5+50.5+3 54 54 (1)+(F) 2.5+50.5+3 53 53 (1)+(G) 2.5+50.5+3 54 54 (1)+(H) 2.5+50.5+3 54 54 (1)+(N) 2.5+5000.5+100 54 54 (1)+(I) 2.5+5000.5+100 54 54 (1)+(J) 2.5+5000.5+100 54 54 (1)+(K) 2.5+5000.5+100 54 54

Table 10

Test drug Active ingredient treatment concentration (ppm)   Prevention index residual effect preventive effect (E) 53 10 twenty one (F) 53 10 twenty one (G) 53 20 31 (H) 53 10 twenty one (N) 500100 00 00 (I) 500100 00 00 (J) 500100 00 00 (K) 500100 00 00

Test Example 7 Oryza sheath blight control test (scattering of stems and leaves)

Sandy loam soil was put into plastic tanks, and rice seeds (Nipponbare) were sown and bred in a greenhouse for 20 days. According to formulation example 2, the test agent prepared as a suspension was diluted with water to a specified concentration, and it was sprayed on the leaves of rice seedlings in a manner of fully adhering to the stems and leaves. After the medicinal liquid is air-dried, the sclerotia of sheath blight bacteria is inoculated on each strain. After inoculation, it was kept at 27° C. under humid conditions for 10 days. According to Experimental Example 6, the control effect was investigated by the control index. The results are shown in Table 11.

Table 11

Drugs to be tested Active ingredient treatment concentration (ppm) Prevention index (1)+(I) 250+1050+5 42 (1)+(J) 250+550+1.25 42 (1)+(K) 250+1050+5 42 (1)+(L) 250+3050+10 41 (1) 25050 00 (I) 105 31 (J) 51.25 31 (K) 105 31 (L) 3010 30

Test example 8 fusarium wilt control test (seedling box processing)

Artificial soil (Bonsol No. 2: Koura Sangyo Co., Ltd.) was put into a seedling box (30 cm x 60 cm x 3 cm) for Oryza genus, and about 200 g of dry rice seeds of Oryza genus (Nipponbare) were sown per box. After 20 days of sowing, the granules prepared in Preparation Example 5 were evenly spread on the soil surface of the seedling box. Then water it lightly, and then transplant 5 Oryza seedlings into sandy clay (Hyogo Prefecture Po City production) and watered 1/50 ares Wagner pots. Cultivate in the greenhouse while continuously performing water leakage treatment at a rate of 3 cm per day from the lower part of the Wagner pot. After transplanting for 6 weeks, it was moved into the vinyl plastic room together with other rice seedlings with Fusarium wilt, and kept in a humidified state to infect Fusarium wilt. 11 days after the germ inoculation, the fusarium wilt incidence index of the leaves was investigated according to Test Example 2, and the control value was obtained. The incidence rate in the untreated area was 95%.

The results are shown in Table 12.

Table 12

Drugs to be tested Active ingredient processing amount (g/seedling box)   Prevention value % (1) 3 98 1.5 92 O.75 80 (B) 2 39

Test example 9 fusarium wilt control test (seedling box processing)

Artificial soil (Bonsol No. 2: Koura Sangyo Co., Ltd.) was put into a seedling box (30 cm x 60 cm x 3 cm) for Oryza genus, and about 200 g of dry rice seeds of Oryza genus (Nipponbare) were sown per box. After 20 days of sowing, the granules prepared in Preparation Example 5 were evenly spread on the soil surface of the seedling box. Thereafter, the water was lightly watered, and five rice seedlings were transplanted into Wagner pots of 1/500 are filled with sandy loam (produced in Takarazuka City, Hyogo Prefecture) and watered. While continuously performing water leakage treatment from the lower part of the Wagner pot at a rate of 3 cm per day, the cultivation was continued in the greenhouse. After 4 weeks of transplantation, move into the vinyl plastic room together with other rice seedlings that have had Fusarium wilt, and keep it in a humidified state to infect it with Fusarium wilt. After 11 days of bacterial inoculation, investigate the incidence index of Fusarium wilt according to Test Example 2, and obtain the control value. In addition, the incidence rate of the untreated area was 91%.

The results are shown in Table 13.

Table 13

  Drugs to be tested Active ingredient processing amount (g/seedling box) Prevention value (%) (1) 1.50.75 9888 (1)+(a) 1.5+20.75+1 10093 (1)+(b) 1.5+20.75+1 10090 (1)+(c) 1.5+2.50.75+1.25 10093 (1)+(N) 1.5+2.50.75+1.25 10093 (a) 2 0 (b) 2 0 (c) 2.5 0 (N) 2.5 0

Test Example 10 Fusarium wilt control test (water surface treatment)

Sandy loam soil is packed in the Wagner pot of 1/10000 ares and watered, the rice seed (Nihonbare) of the 2-leaf stage is displaced, grown in the greenhouse through 7 days, then will be made into the supply of granules by formulation example 5 The reagent was treated with the water surface in each Wagner pot, cultivated continuously for 7 days (hereinafter referred to as test a) or 14 days (hereinafter referred to as test b), and these rice seedlings were sprayed and inoculated with a spore suspension of Fusarium wilt. After inoculation, it was kept at 24° C. for 10 days under humid conditions. According to Test Example 6, the control effect was investigated by the control index. The results are shown in Table 14.

Table 14

Test drug Active ingredient treatment amount g/10 ares Prevention index Test a Test b (1) 10 3 3 2.5 1 1 (1)+(A) 10+200 5 5 2.5+50 4 3 (1)+(B) 10+50 5 5 2.5+10 4 3 (1)+(c) 10+100 5 5 2.5+30 4 3 (1)+(D) 10+50 5 5 2.5+10 4 3 (A) 200 2 1 50 1 0 (B) 50 2 1 10 1 0 (C) 100 2 1 30 1 0 (D) 50 3 2 10 1 0

Claims (2)

1. A method for producing N-formyl-1-arylmethylamines represented by the general formula [VI], RArCH-NH-CHO [VI] In the formula, R represents a C ₁ -C ₄ alkyl group, and Ar represents the following groups:

In the formula, _R represents hydrogen or chlorine; The method comprises injecting formamide and/or ammonium formate simultaneously with aryl ketone represented by general formula [V] and formic acid: RArC＝O [V] In the formula, R and Ar have the same meanings as above. 2. The method according to claim 1, wherein the formic acid injected simultaneously is formic acid containing ammonium formate obtained by absorbing ammonia generated in the reaction system into formic acid.