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

Abstract

To obtain the subject amine by using a specific carboxylic acid as a reagent for optical resolution, readily and efficiently producible in high optical purity, readily recovering the carboxylic acid, recycling it, useful as an intermedi ate for a medicine. An R or S isomer of 1-(dichloro-substituted phenyl)ethylamine of the formula 2,3-,2,4-,2,6- or 3,4-positions are substituted with chlorine atoms; *is an asymmetric carbon) is optically resolved with mandelic acid in the presence of an organic solvent (preferably at least one selected from an alcohol- based solvent, an ester-based solvent and an ether-based solvent such as ethanol, etc.). The mandelic acid is preferably acidified with an acid such as hydrochloric acid, etc., and recovered by extraction with an organic solvent such as methyl-t- butyl ether, etc.

Description

The manufacture method of N-formyl radical-1-aryl methylamine class

The application is be October 27 nineteen ninety-five, denomination of invention the applying date for " N-[1-(2,4 dichloro benzene base) ethyl]-2-cyano group-3, the manufacture method of 3-dimethyl butane amide " and application number be dividing an application of 200310120789.6 application for a patent for invention.

Technical field

The present invention relates to manufacture method as the useful N-formyl radical of plant disease control agent-1-aryl methylamine class.

Background technology

As N-[-1-(2, the 4-dichlorophenyl) ethyl]-2-cyano group-3, the manufacture method of 3-dimethyl butane amide, be known that 2-cyano group-3, the hydrolysis in the presence of alkali of 3-dimethyl butyrate acid esters becomes carboxylic acid, make thionyl chloride act on the method that the resulting reactive carboxylic acid chloride of this carboxylic acid and 1-(2,4 dichloro benzene base) ethamine react in the presence of alkali.

But owing to hydrolysis must be arranged in this method and make acid become muriatic process, and must thionyl chloride etc. reagent, so people are just seeking more easy method.

Summary of the invention

The inventor is to obtaining N-[1-(2 easily, the 4-dichlorophenyl) ethyl]-2-cyano group-3, the method of 3-dimethyl butane amide is studied, the result has found unnecessary hydrolysis and has made acid become muriatic process, and also reagent such as unnecessary thionyl chloride, but by making 2-cyano group-3,3-dimethyl butyrate acid esters and 1-(2, the 4-dichlorophenyl) ethamine direct reaction, easily with high recovery rate obtain N-[1-(2 as target product, the 4-dichlorophenyl) ethyl]-2-cyano group-3, the method of 3-dimethyl butane amide, and found and become the 2-of its raw material cyano group-3,3-dimethyl butyrate acid esters and 1-(2, the 4-dichlorophenyl) manufacture method of the improvement of ethamine, thus the present invention finished.

At first illustrate about making the C of alpha-cyano-tert.-butylacetic acid ₂-C ₄Alkyl (for example ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-etc.) ester and 1-(2, the 4-dichlorophenyl) ethamine, reaction is the N-[1-of feature (2 under 130～250 ℃, the 4-dichlorophenyl) ethyl]-2-cyano group-3, the manufacturing process of 3-dimethyl butane amide (following note is made compound 1) (following note is made manufacturing process 1 of the present invention), and

Make the C of alpha-cyano-tert.-butylacetic acid ₂-C ₄Alkyl ester and (R)-1-(2, the 4-dichlorophenyl) ethamine, reaction is the N-[(R of feature under 130～250 ℃)-1-(2,4 dichloro benzene base) ethyl]-2-cyano group-3, the manufacturing process of 3-dimethyl butane amide (following note is made compound 1a) (following note is made manufacturing process 2 of the present invention).

At first explanation is about manufacturing process 1 of the present invention.

This reaction can make the C of alpha-cyano-tert.-butylacetic acid ₂-C ₄Alkyl ester (no matter be racemic modification or optically active substance all can) and 1-(2, the 4-dichlorophenyl) ethamine (no matter be racemic modification or optically active substance all can), under solvent-free situation or in solvent, at 130～250 ℃, preferable under 130～220 ℃ temperature of reaction, carry out 0.5-24 hour reaction usually.The amount of employed reagent is for the C of 1 mole of alpha-cyano-tert.-butylacetic acid ₂-C ₄Alkyl ester, the ratio of 1-(2,4 dichloro benzene base) ethamine is generally the 0.9-1.2 mole.As solvent by necessary use, so long as be that inertia and the solvent with boiling point of 130～250 ℃ just are not particularly limited in reaction, for example can enumerate dimethylbenzene, isopropyl benzene, 1,3, hydrocarbon solvents such as 5-Three methyl Benzene, halogenated aromatic such as chlorobenzene, dichlorobenzene hydrocarbon solvent, ether solvents such as diglyme, triglyme, perhaps their mixture.

Reaction solution after reaction ends is separated out operation through crystallizations such as cool to room temperature usually, and with the crystallization leaching that generates, use appropriate solvent (organic solvent, water or their mixed solvents such as methyl alcohol, ethanol, Virahol, hexane, mono chloro benzene) to clean after drying again, in case of necessity by further making with extra care such as recrystallize, the compound 1 of the demand of can emanating out.The following describes relevant manufacturing process 2 of the present invention.

This reaction can make the C of alpha-cyano-tert.-butylacetic acid ₂-C ₄Alkyl ester (no matter be racemic modification or optically active substance all can) and (R)-1-(2, the 4-dichlorophenyl) (optical purity needn't be 100%ee (enantiomeric excess) to ethamine, for example can be that integral body is rich in the optically active substance that optical purity is 75%ee above (R)), in solvent-free or solvent, at 130～250 ℃, preferable under 130～220 ℃ temperature of reaction, carry out 0.5-24 hour reaction usually.The amount of employed reagent is for the C of 1 mole of alpha-cyano-tert.-butylacetic acid ₂-C ₄Alkyl ester, (R)-ratio of 1-(2,4 dichloro benzene base) ethamine is generally the 0.9-1.2 mole.As solvent by necessary use, so long as be that inertia and the solvent with boiling point of 130～250 ℃ just are not particularly limited in reaction, for example can enumerate dimethylbenzene, isopropyl benzene, 1,3, hydrocarbon solvents such as 5-Three methyl Benzene, halogenated aromatic such as chlorobenzene, dichlorobenzene hydrocarbon solvent, ether solvents such as diglyme, triglyme, or their mixture.

Reaction solution after reaction ends is separated out operation through crystallizations such as cool to room temperature usually, the crystallization that leaching generates, make it dry after cleaning with appropriate solvent (organic solvent, water or their mixed solvent solvents such as methyl alcohol, ethanol, Virahol, hexane, mono chloro benzene), can obtain required compound 1a whereby.

For improving the crystalline characteristic, also can separate out operation and take out crystallization in addition by following crystallization.

Reaction solution after the reaction that promptly will heat up in a steamer organic solvent as required ends, on one side 130～170 ℃ of insulations, add mono chloro benzene, dichlorobenzene etc. and water azeotropic organic solvent to wherein annotating on one side, after the dissolving this solution is cooled to 70～100 ℃, under uniform temp, be incubated.On the other hand, with water, by necessary a spot of acid (hydrochloric acid, sulfuric acid etc.) and a small amount of plant brilliant add thermometer is installed, for to make in another container of condensing cooling tube of distillate and stirrer, after being warmed up to 100 ℃, the slow notes of solution (in 70-100 ℃ of insulation) that will dissolve in above-mentioned organic solvent under same temperature is added to wherein.Roughly with organic solvent and water azeotropic, heat up in a steamer in, separate out the crystallization of compound 1a.The water slurry of the compound 1a that obtains like this slowly is cooled to 20～40 ℃, and leaching crystallization then makes it dry after washing, can obtain the compound 1a of the good crystalline powder of filter operation whereby.

The availability of relevant manufacturing process 2 of the present invention below is described.

In compound 1, because respectively there are 1 asymmetric carbon in sour side and amine side, add up to 4 kinds of optically active isomers so exist, promptly by (sour side, the amine side) there is X1 body (R in order, R), the X2 body (S, S), (R is S) with Y2 body (S for the Y1 body, R), there are 2 kinds of diastereoisomers, i.e. X body (racemic modification: X1 body and X2 body) and Y body (racemic modification: Y1 body and Y2 body), but indicated as the aftermentioned reference example, the inventor finds, the plant disease control activity concentrates in Y2 body and the X1 body, finds that simultaneously the plant disease control activity of Y2 body is strong more than the X1 body, that is to say that the plant disease control activity of Y body is strong more than the X body.

When obtaining with technical scale by raceme amine derived compounds 1, if separate out by crystallization, then preventing and kill off active weak X body preferential crystallization in above-mentioned 2 kinds of diastereomer implants diseases separates out, and the ratio of its diastereomer multiple factor affecting such as easily be heated, thereby know that existence may not stablize the problem of (control difficulty) and therefore carry out multiple research, the result is surprised to find that, in by optically active amines (for example optically active isomer that is rich in the R body more than optical purity 75%ee) derived compounds 1a (optically active form), X1 body and Y2 body roughly equally crystallization separate out, and the ratio of this diastereomer factor affecting and not changing such as under common operation bar condition, be not heated, thereby obtained manufacturing process 2 of the present invention.

The C of the alpha-cyano-tert.-butylacetic acid that uses as starting compound in the present invention ₂-C ₄Alkyl ester, the method manufacturing of record such as for example also available J.Am.Chem.Soc.Vol.4791 (1950), but can obtain expeditiously with following raw material manufacturing process.

The for example available Organic Reaction of 1-(2,4 dichloro benzene base) ethamine, Vol 5,301-330 (1949) and special manufacturings such as method of opening records such as flat 2-306942 communique.

Below explanation constitutes the C of the raw material alpha-cyano-tert.-butylacetic acid of manufacturing process 1 ₂-C ₄The manufacture method of alkyl ester.

The C of alpha-cyano-tert.-butylacetic acid ₂-C ₄Alkyl ester is by the C of 2-cyano group-3-methyl-2-butene acid ₂-C ₄Alkyl ester and methylmagnesium-halide react in the presence of copper catalyst and obtain.

C as employed 2-cyano group-3-methyl-2-butene acid ₂-C ₄Alkyl ester for example can be enumerated 2-cyano group-3-methyl-2-butene acetoacetic ester, 2-cyano group-3-methyl-2-butene acid n-propyl, 2-cyano group-3-methyl-2-butene isopropyl propionate, the 2-cyano group-positive butyl ester of 3-methyl-2-butene acid, 2-cyano group-3-methyl-2-butene acid isobutyl ester etc.

As used methylmagnesium-halide, can enumerate methylmagnesium-chloride (CH ₃MgCl), methyl-magnesium-bromide (CH ₃MgBr), methyl magnesium iodide (CH ₃MgI), these all use commercially available product, and perhaps available common method is modulated magnesium and methyl halide reaction.

As copper catalyst, use monovalence or cupric salt usually, for example can enumerate cupric chloride (I) [CuCl], cupric bromide (I) [CuBr], cupric iodide (I) [CuI].Reaction is carried out in organic solvent usually, as employed organic solvent, for example can enumerate ether solvents such as tetrahydrofuran (THF) (following note is made THF), ether, dibutyl ether, aromatic hydrocarbon solvents such as toluene, dimethylbenzene, benzene, the mixed solvent of ether solvents and aromatic hydrocarbon solvents etc.

Temperature of reaction is generally 10～60 ℃, and the reaction times is generally 0.5-10 hour, and used amounts of reactants in the reaction is for the C of 1 mole of 2-cyano group-3-methyl-2-butene acid ₂-C ₄Alkyl ester, the ratio of methyl halide magnesiumization is generally the 1-2 mole, for the C of the 2-cyano group-3-methyl-2-butene acid of 1 parts by weight ₂-C ₄Alkyl ester, the ratio of copper catalyst is generally the 0.0005-0.1 parts by weight.

Reacted reaction solution usually for example water, ammonium chloride water, dilute sulphuric acid water etc. handle the back and concentrate organic layers, if necessity such as distills again at purification operations, can emanate out as the C of the alpha-cyano-tert.-butylacetic acid of object with this ₂-C ₄Alkyl ester.

At this is the C of raw materials used 2-cyano group-3-methyl-2-butene acid ₂-C ₄Alkyl ester can be made effectively with following manufacturing process.

The specific embodiment mode

Below describe C in detail about 2-cyano group-3-methyl-2-butene acid ₂-C ₄The manufacturing process of alkyl ester is characterized in that, in the presence of catalyzer, as main solvent, makes the C of acetone and cyanoacetic acid with hexane ₂-C ₄Alkyl ester reacts.

C as employed cyanoacetic acid ₂-C ₄Alkyl ester for example can be enumerated ethyl cyanacetate, cyanoacetic acid n-propyl, cyanoacetic acid isopropyl ester, the positive butyl ester of cyanoacetic acid, cyanoacetic acid isobutyl ester etc., these all available commercially available products, perhaps available usual method manufacturing.

As catalyzer, usually with commutable aniline and carboxylic acid, as the substituting group in commutable aniline, for example can enumerate hydroxyl, methyl, methoxyl group etc., as commutable aniline example, can enumerate amino-phenol (p-aminophenol, Ortho-Aminophenol, Metha Amino Phenon etc.), Tolylamine (para-totuidine, Ortho Toluidine, meta-aminotoluene).

As the example of carboxylic acid, for example can enumerate rudimentary (C for example ₁-C ₃) lipid acid (for example acetate, formic acid, propionic acid etc.) and phenylformic acid.

As copper catalyst, can enumerate cupric chloride (II) (CuCl ₂), cupric bromide (II) (CuBr ₂), cupric iodide (II) (CuI ₂).

As reaction solvent, use is based on the solvent of normal hexane, and more particularly, normal hexane is generally 50-100% (weight) with respect to the usage ratio of whole solvents, as mixing the reaction solvent that uses, for example can enumerate aromatic hydrocarbon solvents such as toluene, dimethylbenzene etc. with normal hexane.

Temperature of reaction is generally 50-100 ℃, and the reaction times is generally 5-20 hour, removes the water that generates in the dereaction while react usually.

The amount of the reagent that uses in the reaction is with respect to the C of 1 mole of cyanoacetic acid ₂-C ₄Alkyl ester, acetone ratio are generally the 1-4 mole, and catalyst ratio is generally 0.001-0.2 mole (commutable aniline ratio is generally the 0.001-0.1 mole, and the carboxylic acid ratio is generally the 0.1-0.2 mole).

Reacted reaction solution concentrates under decompression or normal pressure usually, or intactly distillation, or be dissolved in ethyl acetate, toluene, the dimethylbenzene equal solvent, wash, again this solution decompression is concentrated to remove and desolvate, if necessity such as distills again at purification operations, can emanate out as the C of the 2-cyano group-3-methyl-2-butene acid of target compound with this ₂-C ₄Alkyl ester.

According to method of the present invention, can make the lower alkyl esters of 2-cyano group-3-methyl-2-butene acid in high recovery rate ground.

As opticity 1-(2,4 dichloro benzene base) ethamine that raw material of the present invention uses, in plant-scale enforcement, can use cheap opticity aspartic acid easily, obtain by optical resolution (RS)-1-(2,4 dichloro benzene base) ethamine.

Below explanation is characterized in that about the manufacturing process of opticity 1-(2,4 dichloro benzene base) ethamine, uses the opticity aspartic acid, optical resolution (RS)-1-(2,4 dichloro benzene base) ethamine.

In this optical resolution method, usually carry out through three processes, (process is a) with opticity aspartic acid and (RS)-1-(2, the 4-dichlorophenyl) ethamine mixes, generate salt, then, opticity diastereoisomer salt is separated out in (process b) crystallization in solvent, this salt is waited segregation after filtration, and (process c) is with this salt of alkaline purification.Below to process a, b and c are described in more detail.

(process a)

Opticity (L-or D-) aspartic acid can obtain with technical scale, uses the above person of optical purity 90%ee usually.(RS)-and 1-(2,4 dichloro benzene base) ethamine, for example can 2, the 4-Er Lvyixianben is as raw material, by carrying out Organic Reaction Vol.5, the Leuckert of record reaction and making among the 301-330 (1949).

The amount of used reagent, for 1 mole of (RS)-1-(2,4 dichloro benzene base) ethamine, the ratio of opticity aspartic acid is generally the 0.1-1.2 mole, is preferably the 0.3-1 mole.Mix and also can in solvent, carry out,, for example can enumerate lower alcohols such as water, methyl alcohol, ethanol as the solvent that uses on demand, or their mixed solution etc.

(process b)

With gained salt in solvent usually with the temperature heating for dissolving of 50～120 ℃ of scopes, this solution is cooled to 0～40 ℃ temperature range usually, to separate out than the diastereomeric salt that makes opticity.As solvent, lower alcohols such as common water, methyl alcohol, ethanol, perhaps their mixed solution.

The salt of being separated out waits segregation after filtration, but also can be made with extra care by recrystallize in lower alcohols such as water, methyl alcohol, ethanol or their mixed solution etc. by necessary again.

(process c)

Common temperature 0～40 ℃ of scope, press for 1 mole of this salt, usually use the alkali such as sodium hydroxide of the ratio of 1-10 mole, this salt is become alkalescence, with unhindered amina with organic solvent extractions such as toluene after, wait operation through concentrating, can emanate out as opticity 1-(2,4 dichloro benzene base) ethamine of object.

Adopting the steric configuration-opticity of opticity 1-(2,4 dichloro benzene base) ethamine that manufacturing process of the present invention obtains, is R-(+) using the L-aspartic acid as the occasion of segregation agent, is (S)-(-) using the D-aspartic acid as the occasion of segregation agent.

Have again, in manufacturing process of the present invention, unreacted (RS)-1-(2, the 4-dichlorophenyl) ethamine, can reclaim by having filtered salt filtrate afterwards, in addition, used opticity aspartic acid can easily be reclaimed by the water layer behind this filtrate and the amine extraction, and the opticity aspartic acid that is reclaimed can re-use.

In addition, optical resolution method as 1-phenyl-ethyl amine class, the known method (spy opens clear 56-26848) that use mandelic acid under water solvent is arranged, under water solvent, use tartrate, method (the Org.Synthesis of oxysuccinic acid, Coll, Vol.2,506 (1943)), even but make the optical resolution method of these 1-phenyl-ethyl amine classes be applicable to 1-(2, the 4-dichlorophenyl) ethamine, but owing to cause at the adjacent substituting group of phenyl exists or can not optical resolution, perhaps only obtain the problem of the significantly reduced 1-of optical purity (2,4 dichloro benzene base) ethamine.

This has been carried out research repeatedly, found that, with an organic solvent as the segregation solvent, and the mandelic acid that uses opticity is as the optical resolution agent, whereby can be with high-optical-purity and high efficiency industrial opticity 1-(2,4 dichloro benzene base) ethamine of advantageously making as object.

Below detailed description has the method for 1-(2,4 dichloro benzene base) ethamine of good opticity with industrial mode manufacturing, it is characterized in that, under organic solvent, uses mandelic acid optical resolution (RS)-1-(2,4 dichloro benzene base) ethamine of opticity.

(RS)-1-(2,4 dichloro benzene base) ethamine is the racemic mixture that contains R-body and S-body equally, even but the mixture that contains a kind of optically active isomer superfluously also can use.

No matter is the opticity mandelic acid of optical resolution agent of the present invention, be that D-body, L-body all can use.

Its usage quantity is counted 0.1-1.2 doubly for (RS)-1-(2,4 dichloro benzene base) ethamine by mole, is preferably 0.3-1 doubly.

Organic solvent as the use of segregation solvent, for example can enumerate pure series solvents such as methyl alcohol, ethanol, n-propyl alcohol, ketone such as acetone, hexone series solvent, ester series solvents such as ethyl acetate, ether series solvents such as methyl tertiary butyl ether, two  alkane, ether, aromatic series series solvents such as toluene, dimethylbenzene, chlorobenzene, nitrile series solvents such as acetonitrile, their mixture etc.In organic solvent, also can contain water.

The usage quantity of solvent is different because of employed solvent, but for (RS)-1-(2,4 dichloro benzene base) ethamine, is generally 2-100 doubly (weight), is preferably 2-10 doubly (weight).

When carrying out optical resolution, for example in above-mentioned solvent, make (RS)-1-(2, the 4-dichlorophenyl) mandelic acid of ethamine and opticity reaction, form after the diastereomeric salt, perhaps make after the synthetic in advance diastereomeric salt dissolving, a kind of diastereomeric salt is separated out by leaving standstill or stirring.Also can cool off on demand, concentrate.Temperature range is generally the boiling point of-20 ℃～solvent.

Separate this salt of being separated out then.Also can make this salt recrystallize of gained on demand.Then decompose this salt, with the organic layer separatory that generates or use organic solvent extraction, can obtain 1-(2,4 dichloro benzene base) ethamine as the opticity of object with this with alkali.

With the residual water layer of organic layer separatory or extraction back, change into acidity with acid after, use organic solvent extraction, with the mandelic acid of this recyclable opticity.

On the other hand, the mother liquor of isolating diastereomer is implemented operation same as described above, with 1-(2,4 dichloro benzene base) ethamine of this recyclable opticity and the mandelic acid of opticity.

Used alkali when decomposing diastereomeric salt is usually with for example sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate etc.Its consumption is generally 1-5 doubly (mole) with respect to salt.

In the occasion that extracts the amine that behind salt decomposition, generates, as extraction solvent, for example use ester series solvents such as ethyl acetate usually, ether series solvents such as methyl tertiary butyl ether, tetrahydrofuran (THF), ether, aromatic series series solvents such as toluene, dimethylbenzene, chlorobenzene etc. in addition.Its consumption is with respect to salt 0.1-5 doubly (weight) normally.

As the acid of when reclaiming the mandelic acid of opticity, using, for example can enumerate mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid.Make the pH value of water layer become 0.5-2 and use acid like that.In this occasion, also can add salt such as sodium-chlor in addition, its consumption is generally 0.1-0.2 times of water layer weight.

As the extraction solvent of the mandelic acid of opticity, can enumerate ether series solvents such as methyl tertiary butyl ether, ester series solvents such as ethyl acetate, n-propyl alcohol etc. form two coating systems with water and the pure series solvent that obtains.Its usage quantity is 0.1-10 times with respect to the weight of water layer.

According to the method, with an organic solvent as solvent, and this specific carboxylic acid of mandelic acid that uses opticity is as the optical resolution agent, with this can with high optical purity, easily and efficient make opticity 1-(2,4 dichloro benzene base) ethamine well as object.Opticity mandelic acid as the optical resolution agent also can reclaim easily in addition because can recirculation use, so industrial be favourable.

Have again, also can be as opticity 1-(2,4 dichloro benzene base) ethamine of object by industrial superior method acquisition, the feature of this method is, under organic solvent, with dibenzoyl tartrate optical resolution (RS)-1-(2,4 dichloro benzene base) ethamine of opticity.Below describe this kind method in detail.

(RS)-1-(2,4 dichloro benzene base) ethamine is the racemic mixture that equivalent is closed R-body and S-body, even but contain wherein a kind of optically active isomer and also can use superfluously.

No matter is the opticity dibenzoyl tartrate of optical resolution agent of the present invention, be that D body, L body all can use.

Its usage quantity with respect to (RS)-1-(2,4 dichloro benzene base) ethamine, is generally 0.3-1.2 doubly (mole), is preferably 0.5-1 doubly (mole).

As the employed organic solvent of segregation agent, for example can enumerate pure series solvents such as methyl alcohol, ethanol, n-propyl alcohol, ketone such as acetone, hexone series solvent, ester series solvents such as ethyl acetate, ether series solvents such as methyl tertiary butyl ether, two  alkane, ether, aromatic series series solvents such as toluene, dimethylbenzene, chlorobenzene, nitrile series solvents such as acetonitrile, their mixture etc.Organic solvent also can contain water.

The usage quantity of solvent is different because of solvent for use, but for (RS)-1-(2,4 dichloro benzene base) ethamine, is generally 2-100 doubly (weight), is preferably 2-20 doubly (weight).

When carrying out optical resolution, for example in above-mentioned solvent, make (RS)-1-(2, the 4-dichlorophenyl) the dibenzoyl tartrate of ethamine and opticity reaction, form after the diastereomeric salt, perhaps make after the synthetic in advance diastereomeric salt dissolving, a kind of diastereomeric salt is separated out by leaving standstill or stirring.Also can cool off on demand, concentrate.Temperature range is generally the boiling point of-20 ℃～solvent.

This salt that to separate out then separates.This salt that is obtained also can carry out recrystallize on demand.Then this salt is decomposed with alkali, with the organic layer separatory that generates or use organic solvent extraction, can obtain opticity 1-(2,4 dichloro benzene base) ethamine as the thing of purpose with this.

With the residual water layer of organic layer separatory or extraction back, become acidity with acid, use organic solvent extraction then, can easily reclaim the dibenzoyl tartrate of opticity with this.

On the other hand, the mother liquor that has separated diastereomeric salt is carried out operation same as described above, the dibenzoyl tartrate of recyclable opticity 1-(2,4 dichloro benzene base) ethamine and opticity.

At this, the alkali as used when decomposing the different loose body salt of non-mapping for example uses sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate etc. usually.Its consumption is generally 1-5 doubly (mole) with respect to salt.

The occasion of the amine extraction that will generate by salt decomposition as extraction solvent, is for example used ester series solvents such as ethyl acetate, ether series solvents such as methyl-tertbutyl ether, tetrahydrofuran (THF), ether, aromatic series series solvents such as toluene, dimethylbenzene, chlorobenzene etc. usually in addition.Its consumption is generally 0.1-5 doubly (weight) with respect to salt.

As the acid of using in the tartaric occasion of the dibenzoyl that reclaims opticity, for example can enumerate mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid.Usually to make the pH value of water layer become 0.5-2 and use acid like that.Also can add salt such as sodium-chlor in addition in this occasion, its amount is generally 0.1-0.2 times of water layer weight.

As the tartaric extraction solvent of the dibenzoyl of opticity, can enumerate ether series solvents such as methyl tertiary butyl ether in addition, ester series solvents such as ethyl acetate, propyl carbinols etc. form the pure series solvent that two coating systems obtain with water.Its usage quantity is 0.1-10 times with respect to the weight of water layer.

According to the present invention, with an organic solvent as solvent, and with this specific carboxylic acid of dibenzoyl tartrate of opticity as the optical resolution agent, with this can be high optical purity, easy and efficient is made opticity 1-(2,4 dichloro benzene base) ethamine as object well.

Dibenzoyl tartrate as the opticity of optical resolution agent also can reclaim easily in addition because can recycle, so industrial be favourable.

Phenyl-ethyl amine through S body residual in the part of the filtrate after the above-mentioned optical resolution method, pass through racemization, its part can be utilized as the R body, as such method, the known so far manufacture method (spy opens clear 50-49235 number) that the racemize α-phenyl-ethyl amine that for example makes the effect of naphthalene sodium and form is arranged, make the sodium hydroxide effect and form the manufacture method (spy opens clear 54-5967 number) of α-naphthalene ethylamine, make the sodium effect that aluminum oxide supports and form the manufacture method (spy opens clear 50-50328 number) of α-phenyl-ethyl amine, in dimethyl sulfoxide (DMSO), make the alkali metal alcohol salt action and manufacture method (spy opens flat 4-275258 number) of racemize 1-(4-chloro-phenyl-) ethamine that forms etc.

But when above-mentioned known method being applied to opticity 1-(2,4 dichloro benzene base) ethamine, produce the problem that the racemic modification reaction can not be carried out fully.

Therefore found such method, with opticity 1-(2,4 dichloro benzene base) ethamine and 2, the condensation of 4-dichloroacetophenone, make novel optically active compounds N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine, it acts on if make the alkali metal alcohol salt pair in dimethyl sulfoxide (DMSO), then the racemic modification reaction is carried out expeditiously, finds simultaneously, if with this racemize imines hydrolysis, then obtain racemize 1-(2,4 dichloro benzene base) ethamine easily as object.

Below describe racemize 1-(2,4 dichloro benzene base) ethamine in detail, the manufacture method of N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine of process opticity.

The N-of opticity of the present invention (alpha-methyl-2,4-dichlorobenzene fork)-α-(2,4 dichloro benzene base) ethamine can pass through dehydrating condensation opticity 1-(2,4 dichloro benzene base) ethamine and 2, and the 4-Er Lvyixianben is made.No matter at this opticity 1-(2,4 dichloro benzene base) ethamine is that R body, S body are any, and still wherein a kind of is that superfluous mixture is all passable.

Dehydrating condensation can be by known method, J.Chem.Soc for example, and 14,2624 (1984) method is implemented.2, the consumption of 4-Er Lvyixianben with respect to opticity 1-(2,4 dichloro benzene base) ethamine, is generally 0.5-2 doubly, is preferably 0.9 5-1.05 doubly (mole).

Reaction is implemented under solvent, catalyzer usually, even but also can implement under solvent-free, catalyst-free.In the occasion of using solvent, as solvent, as long as do not hinder reaction, for example can enumerate aromatic series series solvents such as toluene, benzene, dimethylbenzene, chlorobenzene, ether series solvents such as two  alkane, methyl tertiary butyl ether, aliphatics such as hexane, heptane series solvent, halogen series solvents such as ethylene dichloride, trichloromethane etc.Preferably be removed to outside the system while reacting the water that dehydrating condensation is generated.

The usage quantity of solvent with respect to opticity 1-(2,4 dichloro benzene base) amine, is generally 0-20 doubly (weight), is preferably 3-10 doubly (weight).

As the dehydrating condensation catalyzer, for example can enumerate Louis's acids such as zinc chloride, zinc bromide, zinc fluoride, titanium tetrachloride, boron trifluoride, boron tribromide, phosphorus trichloride, magnesium bromide, iron(ic) chloride, aluminum chloride, tin tetrachloride, titan-alkoxide, copper (II) ト リ Off ラ ト, the sulfonic acid classes such as ion exchange resin of Phenylsulfonic acid, tosic acid, sulfonic acid system, heteropllyacids such as the acid of 12 phosphorus tungsten (IV), 12 silicon tungsten (IV) acid etc.

Wherein preferably use zinc chloride, titan-alkoxide, titanium tetrachloride, boron trifluoride, tosic acid etc.Preferably zinc chloride, titan-alkoxide etc.

The usage quantity of catalyzer with respect to opticity 1-(2,4 dichloro benzene base) ethamine, often is 0.001-0.1 times, is preferably 0.00 5-0.05 doubly (mole).

The temperature of reaction of condensation is generally 70～180 ℃, and the water that dehydrating condensation is generated with the limit coronite is removed to system outward for good.Reaction times is generally 1-20 hour.

The N-of the opticity that is generated (alpha-methyl-2,4-dichloro benzal)-α-(2, the 4-dichlorophenyl) ethamine, after removing catalyzer by reactive material, also but former state is used for back step operation, also can separate by for example heating up in a steamer method such as low boiling component, also separable after means such as all again distillations, recrystallize, various chromatographys refining.

With N-(alpha-methyl-2,4-dichloro the benzal)-α of opticity-(2,4 dichloro benzene base) ethamine racemic modification manufacturing racemic modification the time, under the dimethyl sulfoxide (DMSO) coexistence, implement by making the alkali metal alcohol salt action.

As alkali metal alcoholates, it is good for example using the metal alkoxide of the tertiary alcohols such as potassium tert.-butoxide, sodium tert-butoxide, tertiary amyl alcohol potassium, sodium tert-amyl alcohol.

Its usage quantity with respect to N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine of opticity, is generally 0.01-2 doubly, is preferably 0.03-0.2 doubly (mole).

In addition, the usage quantity of dimethyl sulfoxide (DMSO) with respect to N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine of opticity, is generally 0.1-10 doubly, is preferably 0.5-5 doubly (mole).Certainly also can be used as solvent uses.

The racemic modification reaction is implemented in the presence of solvent usually.As such solvent,, for example can enumerate aromatic series series solvents such as toluene, benzene, dimethylbenzene, chlorobenzene, aliphatics series solvents such as ether series solvent, hexane, heptane such as ether, methyl tertiary butyl ether, two  alkane, dimethyl sulfoxide (DMSO) etc. as long as do not hinder reaction.The usage quantity of solvent is different because of the kind of solvent for use, but with respect to N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine of opticity, is generally 0.3-100 doubly (weight), is preferably 0.5-10 doubly (weight).

The temperature of reaction of racemic modification reaction, reaction times are different because of the kind of alkali metal alcoholates, consumption etc., but temperature is generally the boiling point of 0 ℃～solvent, is preferably 0～100 ℃, is more preferred from 10～50 ℃, and the reaction times is generally 1-48 hour.

The available following method of carrying out of reaction is followed the trail of: get a part of reactive material and measure specific rotation, perhaps use after the hydrolysis to have the methods such as high speed liquid chromatography analysis of opticity post.

Optically-active N-(the alpha-methyl-2 that is generated, 4-dichloro benzal)-α-(2, the 4-dichlorophenyl) ethamine, clean by reactive material with the aqueous solution that for example contains inorganic salt such as salt and to remove after dimethyl sulfoxide (DMSO), the alkali metal alcoholates etc., usually former state is used for back step operation, but the both available low boiling component etc. of heating up in a steamer is separated, also can be refining by means such as distillation, recrystallize, various chromatographys again after separation.

Racemize N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine for example can resolve into racemize 1-(2,4 dichloro benzene base) ethamine and 2,4-Er Lvyixianben with this by the usual method hydrolysis.

Hydrolysis is for example implemented without solvent or use solvent in the presence of acids such as dilute hydrochloric acid, sulfuric acid.The usage quantity of acids with respect to racemize N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine, is counted 1-10 doubly by equivalent usually at this moment, is preferably 1.05-1.5 doubly.

The consumption of water with respect to racemize N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine, is generally 1-1000 doubly by mole, is preferably 20-100 doubly.

In the occasion of using solvent, with respect to racemize N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine, usage quantity is 0.1-5 doubly (weight) usually.As solvent, only otherwise hindering reaction gets final product, for example can enumerate pure series solvents such as methyl alcohol, ethanol, aliphatics such as hexane, heptane series solvent, halogen such as ethylene dichloride, trichloromethane series solvent, ester series solvents such as ethyl acetate, ether series solvents such as two  alkane, ether, aromatic series series solvents such as toluene, dimethylbenzene, chlorobenzene etc.

The temperature of reaction of hydrolysis, the reaction times is also depended on the kind and the consumption of used acids, and temperature is generally the boiling point of 0 ℃～solvent, is preferably 30～70 ℃, and the reaction times was generally 10 minutes-5 hours.

Usually hydrolysis generates the salt of water miscible 1-(2,4 dichloro benzene base) ethamine and acids, and 2, the 4-Er Lvyixianben.In the solvent-free occasion of implementing down, for example can in reactive material, add non-water-soluble solvent, and in organic layer extracting and separating 2, the 4-Er Lvyixianben, the aqueous solution with alkali such as aqueous sodium hydroxide solutions makes water layer become alkalescence then, then with water-insoluble solvent it is extracted, usually with resulting organic layer concentrating under reduced pressure, 1-(2,4 dichloro benzene base) ethamine can be taken out.

Use the occasion of water-soluble solvent hydrolysis such as pure series solvent, heat up in a steamer alcohol after, can carry out processing same as described above, use the occasion of non-water-soluble solvent,, remove and in organic layer, extract 2 reactive material former state separatory, beyond the 4-Er Lvyixianben, can carry out and above-mentioned same processing.

In addition, reactive material is carried out steam distillation, distillate whereby and separate 2, after the 4-Er Lvyixianben, the aqueous solution of alkali such as use aqueous sodium hydroxide solution becomes alkalescence, extracts with water-insoluble solvent again, by organic layer concentrating under reduced pressure, can take out 1-(2,4 dichloro benzene base) ethamine with gained.

In addition, the aqueous solution with alkali such as aqueous sodium hydroxide solutions makes reactive material become alkalescence, extract with water-insoluble solvent again, obtain 2, the mixture of 4-Er Lvyixianben and 1-(2,4 dichloro benzene base) ethamine is by using the separation means of usual method to it, for example separation means such as chromatography can make both separate.2 of institute's Separation and Recovery, the 4-Er Lvyixianben can recirculation.

According to the present invention, useless opticity 1-(2,4 dichloro benzene base) ethamine, N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine via opticity, can make useful racemization 1-(2,4 dichloro benzene base) ethamine whereby easily and expeditiously.

As the manufacture method of chlorine substituted benzene alkyl amine [II], in the chlorine substituted benzene alkyl ketone of correspondence, known have an ammonia and hydrogen method (spy opens clear 2-73042) in the reaction of 120 normal atmosphere under the Raney nickel catalyst that chalcogenide compound is poisoned that makes.

But in this method,, also there is the subsidiary problem that forms reductive alcohol body of raw ketone except because of must high pressure causing the problem on the equipment.

The inventor obtains following result after deliberation: for the chlorine substituted benzene alkyl amine [II] that uses among the present invention can industrially more advantageously be made, use its oxime acetate salt, if at specific solvent, catalyzer, be that organic acid solvent, platinum catalyst exist down and make its shortening, though then under low pressure with can also high recovery rate and the mode of the pure body of subsidiary hardly generation make chlorine substituted benzene alkyl amine [II] effectively.

Below explanation is by will be with general formula [I]

(R in the formula ₁The expression low alkyl group, R ₂Expression hydrogen atom or chlorine atom.) the chlorine substituted benzene alkyl ketoxime acetate class of expression, under organic acid solvent, platinum catalyst, carry out shortening, make with general formula [II]

(R in the formula ₁, R ₂Represent connotation same as described above)

The method of the chlorine substituted benzene alkyl amine of expression.

In this process, as the R in the employed chlorine substituted benzene alkyl ketoxime acetate salt [I] ₁, for example can enumerate low alkyl groups such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, amyl group.

As R ₂, for example can enumerate hydrogen atom, chlorine atom.

Concrete compound as acetate salt [I], for example can enumerate 2 '-chloro-acetophenone, 3 '-chloro-acetophenone, 4 '-chloro-acetophenone, 2 ', 3 '-Er Lvyixianben, 2 ', 4 '-Er Lvyixianben, 2 ', 5 '-Er Lvyixianben, 3 ', 4 '-Er Lvyixianben, 3 ', 5 '-Er Lvyixianben, 2 '-chlorobenzene ethyl ketone, 3 '-chlorobenzene ethyl ketone, 4 '-chlorobenzene ethyl ketone, 2 ', 3 '-the dichlorobenzene ethyl ketone, 2 ', 4 '-the dichlorobenzene ethyl ketone, 2 ', 5 '-the dichlorobenzene ethyl ketone, 3 ', 4 '-the dichlorobenzene ethyl ketone, 3 ', 5 '-the dichlorobenzene ethyl ketone, 2 '-chloro-phenyl--nezukone, 3 '-chloro-phenyl--nezukone, 4 '-chloro-phenyl--nezukone, 2 ', 3 '-dichlorophenyl-nezukone, 2 ', 4 '-dichlorophenyl-nezukone, 2 ', 5 '-dichlorophenyl-nezukone, 3 ', 4 '-dichlorophenyl-nezukone, 3 ', 5 '-dichlorophenyl-nezukone, 2 '-chloro-phenyl--n-propyl ketone, 3 '-chloro-phenyl--n-propyl ketone, 4 '-chloro-phenyl--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 '-the chloro-phenyl-amyl ketone, 3 '-the chloro-phenyl-amyl ketone, 4 '-the chloro-phenyl-amyl ketone, 2 ', 3 '-the dichlorophenyl amyl ketone, 2 ', 4 '-the dichlorophenyl amyl ketone, 2 ', 5 '-the dichlorophenyl amyl ketone, 3 ', 4 '-the dichlorophenyl amyl ketone, 3 ', 5 '-oxime acetate salts such as dichlorophenyl amyl ketone.

Acetate salt [I] for example can be according to Organic Synthesis Collective Vol.6, and the method for 278 records is easily made, even azanol and acid and salt action are promptly used the chlorine substituted benzene alkyl ketone of general formula [IV] expression in the ketone of correspondence,

Be derivatized to the ketoxime class whereby, promptly use the chlorine substituted benzene alkyl ketoxime class of general formula [III] expression,

Acidylate the agent effect then and carry out the acetate salinization.

Wherein at the salt action that makes azanol and acid in the middle of ketone [IV], as the salt of employed azanol and acid, for example can enumerate the salt of hydrochloride, vitriol, phosphoric acid salt etc. and mineral acid.Its usage quantity is generally 1-1.1 doubly with respect to ketone [IV] by mole.

Reaction is implemented under solvent usually.As such solvent, for example can enumerate the mixture of water and methyl alcohol, ethanol etc. and the pure series solvent of water dissolubility, mixture of water and hexane, pentane, toluene, methylene dichloride, ethylene dichloride, methyl tertiary butyl ether etc. and the solvent of the immiscible property of water etc.In the latter's occasion, move and use catalyzer by alternate, reaction is carried out more reposefully.The usage quantity of solvent is 1-10 doubly (weight) with respect to ketone [IV].

Reaction is also at room temperature carried out, but also can promote reaction by being heated to 50～60 ℃.Along with the mineral acid generation of carrying out of reacting dissociates, but can or use the aqueous solution of alkali such as sodium hydroxide, yellow soda ash, ammonia to neutralize in reaction after the reaction.The ketoxime class [III] that is generated, for example, can desolvate by heating up in a steamer in the occasion that obtains with crystallized form, with gained crystallization water etc. clean, dry and emanate, and be dissolved in the occasion of organic layer, also can be by making the organic layer separatory, wash, heating up in a steamer to desolvate and emanate.

Acidylating agent when acting on ketoxime class [III] and carrying out the acetate salinization, as acylating agent, can enumerate diacetyl oxide, acetate halogenide such as acetate muriate, acetate bromide etc.The acylating agent consumption is with respect to ketoxime class [III], is generally 1-1.1 doubly by mole, but do not emanating acetate salt [I] and the occasion of former state shortening, and preferable use range is counted 1-1.05 doubly by mole, can suppress the object by-product whereby and go out acid amides.

Reaction is implemented under solvent usually.As such solvent, for example can enumerate organic carboxyl acids such as formic acid, acetate, propionic acid, hexane, pentane, toluene, methylene dichloride, ethylene dichloride, methyl tertiary butyl ether etc.Its usage quantity is generally 1-10 doubly (weight) with respect to ketoxime class [III].Temperature of reaction is generally the boiling point of 20 ℃～solvent, is preferably the boiling point of 50 ℃～solvent.

After the reaction, acetate salt [I] for example can desolvate and superfluous acylating agent etc. is obtained by heating up in a steamer.As solvent, in the occasion of using the organic carboxyl acid class, but also former state is carried out catalytic hydrogenation reaction in addition.

The present invention carries out shortening as feature with acetate salt [I] under organic acid solvent and platinum catalyst, though be not particularly limited as platinum catalyst, use usually and upload the platinum catalyst of holding at carriers such as carbon, silica gel, aluminum oxide.

The consumption of platinum catalyst with respect to acetate salt [I], is generally 0.05-1% (weight) by the metal conversion, comes 0.1-0.2% (weight) than debt.

As organic carboxylic carboxylic that solvent uses, for example can enumerate formic acid, acetate, propionic acid, their low-grade carboxylic acid's classes such as mixture.Be good wherein to use acetate.

The consumption of organic carboxyl acid is 1-100 doubly (weight) with respect to acetate salt [I], is preferably 5-10 doubly (weight).

Catalytic hydrogenation reaction is usually at 10～50 ℃, preferable 20～40 ℃ of enforcements down.When surpassing 50 ℃, the generation of by products such as dipolymer, ketoboidies has the tendency of increase, therefore be embodied as below 50 ℃ good.

The pressure of hydrogen is generally 5kg/cm ²More than the G, be preferably 5-50kg/cm ²Even G is but at 5-30kg/cm ²Reaction also can fully be carried out during G.At not enough 5kg/cm ²During G, react slack-off, the generation of by products such as dipolymer, acid amides body has the tendency of increasing, therefore at 5kg/cm ²Be embodied as good more than the G.

So just generate amine [II], but after reaction ends, for example catalyst separating can be heated up in a steamer organic carboxyl acid then, with the aqueous solution neutralization of alkali such as caustic soda, use organic solvent extraction again, again organic solvent is heated up in a steamer, take out object whereby as object.Also can make with extra care according to necessity by applying refining means such as distillation, recrystallize.

In addition, but the catalyzer of institute's Separation and Recovery also recirculation use.

According to method of the present invention, even under low pressure also can make 1-chlorine substituted benzene alkyl amine [II] effectively with the high recovery rate and the mode of by-product alcohol body hardly as object.

Raw material 1-phenyl-ethyl amine of the present invention can pass through N-formyl radical-1-arylmethyl amine [VI]

RArCH-NH-CHO [VI]

(R represents that low alkyl group also has substituent aryl sometimes or also has substituent aralkyl sometimes in the formula, and Ar represents also to have sometimes substituent aryl.)

Hydrolysis and obtaining, the past is also known to making N-formyl radical-(for example J.AM.Chem.Soc.Vol.58,1808 (1936)) such as 1-phenyl-ethyl amines by the blend heated method that phenyl methyl ketone, ammonium formiate, formic acid are formed.But can not satisfy the recovery rate of object with this method.

Therefore study, found that, N-formyl radical-1-arylmethyl amine [VI] can be made by the high recovery rate of following method ground, promptly injects simultaneously in methane amide and/or ammonium formiate by general formula [V] (formula, R, Ar represent implication same as described above)

RArC＝0 [V]

The aryl ketones and the formic acid of expression.

Below describe this process in detail.

As used herein in the aryl ketones, R represents low alkyl group, also has a substituent aryl or also have substituent aralkyl sometimes sometimes, but, for example can enumerate methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group etc. as low alkyl group.

As also having substituent aryl sometimes, for example can enumerate except that phenyl, naphthyl, also can enumerate by halogen atom, nitros such as fluorine, chlorine, bromines, with aforementioned same low alkyl group, lower halogenated bases such as two fluoro methyl, three fluoro methyl, lower alkoxies such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, the phenyl that elementary halogenated alkoxies such as two fluoro methoxyl groups, three fluoro methoxyl groups etc. replace, naphthyl etc.As also having substituent aralkyl sometimes, for example can enumerate except that benzyl, naphthyl methyl, also can enumerate by halogen atoms such as fluorine, chlorine, bromines, nitro, with aforementioned same low alkyl group, lower halogenated bases such as two fluoro methyl, three fluoro methyl, lower alkoxies such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, the benzyl that elementary halogenated alkoxies such as two fluoro methoxyl groups, three fluoro methoxyl groups etc. replace, menaphthyl etc.

As Ar, can enumerate and have and substituent aryl such as above-mentioned same halogen atom, nitro, low alkyl group, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy etc.

Representation compound as aryl ketones [V], for example can enumerate methyl phenyl ketone, the 2-chloro-acetophenone, 3 '-chloro-acetophenone, 4 '-chloro-acetophenone, 4 '-the fluorobenzene ethyl ketone, 4 '-bromoacetophenone, 2 ', 3 '-dichloroacetophenone, 2 ', 4 '-dichloroacetophenone, 2 ', 5 '-dichloroacetophenone, 2 ', 6 '-dichloroacetophenone, 3 ', 4 '-dichloroacetophenone, 3 ', 5 '-dichloroacetophenone, 3 ', 4 '-the dibromo-benzene ethyl ketone, 2 '-nitro-acetophenone, 3 '-nitro-acetophenone, 4 '-nitro-acetophenone, 2 '-trifluoromethyl acetophenone, 3 '-trifluoromethyl acetophenone, 4 '-trifluoromethyl acetophenone, 2 '-methoxyacetophenone, 3 '-methoxyacetophenone, 4 '-methoxyacetophenone, 2 '-the trifluoromethoxy methyl phenyl ketone, 3 '-the trifluoromethoxy methyl phenyl ketone, 4 '-the trifluoromethoxy methyl phenyl ketone, 2 ', 4 '-dimethoxy-acetophenone, Propiophenone, 2 '-the chloro-phenyl-ethyl ketone, 3 '-the chloro-phenyl-ethyl ketone, 4 '-the chloro-phenyl-ethyl ketone, phenylpropyl ketone, 2 '-chloro-phenyl--isopropyl acetone, 3 '-chloro-phenyl--isopropyl acetone, 4 '-chloro-phenyl--isopropyl acetone, 2 '-chloro-phenyl--positive acetone, 3 '-the chloro-phenyl-pentanone, 2 '-methyl acetophenone, 2 '-chloro-4 '-the trifluoro-benzene ethyl ketone, 2 '-methoxyl group-4 '-bromoacetophenone, 2 '-nitrophenyl-isobutyl ketone, 4 '-tolyl acetone, benzophenone, 4 '-chlorobenzophenone, the benzyl phenyl ketone, 4 '-the methyl-benzyl phenyl ketone, 1-methyl naphthalenone, 2-methyl naphthalenone etc.

Raw material methane amide of the present invention in addition, ammonium formiate both can use commercially available product, also can use the manufacture of formic acid and ammoniacal liquor or ammonia gas react.Its usage quantity is generally 1-10 doubly by the nitrogen conversion in mole with respect to aryl ketones [V], is preferably 2-4 doubly.

The usage quantity of formic acid is generally 0.1-10 doubly with respect to aryl ketones [V] by mole, is preferably 0.5-5 doubly, is more preferred from 0.7-4 doubly.Even moisture or ammonium formiate etc. also can use in the formic acid.

The present invention is to be feature to inject aryl ketones [V] and formic acid simultaneously in methane amide and/or ammonium formiate, but with aryl ketones [V] and formic acid add respectively in methane amide and/or the ammonium formiate also can, both are mixed adding also can.

Temperature of reaction is generally 150～200 ℃, is preferably 155～175 ℃, also depends on the scale of manufacturing etc., but aryl ketones [V] and formic acid injected in 0.5-10 hour usually simultaneously.After injecting simultaneously, carry out, continue usually to stir 1-10 hour for reacting fully.

Wherein the ammonia that is generated by reaction system is caught with formic acid, is recycled in the reaction system and/or in following secondary response as ammonium formiate and uses to good.Can seek effective utilization of secondary ammonifying gas whereby, also can cut down the usage quantity of ammonium formate.

For example as concurrently injected formic acid, formic acid at the ammonium formiate that will contain the generation of formic acid absorption ammonia is recycled to the occasion of using in the reaction system, for the amount of the aryl ketones [V] that injects with respect to time per unit, be recycled to the amount of formic acid of ammonia recovery tower, be generally 10-100 doubly by mole, and be recycled to the amount of formic acid that reclaims in the liquid reaction system, then be generally 0.1-10 doubly by mole, be preferably 0.5-5 doubly, be more preferred from 0.7-4 doubly.

Having, lead to the pipe arrangement of ammonia recovery tower, is good 80～120 ℃ of insulations usually, can prevent volatile salt whereby attached on the wall, and the rate of recovery of ammonia is improved.

So just generated N-formyl radical-1-arylmethyl amine [IV], but after reaction ends, heated up in a steamer low boiling point component, can obtain object whereby by reactive material as object.

Also can make with extra care by necessity by applying refining means such as distillation, recrystallize.The low boiling point component that is reclaimed contains methane amide etc. and can reuse.

Resulting N-formyl radical-1-arylmethyl amine [IV] uses hydrolysis such as hydrochloric acid, sulfuric acid, can easily derive 1-aryl methylamine class whereby.

According to method of the present invention,, just can make to high recovery rate N-formyl radical-1-aryl methylamine class as object by in methane amide and/or ammonium formiate, injecting this easy operation of aryl ketones [V] and formic acid simultaneously.

The following grade according to embodiment is described more specifically the present invention, but the invention is not restricted to these

Embodiment.

Embodiment 1-9

(method A)

In the four-hole boiling flask that disposes PVC Network リ エ ウ type rectifying tower, thermometer and machine mixer, add the C of (RS)-alpha-cyano-tert.-butylacetic acid of specified amount ₂-C ₄Alkyl ester and 1-(2,4 dichloro benzene base) ethamine.Be warming up to after 180 ℃, one side distillate the alcohol that is generated at 180-190 ℃, Yi Bian carry out 5-10 hour reaction.Reaction end of a period postcooling is to room temperature, and the crystallization that leaching again generated is cleaned twice with normal hexane.By with gained crystallization drying under reduced pressure, obtain the compound 1 of demand.

(method B)

In the four-hole boiling flask of the rectifying tower that filling spiral thing is housed (20cm), thermometer and machine mixer, add the C of (RS)-alpha-cyano-tert.-butylacetic acid of specified amount ₂-C ₄Alkyl ester and 1-(2,4 dichloro benzene base) ethamine adds specified solvent 50ml again.Heat this solution, Yi Bian the alcohol and solvent that is generated is distillated together, (about 30ml) carries out 8-20 hour backflow on one side.Reaction end of a period postcooling is to room temperature, and washcoated twice of normal hexane used in adding 50ml normal hexane, the crystallization that leaching again generated.With the crystallization drying under reduced pressure of gained, obtain required compound 1.

Recovery rate with compound 1 (racemic modification) is shown in table 1 respectively, and the recovery rate of compound 1a (optically active form) is listed in table 2.

As with reference to comparative example, in aforesaid method A or method B, replace the C of alpha-cyano-tert.-butylacetic acid with the methyl esters of alpha-cyano-tert.-butylacetic acid in addition ₂-C ₄Alkyl ester, the example under this occasion also is shown in table 1.

[table 1]

Embodiment	Method	R *1	CYBR *2 (g)	DCEA *3 (g)	Solvent (g)	Acquisition amount (g)	Recovery rate (CYBR relatively)	Diastereomer compares X/Y *4
									1	A	Et	20.0	23.6	Do not have	34.6	93.5％	88/22
2	B	Et	20.0	27.0	Dimethylbenzene	35.8	96.7％	67/33
									3	A	Bu	19.7	20.0	Do not have	28.8	90.8％	63/37
	B	Et	20.0	27.7	Isopropyl benzene	34.3	92.7％	52/48
									With reference to Comparative examples A	A	Me	20.0	28.2	Do not have	22.6	56.0％	79/21
With reference to comparative example B	B	Me	20.0	36.8	Dimethylbenzene	26.3	65.2％	71/29

* the alkyl of 1. (RS)-alpha-cyano-tert.-butylacetic acid alkyl ester (Me.Et.Bu represents methyl, ethyl, normal-butyl respectively).

* 2. (RS)-alpha-cyano-uncle's guanidine-acetic acid alkyl ester.

* 3. (RS)-1-(2,4 dichloro benzene base) ethamine.

* the area relative method of 4. usefulness high speed liquid chromatography analyses is calculated ratio.

[analysis condition of high speed liquid chromatography (HPLC) is as follows:

Device: the L-6200 of Hitachi

Post: SUMIPAX YMC-GEL SIL 120A

(5 μ m, diameter 4mm * length 25cm)

Mobile phase: normal hexane/ethanol/three fluoro acetate=240: 10: 1

Detect: UV254nm]

[table 2]

Embodiment	Method	R *1	CYBR *2 (g)	DCEA *3 (g)	Solvent	Quantities received (g)	Recovery rate (CBR relatively)	Diastereomer compares X1/Y2 *4
									5 *13	B	Et	20.0	27.0 *5	Dimethylbenzene	35.3	95.4％	50/50 *8
6	A	Et	20.0	23.6 *5	Do not have	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	Do not have	33.8	91.3％	46/46 *11
									9	A	Et	17.0	20.0 *7	Do not have	27.2	86.7％	44/44 *12

* the alkyl of 1. (RS)-alpha-cyano-tert.-butylacetic acid alkyl ester (Et.Bu represents ethyl, normal-butyl respectively)

* 2. (RS)-alpha-cyano-tertiary butyl guanidine-acetic acid alkyl ester.

* the 3. opticity 1-that in (R)-body, are rich in (2,4 dichloro benzene base) ethamine

* the area relative method of 4. usefulness high speed liquid chromatography analyses is calculated ratio

[analysis condition of high speed liquid chromatography (HPLC) is as follows:

Device: the L-6200 of Hitachi

Post: SUMIPAX YMC-GEL SIL120A+SUMICHIRAL OA-4700 (5 μ m, diameter 4mm * length 25cm) (5 μ m, diameter 4.6mm * length 25cm)

Mobile phase: normal hexane/ethanol/three fluoro acetate=240: 10: 1

Detect: UV254nm

* 5. use above (R)-1-(2,4 dichloro benzene base) ethamine of optical purity 99.8%ee

* 6. (R)-1-(2,4 dichloro benzene base) ethamine that use optical purity 84%ee

* 7. use above (R)-1-(2,4 dichloro benzene base) ethamine of optical purity 76%ee

*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

* the physics value of 13. The compounds of this invention that obtained by embodiment 5 is as follows:

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

Embodiment 10

In the four-hole boiling flask that is equipped with PVC Network リ ュ ウ rectifying tower, thermometer and machine mixer, pack into (RS)-alpha-cyano-tert.-butylacetic acid ethyl ester 17.95g (0.105 mole), be warmed up to 190 ℃.Under uniform temp with two hours to wherein splashing into (R)-1-(2,4 dichloro benzene base) ethamine (optical purity 92.4%ee) 20.0g (0.105 mole).The alcohol that will generate on one side down in uniform temp distillates again, Yi Bian carry out 17 hours reaction.Reaction is cooled to 140～150 ℃ with reactive material after ending, again to its filling mono chloro benzene 91.9g.Then this solution is cooled to 80～90 ℃, and under uniform temp, is incubated.On the other hand, to be equipped with thermometer, make the water 215g that packs in another four-hole boiling flask of condensing coil prolong of distillate and machine mixer, 35% aqueous hydrochloric acid 1.14g and crystal seed 0.03g, after being warmed up to 97～100 ℃, under uniform temp with time of 2 hours 15 minutes to wherein splashing into above-mentioned mono chloro benzene solution (in 80 ℃ of insulations).Make water and mono chloro benzene azeotropic, roughly when heating up in a steamer mono chloro benzene, separate out the crystallization of compound 1a, obtain the water slurry body of compound 1a.This water slurry body and function was cooled to after 25 ℃ in 2 hours, stirred 30 minutes down in uniform temp.The leaching crystallization is with 100ml water washing 1 time.With gained crystallization drying under reduced pressure, obtain compound 1a 30.0g.(yield 91,2%, optically active isomer than X1 body: X2 body: Y1 body: Y2 body=47.2: 1.9: 1.8: 49.1)

Test example 1

Each optically active isomer (X1 body, X2 body, Y1 body and Y2 body) of racemic compound 1 is got, made with extra care by the high speed liquid chromatography branch with following method, it is prevented and kill off the active investigation result of Plant diseases (blight) be summarized in table 3.

(1) HPLC divides the condition of getting as follows:

Device: the L-6200 of Hitachi

Post: SUMIPAX YMC-GEL SIL 120A+SUMICHIRAL OA-4700 (5 μ m, diameter 4mm * length 25cm) (5 μ m, diameter 4.6mm * length 25cm)

Mobile layer: normal hexane/ethanol/three fluoro acetate=240: 10: 1

Detect: UV254nm]

Stripping X1, X2, Y1, Y2 in order.Absolute structure is separately resolved decision by X1 body and Y body (Y1+Y2) X line structure separately in addition

(2) test example

Sandy loam is packed in the plastic box, and sowing oryza plant (No. 33, nearly Ji) was cultivated 20 days in the greenhouse.Be modulated into the reagent agent (50 parts of compounds, 3 parts of wooden calcium sulfonates, 2 parts of Sodium Lauryl Sulphate BP/USPs and 45 parts of pulverizing mixing well of synthetic oxidizing aqueous silicon are obtained) of wettable powder then, the medicament of this confession test is diluted with water to the concentration of regulation, it is made fully on the blade face attached to this oryza plant to scattering on the cauline leaf.After scattering that plant is air-dry, spore suspension, the inoculation of the Pyricularia oryzae of spraying again.Left standstill 4 days under 28 ℃ of black dull many wet conditions the inoculation back, investigates it then and prevent and kill off effectiveness.

The evaluation method of preventing and kill off effectiveness is: the morbidity state of the test plant that detects by an unaided eye during investigation, be the degree of the flora located such as leaf, stem, scab and be divided into 6 grades: distinguish be decided to be " 5 " that misknow flora, scab fully, recognize be decided to be " 4 " of 10% degree, recognize be decided to be " 3 " of 30% degree, recognize be decided to be " 2 " of 50% degree, recognize be decided to be " 1 " of 70% degree, below it, can not recognize and not test (N.T.) compound situation under morbidity state between being decided to be of difference " 0 ", represent with 5,4,3,2,1,0 respectively.

[table 3]

Concentration (ppm)	Prevent and kill off effectiveness
								X1 (R，R) *	X2 (S，S) *	Y1 (R，S) *	Y2 (S，R) *	X1+Y2 (1∶1)	Racemic modification (1: 1: 1: 1)	Pay La Saite (commercially available medicament)
	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 representing each asymmetric carbon by the order of (sour side, amine side).

The manufacturing of embodiment 11 alpha-cyanos-tert.-butylacetic acid ethyl ester

Be modulated into methylmagnesium-chloride solution by methyl chloride 119g, magnesium 49.6g and THF509g, under 35～40 ℃, add cupric iodide (I) 6.0g to this solution, under uniform temp, be dissolved in the solution that forms in the 480g toluene to wherein splashing into 2-cyano group-3-methyl-2-butene acetoacetic ester 240g then with about 1 hour.After splashing into end, the regeneration uniform temp reacted 1 hour down.Reaction mixture is cooled to 20～30 ℃, under 10～20 ℃, injects among the 20% ammonium chloride water of 1742g then.Under room temperature, leave standstill, after the separatory, water layer with 480ml ethyl acetate extraction 2 times, merged organic layer, and with 480g saturated common salt water washing 2 times.After making the organic layer drying with anhydrous magnesium sulfate, concentrating under reduced pressure, (boiling point 80～86 ℃/12～15mmHg) of main distillate fraction obtains object with the distillation of residue former state.The yield of the alpha-cyano after the distillation-tert.-butylacetic acid ethyl ester is 249g, and yield is 94%.

In above-mentioned Production Example, except the kind or amount of replacing catalyzer, by reacting equally, its result gathers and is shown in Table 4.Yield in the table is represented the ratio with respect to the alkyl ester of 2-cyano group-3-methyl-2-butene acid in addition.

[table 4]

Embodiment	Reaction solvent THF: toluene	Catalyzer (parts by weight) *2	The raw material alkyl *3	Reaction times (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
						With reference to comparative example 1	1∶1 *1	Do not have	Ethyl	1	60
With reference to comparative example 2	THF only	Do not have	Methyl	2.5	35

* 1. weight ratios

* the catalytic amount (parts by weight) of the lower alkyl esters of 2. raw material 2-cyano group-3-methyl-2-butene acid with respect to 1 parts by weight.

* the alkyl of the lower alkyl esters of 3. raw material 2-cyano group-3-methyl-2-butene acid.

* 4. the distillation after yield.

The Production Example of raw material below is shown.In addition, reactivity is the value of obtaining with following formula.

The area ratio of the alkyl ester of the cyanoacetic acid that reactivity=100-is remaining (%)

The analysis condition of vapor-phase chromatography (GC): pool, island GC-7A,

Post: 10%DEXSIL 300GC diameter 3mm * length 1m UNIPORTHP100～200 orders

Column temperature: press 5 ℃ of/minute intensifications by 70 ° to 150 ℃

The manufacturing of embodiment 172-cyano group-3-methyl-2-butene acetoacetic ester

Pack into ethyl cyanacetate 50.0g, acetone 51.34g, acetate 1.99g, p-aminophenol 0.24g and normal hexane 41ml, with azeotropic remove the water that in dereaction generates on one side, reflux is 9 hours on one side.When using gc analysis, the reactivity of ethyl cyanacetate is 99%.Reaction solution concentrating under reduced pressure after reaction ended is removed hexane, acetate and unreacted acetone, then with residue under the decompression of 20mmHg, use the rectifying tower distillation of the 30cm that is filled with the spiral thing, divide and get 110～113 ℃ cut.The yield of the 2-cyano group after the distillation-3-methyl-2-butene acetoacetic ester is 63.6g, and yield is 94%.

In above-mentioned Production Example, except the alkyl kind of the alkyl ester of the kind of the kind of replacing reaction solvent, catalyzer, cyanoacetic acid or the reaction times, react in the same way, the results are summarized in the table 5.Yield in the table is represented the ratio with respect to the alkyl ester of cyano group second acetate in addition.

[table 5]

Embodiment	Reaction solvent hexane: toluene	Catalyzer	R *1	Reaction times (hr)	Reactivity (%)	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
							21	Hexane only	D *7	Et	10	99	95
22	2∶1		Et	10	99	92
							With reference to comparative example	Toluene only	A *4	Et	30	80	63

* the alkyl of the lower alkyl esters of 1. raw material cyanoacetic acids.(Et, Me, Bu represent ethyl, methyl, normal-butyl respectively.)

* 2. the distillation after yield

* 3. weight ratios

* 4.A: p-aminophenol and acetate

* 5.B: para-totuidine and acetate

* 6.C: p-aminophenol and phenylformic acid

* 7.D: p-aminophenol and propionic acid

Below record and narrate the embodiment of the optical resolution of 1-(2,4 dichloro benzene base) ethamine.Yi Xia % all represents weight % in addition.

In addition, the optical purity (ee:enautiomericexcess) of 1-(2,4 dichloro benzene base) ethamine uses the opticity post to obtain by the high speed liquid chromatography (HPLC) with following condition.

HPLC condition: post: SUMICHIRAL OA-4100

(diameter 6 μ m * length 25cm)

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

Detect: UV254nm

In addition, opticity 1-(2, the 4-dichlorophenyl) absolute configuration of ethamine (R or S) determines by the following method: the method for opening flat 2-76846 communique record with the spy, R-(+)-1-(2 that the inventive method is obtained, the 4-dichlorophenyl) ethamine (99.9%ee) and (RS)-alpha-cyano-tert.-butylacetic acid reaction, the non-enantiomer mixture that obtains is separated, steric isomer ((R)-N-[1-(2 to obtaining again, the 4-dichlorophenyl) ethyl]-(R)-2-cyano group-3, and the 3-butane amide]) carry out the X line structure and resolve.

Embodiment 23

With L-aspartic acid (the reagent select quality of Wako Pure Chemical Industries, Ltd.: chemical purity＞99.0%, [α] D=+24.9～+ 25.8 °) 53.24g and (RS)-1-(2, the 4-dichlorophenyl) ethamine 76.5g adds in the mixed solution of 2.8 liters of 1.2 liters of entry and 95% ethanol, and under agitation reflux is 1 hour.While stirring this solution with its air cooling to 40 ℃, water-cooled to 20 ℃ again.Stirred 30 minutes down in 20 ℃, take out the crystallization that generates, with cold ethanol 100ml washing.Dry gained crystallization obtains white (+)-1-(2,4 dichloro benzene base) the ethylamine L-aspartate of 27.8 grams.This crystallization is dissolved in the 100ml 20%NaOH aqueous solution, with 100ml toluene extraction free amine.With the toluene layer anhydrous magnesium sulfate drying that obtains, concentrate with vaporizer then, obtain required (R)-(+)-1-(2,4 dichloro benzene base) ethamine 19.2g.Optical purity is 87%ee.

Embodiment 24

With L-aspartic acid (the reagent select quality of Wako Pure Chemical Industries, Ltd.'s system: chemical purity＞99.0%, [α] _n=+24.9～+ 25.8 °) 13.31g and (RS)-1-(2,4 dichloro benzene base) ethamine 38.14g adds in 150ml water and the 200ml95% alcoholic acid mixed solution, and under agitation reflux is 1 hour.While stirring this solution air cooling to 40 ℃, water-cooled to 20 ℃ again.In 20 ℃ of maintenances 30 minutes, take out the crystallization that is generated, with cold ethanol 50ml washing.Obtain 14.2g white (+)-1-(2,4 dichloro benzene base) ethamine L-aspartate after the dry gained crystallization.This crystallization is dissolved in the 50ml 20%NaOH aqueous solution, with 100ml toluene extraction free amine.With the toluene layer anhydrous magnesium sulfate drying of gained, concentrate with vaporizer then, obtain (R)-(+)-1-(2,4 dichloro benzene base) ethamine 8.3g of demand.Optical purity is 91%ee.

Embodiment 25

With L-aspartic acid (the reagent superfine of Wako Pure Chemical Industries, Ltd.'s system: chemical purity＞99.0%, [α] _D=+24.9～+ 25.8 °) 66.6g and (RS)-1-(2,4 dichloro benzene base) ethamine 190.07g adds in the mixed solution of 1 liter of 1 liter of entry and methyl alcohol, and under agitation reflux is 1 hour.While stirring this solution air cooling to 40 ℃, water-cooled to 20 ℃ again.Stirred 30 minutes down at 20 ℃, take out the crystallization that generates, with the washing of 100ml cold methanol.The crystallization of dry gained obtains 67.35g white (+)-1-(2,4 dichloro benzene base) ethamine L-aspartate.This crystallization is dissolved in the 200ml 20%NaOH aqueous solution, with 200ml toluene extraction free amine.With the toluene layer of the bright dry gained of anhydrous slufuric acid, concentrate with vaporizer then, obtain required (R)-(+)-1-(2,4 dichloro benzene base) ethamine 39.6g.Optical purity is 92%ee.

Embodiment 26

With L-aspartic acid (the reagent superfine of Wako Pure Chemical Industries, Ltd.'s system: chemical purity＞99.0%, [α] _D=+24.9～25.8 °) 10.7g and (RS)-1-(2,4 dichloro benzene base) ethamine 15.0g adds in the 200ml water, refluxed 1 hour in stirring heating.While stirring this solution air cooling to 45 ℃, roughly be cooled to 5 ℃ equably with 3 hours.Take out the crystallization of gained, with cold water 30ml washing 2 times.With the crystallizing and drying that obtains, obtain 3.7g white (+)-1-(2,4 dichloro benzene base) ethamine L aspartate.This crystallization is dissolved in the 10ml20%NaOH aqueous solution, again with 50ml toluene extraction free amine.With the toluene layer anhydrous magnesium sulfate drying of gained, concentrate with vaporizer then, obtain required (R)-(+)-1-(2,4 dichloro benzene base) ethamine 2.15g.Optical purity is 87%ee.

Embodiment 27

With L-aspartic acid (the reagent select quality of Wako Pure Chemical Industries, Ltd.'s system: chemical purity＞99.0%, [α] _D=+24.9～+ 25.8 °) 53.24g and (RS)-1-(2,4 dichloro benzene base) ethamine 76.5g adds in the mixed solution of 2.8 liters of 1.2 liters of entry and 95% ethanol, in stirring time reflux 1 hour.While stirring this solution air cooling to 40 ℃, water-cooled to 20 ℃ again.In 23 ℃ of stirrings 30 minutes, take out the crystallization that generates, with the cold washing with alcohol of 100ml.The crystallization of dry gained, (+)-1-(2,4 dichloro benzene base) ethamine L-aspartate of acquisition 25.6g white.Make this crystallization recrystallize with 50% aqueous ethanolic solution 200ml, obtain 20.4g (+)-1-(2,4 dichloro benzene base) ethamine L asparagus fern amino acid salt whereby.Again this crystallization is dissolved in the 100ml20%NaOH aqueous solution, again with 100ml toluene extraction free amine.With the toluene layer of anhydrous magnesium sulfate drying gained, concentrate with vaporizer then, obtain required (R)-(+)-1-(2,4 dichloro benzene base) ethamine 11.9g.Optical purity is 99.9%ee.Specific rotatory power is [α] _D ²⁵=+44.86 ° (C=1.114).

Embodiment 28

With D-aspartic acid (the reagent select quality of Wako Pure Chemical Industries, Ltd.'s system: chemical purity＞99.0%, [α] _D=-24.0～-26.0 °) 53.24g and (RS)-1-(2,4 dichloro benzene base) ethamine 76.5g adds in the mixed solution of 2.8 liters of 1.2 liters of entry and 95% ethanol, in stirring time reflux 1 hour.With this solution while stirring air cooling to 40 ℃, water-cooled to 20 ℃ again.Stirred 80 minutes down in 20 ℃, take out the crystallization that is generated, with cold ethanol 100ml washing.With the gained crystallizing and drying, obtain ethamine D-days section's propylhomoserin salt of (-)-1-(2,4 dichloro benzene base) of 27.1g white.Make this crystallization recrystallize with 50% aqueous ethanolic solution 200ml, obtain 22.1g (-)-1-(2,4 dichloro benzene base) ethamine D-aspartate.Again this crystallization is dissolved in the 100ml20%NaOH aqueous solution, with toluene 100ml extraction free amine.Use the toluene layer of anhydrous magnesium sulfate drying gained again, concentrate with vaporizer then, obtain required (S)-(-)-1-(2,4 dichloro benzene base) ethamine 11.9g.Optical purity is 99.6%ee.Specific rotatory power [α] _D ²⁴=-43.87 ° (C=1.082).

Embodiment 29

Will be by (RS)-1-(2, the 4-dichlorophenyl) solution stirring of ethamine 2g and ethanol l2ml composition is heated to 70 ℃,, stir then and naturally cool to 25 ℃ to wherein adding the solution of forming by D-mandelic acid 1.6g and ethanol 12ml with 1 fen clock time, under same temperature, stir again and placed 12 hours.Leach the crystallization of being separated out and make it dry, obtain the 1.4g diastereomeric salt.Add 20% aqueous sodium hydroxide solution 1g to this crystallization, with toluene 2ml extraction 2 times,, heat up in a steamer and desolvate then, obtain (S)-1-(2, the 3-dichlorophenyl) ethamine 0.77g with the resulting toluene layer of dried over mgso.

Analyze its optical purity by the high speed liquid chromatography of using the opticity post, the result is 91%ee.

Embodiment 30

(1) will be by (RS)-1-(2, the 4-dichlorophenyl) solution of ethamine 16g and ethanol 10ml composition is heated to 70 ℃, stir, wherein add the solution of forming by L-mandelic acid 12.8g and ethanol 40ml, be warmed up to 75 ℃ and under same temperature, stirred 30 minutes then with about 30 minutes clockwise.Then be cooled to 20 ℃, leach the crystallization of being separated out, be dried, obtain diastereomeric salt 13.2g with 5 hours.In this crystallization, add 20% aqueous sodium hydroxide solution 10g, then with toluene 20ml extraction 2 times, with the resulting organic layer of dried over mgso and heat up in a steamer and desolvate, acquisition (R)-1-(2,4 dichloro benzene base) ethamine 7.3g.Its optical purity is 82%ee.

(2) by obtaining residue 15.6g by heating up in a steamer low boiling component in the mother liquor that leaches behind the diastereomer.To wherein adding 20% aqueous sodium hydroxide solution 13g, then with toluene 30ml extraction 2 times, with the toluene layer of dried over mgso gained and heat up in a steamer and desolvate, acquisition (S)-1-(2,4 dichloro benzene base) ethamine 12.7g.Its optical purity is 70%ee.

(3) with after the residual water layer mixing after the toluene extraction in (1) and (2), it is 0.7 that the hydrochloric acid of adding 36% is adjusted its pH value.Then with the ethyl acetate extraction of 50ml 3 times,, obtain L-mandelic acid 12.3g again with dried over mgso and heat up in a steamer and desolvate.

Embodiment 31

Will be by (RS)-1-(2, the 4-dichlorophenyl) solution stirring of ethamine 16g and ethyl acetate 17ml composition is heated to 70 ℃, wherein splash into the solution of forming by L-mandelic acid 6.4g and ethyl acetate 80ml with about 30 minutes clockwise, be warming up to 75 ℃ and under same temperature, continue to stir 30 minutes then.Then be cooled to 20 ℃, leach the crystallization of being separated out then and be dried, obtain diastereomeric salt 12.9g with 5 hours.Its part press after embodiment 29 processing, and determining optical purity is 81.2%ee.

Embodiment 32

After will refluxing by the mixture heating up that (RS)-1-(2,4 dichloro benzene base) ethamine 19g and 95% ethanol 120ml and L-mandelic acid 15.2g form, one night of naturally cooling.Again the crystallization of separating out is leached, drying, obtain diastereomeric salt 10.8g.After its part press embodiment 29 processing, the optical purity that determines was 64%ee.

Embodiment 33

(1) will be by (RS)-1-(2, the 4-dichlorophenyl) solution of ethamine 90g and methyl tertiary butyl ether 167g composition is heated to 45 ℃, stir, wherein add the solution of forming by L-mandelic acid 32g and methyl tertiary butyl ether 197g with about 30 minutes clockwise again, and under same temperature, stirred 30 minutes.Then be cooled to 20 ℃, leach the crystallization of being separated out,, be dried again, obtain diastereomeric salt 84g with 42g methyl tertiary butyl ether washing secondary with 6 hours.Add 5% aqueous sodium hydroxide solution 185g to this crystallization,, the organic layer of gained with dried over mgso and heat up in a steamer and desolvate, is obtained (R)-1-(2,4 dichloro benzene base) ethamine 39.9g then with 42g methyl tertiary butyl ether extraction 2 times.Its optical purity is 95.2%ee.

(2) will leach diastereomeric salt filtrate and washing lotion afterwards and merge, wash to wherein adding 5% aqueous sodium hydroxide solution 18g.By heating up in a steamer the low boiling component of organic layer, obtain (S)-1-(2,4 dichloro benzene base) ethamine 50.1g.Its optical purity is 77.6%ee.

(3) in (1) and (2), use 5% aqueous sodium hydroxide solution that salt is decomposed, remaining water layer after separating organic layer is mixed, add 36% hydrochloric acid then the pH value is modulated to 1.4.Then with 150g methyl tertiary butyl ether extraction 3 times, with dried over mgso and heat up in a steamer and desolvate, obtain L-mandelic acid 31.7g.

Comparative example 1

In embodiment 32,15g replaces the L-mandelic acid with L-tartrate, but with 95% ethanol 120ml the time, because the tartaric crystallization remaining quantity of L-is many, so append 9% ethanol 1080ml.In addition press embodiment 32 and implement, obtain diastereomeric salt 10.8g whereby.

Its part press after embodiment 29 processing, and determining its optical purity is 36%ee.

Comparative example 2

In present embodiment 32, use oxysuccinic acid 13.4g to replace the L-mandelic acid, but with 95% ethanol 120ml the time, because the result of L MALIC ACID is remaining, so append 95% ethanol 360ml.In addition according to embodiment 32 embodiment, obtain diastereomeric salt 14.5g whereby.

Its part press after embodiment 29 processing, and determining its optical purity is 0.8%ee.

Comparative example 3

In embodiment 29, except that water 120ml replaces ethanol, implement according to embodiment 29, the result is separated into water layer and oil reservoir, does not separate out crystallization.

Embodiment 34

(1) will be warming up to 60 ℃ by the solution that D-dibenzoyl tartrate 3.95g and 95% ethanol 60ml form, to wherein adding the solution of forming by (RS)-1-(2,4 dichloro benzene base) ethamine 2g and 95% ethanol 20ml, and under same temperature, stir 5 minutes.Then stir and naturally cool to 25 ℃, under same temperature, stir again and placed 12 hours.

Leach the crystallization of being separated out, resulting thick diastereomeric salt by recrystallize in the 500ml95% ethanol, is carried out drying again, obtain diastereomeric salt 1.6g.In this crystallization, add 20% aqueous sodium hydroxide solution 1.2g, use chloroform extraction then 3 times,, heat up in a steamer and desolvate, obtain (S)-1-(2,4 dichloro benzene base) ethamine 0.66g resulting trichloromethane layer dried over mgso.

Analyze its optical purity by the high speed liquid chromatography of using the opticity post, the result is 92%ee.

(2) from the mother liquor that leaches thick diastereomeric salt, heat up in a steamer low boiling component, after in the residue of gained, adding 2.4g 20% aqueous sodium hydroxide solution, with 7.5ml chloroform extraction 3 times, trichloromethane layer with the dried over mgso gained, heat up in a steamer again and desolvate, obtain (R)-1-(2,4 dichloro benzene base) ethamine 1.15g.

Analyzing its optical purity by the high speed liquid chromatography of using the opticity post is 79%ee.

Embodiment 35

(1) will be by (RS)-1-(2, the 4-dichlorophenyl) solution of ethamine 4g and 95% ethanol 10ml composition is heated to 70 ℃, stir, wherein add the solution of forming by D-dibenzoyl tartrate 7.88g and 95% ethanol 25ml with about 60 minutes clockwise, be warming up to 80 ℃ and under uniform temp, stirred 30 minutes then.Then it is cooled to 20 ℃, and under uniform temp, continues to stir 30 minutes with 5 hours.Leach the crystallization of being separated out, make it by recrystallize in 500ml 95% ethanol, and carry out drying, obtain diastereomeric salt 3.2g.After in this crystallization, adding 20% aqueous sodium hydroxide solution 5g,,, heat up in a steamer and desolvate, obtain (S)-(2,4 dichloro benzene base) ethamine 1.32g gained organic layer dried over mgso with toluene 20ml extraction 2 times.Its optical purity is 91%ee.

(2) by heating up in a steamer low boiling component in the mother liquor that leaches behind the thick diastereomer, in the residue 6.58g of gained, add 20% aqueous sodium hydroxide solution 7g, then with toluene 20ml extraction, with this toluene layer of dried over mgso, heat up in a steamer again and desolvate, obtain (R)-1-(2,4 dichloro benzene base) ethamine 2.3g.Its optical purity is 91%ee.

(3) water layer residual after extracting toluene in (2) is mixed, with 36% hydrochloric acid the pH value is adjusted to 0.7 then.Then after wherein add salt 7g, separating out salt under 40～60 ℃, the ethyl acetate extraction of usefulness 80ml 5 times heats up in a steamer and desolvates, and obtains D-dibenzoyl tartrate 6.82g.

Embodiment 36

(1) to by (S)-1-(2, the 4-dichlorophenyl) (optically active isomer is than the 62g and 2 of S body/R body=80.3/19.7) for ethamine, add zinc chloride 0.28g in the mixture that 4-Er Lvyixianben 62g and toluene 130g form, then on one side with the water that generates except that going to system, Yi Bian refluxed 20 hours.

Then under 25 ℃, it is washed with 5% aqueous sodium hydroxide solution 10g, carry out separatory after, with the toluene layer azeotropic dehydration that obtains 4 hours, remove moisture whereby.

Get its part, use vapor-phase chromatography to analyze, calculate N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine content is 116g, unreacted 1-(2, the 4-dichlorophenyl) ethamine content is 1g, 2, and the content of 4-Er Lvyixianben is 0.5g.

(2) then under 30 ℃, in above-mentioned toluene solution after removing moisture, add the solution of forming by potassium tert.-butoxide 1.2g, dimethyl sulfoxide (DMSO) 10.1g, after under same temperature, stirring 10 hours, with 10% salt solution 233g washing 1 time, with saturated common salt water washing 2 times.

(3) in resulting toluene solution, add 5% hydrochloric acid 285g, after stirring 1 hour under 60 ℃, under same temperature, leave standstill and made its separatory in 3 minutes, obtain water layer and toluene layer.

In water layer, add toluene 194g, under 60 ℃, extract, merge, heat up in a steamer then and desolvate, obtain 2,4-Er Lvyixianben 60.7g with the toluene layer that obtains thus with by above-mentioned resulting toluene layer.

In with the water layer after the extracting toluene, add 27% aqueous sodium hydroxide solution 72g,, obtain 1-(2,4 dichloro benzene base) ethamine 61.7g through heating up in a steamer toluene then with toluene 580g extraction.

Get the latter's a part, use the high speed liquid chromatography of opticity post to analyze, its optically active isomer is than S body/R body=52.3/47.7.

Embodiment 37

In embodiment 36, replace (S)-1-(2 except using (R)-1-(2,4 dichloro benzene base) ethamine (optically active isomer is than S body/R body=1/99), the 4-dichlorophenyl) outside the ethamine, carries out, obtain 2 according to embodiment 36,4 Er Lvyixianben 59.7g and 1-(2,4 dichloro benzene base) ethamine 61g.The latter's optically active isomer is than S body/R body=45.1/54.9.

Embodiment 38

By implementing to press the reaction of embodiment 36-(1), obtain containing the toluene solution of N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine of opticity.

Then, obtain opticity N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine 111g of white crystals by heating up in a steamer toluene and unreacted raw material.E/Z=8/92, fusing 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)

Embodiment 39

In embodiment 36-(2),, all implement according to embodiment 36-(2) except using solution that the crystallization 111g that obtained by embodiment 38 and exsiccant toluene 130g form as the toluene solution.Then with behind the resulting toluene solution concentrating under reduced pressure, under 100 ℃, 20mmHg with heating up in a steamer low boiling component, racemize N-(alpha-methyl-2,4-dichloro benzal)-α-(2,4 dichloro benzene base) ethamine 110g of acquisition water white transparency oily thing in 5 hours.E/z＝8/92。

Embodiment 40

In embodiment 36-(3), except using solution that the oily matter 110g that obtained by embodiment 39 and toluene 130g form, all, obtain 2 according to embodiment 36-(3) enforcement as the toluene solution, 4-Er Lvyixianben 56.9g and 1-(2,4 dichloro benzene base) ethamine 57.8g.

The latter's optically active isomer is than S body/R body=51.9/48.1.

Embodiment 41

In embodiment 36, except replacing the zinc chloride, all implement by embodiment 36 with tetraisopropoxy titanium 0.45g, obtain 2,4-Er Lvyixianben 59.2g and 1-(2,4 dichloro benzene base) ethamine 60.8g.The latter's optically active isomer is than S body/R body=53.3/46.7.

Embodiment 42

In embodiment 36, except replacing zinc chloride, replace outside the toluene with dimethylbenzene with tosic acid 0.62g, all implement according to embodiment 36, obtain 2,4-Er Lvyixianben 59.1g and 1-(2,4 dichloro benzene base) ethamine 60.1g.The latter's optically active isomer is than S body/R body=53/47.

Comparative example 4

In embodiment 36, replace the dimethyl sulfoxide (DMSO) except using trimethyl carbinol 20g, all implement according to embodiment 36, obtain 2 whereby, 4-Er Lvyixianben 60.3g and 1-(2,4 dichloro benzene base) ethamine 61.5g.The latter's optically active isomer is than S body/R body=80.3/19.7.

Comparative example 5

Under 80 ℃ to by with embodiment 36 used identical (S)-1-(2,4 dichloro benzene base) ethamine 6g and dimethyl sulfoxide (DMSO) 9g composition mixture in add potassium tert.-butoxide 1.8g, under same temperature, continue to stir 10 hours.Behind the cool to room temperature, get its part, analyze its optically active isomer ratio by the high speed liquid chromatography of using the opticity post.Its optically active isomer is than S body/R body=80.3/19.7.

Embodiment 43

(1) manufacturing of chlorine substituted benzene alkyl ketoxime class

To 2 ', 4 '-add hydroxy amine hydrochloric acid salt 122g and water 400g in the mixture of Er Lvyixianben 300g and methyl alcohol 1200g, be warming up to 60 ℃ after, under same temperature, add 27% aqueous sodium hydroxide solution on one side and make the pH value become 4～5, continue to stir 3 hour on one side.Then adding 27% aqueous sodium hydroxide solution becomes after 8 pH, under reduced pressure heat up in a steamer anhydrate and methyl alcohol amount to 1200g, in residue, add 1200g water, be cooled to 25 ℃, filter the crystallization of being separated out, use the 1200g water washing, carry out drying, obtain 2 ', 4 '-the white crystals 322g (yield 99%) of Er Lvyixianben oxime.

Purity is 99.5%.

(2) manufacturing of chlorine substituted benzene alkyl ketoxime acetate salt

To 2 ', 4 '-add diacetyl oxide 36.4g in the mixture of Er Lvyixianben oxime 70g and normal heptane 70g, stirred 2 hours down in 70 ℃.Reactive material is taken a sample on a small quantity, use gc analysis again, find that raw material disappears.

Reactive material is cooled to 25 ℃, filters the crystallization separated out, obtain 2 ', 4 '-the white, needle-shaped crystals 60.2g of Er Lvyixianben oxime acetate.Be that 100% filtrate concentrates down in decompression with purity, more resulting residue (crystallization) washed with ice-cold normal heptane 10g that obtain white, needle-shaped crystals 22.5g, purity is 99%.

Embodiment 44

With obtain among the embodiment 43-(2) 2 ', 4 '-autoclave of Er Lvyixianben oxime acetate (purity 100%) 2g, acetate 20g, 5% platinum-charcoal (the 50% moisture product) 100ml that packs in, behind the nitrogen replacement, be warming up to 30 ℃, with pressurized with hydrogen to 20kg/cm ²G.Under same temperature, on one side hydrogen supply pressure is remained on 20kg/cm ²G is Yi Bian reacted 5 hours.

Reaction after-filtration catalyzer, the acetate in the filtrate is heated up in a steamer in decompression, adds toluene 5g in residue, with after the 5% aqueous sodium hydroxide solution 18g washing, heats up in a steamer the solvent of organic layer again, obtains 1.54g oily matter.It is used gc analysis.

1-(2 ', 4 '-dichlorophenyl) ethamine is 94.5%, N-1-(2 '; 4 '-dichlorophenyl) ethyl-α-(2 ', 4 '-dichlorophenyl) ethamine is 0.97%, N-ethanoyl-α-(2 '; 4 '-dichlorophenyl) ethanamide is 0.56%, 2 ', 4 '-Er Lvyixianben is 1%.The pure body of the compound of dechlorination and carbonyl reduction is below sensing range.

Embodiment 45

In embodiment 44, except with 4 '-chloro-acetophenone oxime acetate 2g replaces 2 ', 4 '-Er Lvyixianben oxime acetate outside, all by embodiment 44 enforcements, obtain the oily matter of 1.47g whereby.

1-(4 '-chloro-phenyl-) ethamine is 98.8%, and N-ethanoyl-α-(4 '-chloro-phenyl-) ethanamide is 0.91%, and the pure body of the compound of dechlorination and carbonyl reduction is undetected.

Embodiment 46

In embodiment 44, except with 3 ', 4 '-Er Lvyixianben oxime acetate 2g replaces 2 ', 4 '-Er Lvyixianben oxime acetate outside, all by embodiment 44 enforcements, obtain the oily matter of 1.53g whereby.

1-(3 '; 4 '-dichlorophenyl) ethamine is 89.8%; 1-(4 '-chloro-phenyl-) ethamine is 1.4%; N-1-(3 '; 4 '-dichlorophenyl) ethyl-α-(3 ', 4 '-dichlorophenyl) ethamine is 2.9%, N-ethanoyl-α-(2 '; 4 '-dichlorophenyl) ethanamide is 1.9%, do not detect the pure body of carbonyl reduction.

Embodiment 47

In embodiment 44, except with 3 ', 5 '-Er Lvyixianben oxime acetate 2g replaces 2 ', 4 '-Er Lvyixianben oxime acetate outside, all, obtain the oily matter of 1.54g with this by embodiment 44 enforcements.

1-(3 '; 5 '-dichlorophenyl) ethamine is 88.7%; 1-(3 '-chloro-phenyl-) ethamine is 2%; N-1-(3 '; 5 '-dichlorophenyl) ethyl-α-(3 ', 5 '-dichlorophenyl) ethamine is 2.9%, N-ethanoyl-α-(3 '; 5 '-dichlorophenyl) ethanamide is 2.9%, do not detect the pure body of carbonyl reduction.

Embodiment 48

To 2 ', 4 '-add diacetyl oxide 36.4g in the mixture of Er Lvyixianben oxime 70g and acetate 210g, stirred 2 hours down in 100 ℃.The reactive material that takes a morsel is made sample, uses gc analysis, finds that raw material disappears.Above-mentioned entire reaction mass, acetate 210g, 5% platinum-charcoal (50% moisture product) 3.9g are packed in the autoclave of 1000ml, are warmed up to 30 ℃ behind the nitrogen replacement, again with pressurized with hydrogen to 20kg/cm ²G.One side hydrogen supply gas makes pressure remain on 20kg/cm under same temperature ²G is Yi Bian reacted 10 hours.

Reaction after-filtration catalyzer, the acetate in the filtrate is heated up in a steamer in decompression, adds toluene 100g in residue, again with 5% aqueous sodium hydroxide solution 180g washing, heats up in a steamer the solvent of organic layer, obtains the oily matter of 65g, and it is used gc analysis.

1-(2 ', 4 '-dichlorophenyl) ethamine is 91%, 1-(4 '-chloro-phenyl-) ethamine is 2.9%; N-1-(2 ', 4 '-dichlorophenyl) ethyl-α-(2 ', 4 '-dichlorophenyl) ethamine is 1.1%; N-ethanoyl-α-(2 ', 4 '-dichlorophenyl) ethanamide is 1.5%.Do not detect the pure body of carbonyl reduction.By with its distillation, obtain purity 99% 1-(2 ', 4 '-dichlorophenyl) ethamine 58.5g.130～132 ℃/20mmHg of boiling point.

Embodiment 49

In embodiment 48, except the whole catalyzer that use 5% platinum-charcoal (50% moisture product) 0.57g and embodiment 48 recovery, all implement according to embodiment 48, obtain the oily matter of 64g with this.

1-(2 '; 4 '-dichlorophenyl) ethylamine is 89.9%; 1-(4 '-chloro-phenyl-) ethamine is 1.8%; N-1-(2 '; 4 '-dichlorophenyl) ethyl-α-(2 ', 4 '-dichlorophenyl) ethamine is 3.4%, N-ethanoyl-α-(2 '; 4 '-dichlorophenyl) ethanamide is 1.6%, do not detect the pure body of carbonyl reduction.

Embodiment 50

In embodiment 44, except pressure being remained on 5kg/cm on one side ²Outside G implements on one side, all implement, obtain the oily matter of 1.52g with this according to embodiment 44.

1-(2 '; 4 '-dichlorophenyl) ethamine is 78.2%; 1-(4 '-chloro-phenyl-) ethamine is 4.6%; N-1-(2 ', 4 '-dichlorophenyl) ethyl-α-(2 ', 4 '-dichlorophenyl) ethamine is 6.1%; N-ethanoyl-α-(2 '; 4 '-dichlorophenyl) ethanamide is 1.9%, 2 ', 4 '-Er Lvyixianben is 0.4%.Do not detect the pure body of carbonyl reduction.

Embodiment 51

In embodiment 44, except pressure being remained on 10kg/cm on one side ²Outside G implements on one side, all implement, obtain the oily matter of 1.54g with this by embodiment 44.

1-(2 '; 4 '-dichlorophenyl) ethamine is 87.2%; 1-(4 '-chloro-phenyl-) ethamine is 3.7%, N-(2 ', 4 '-dichlorophenyl) ethyl-α-(2 '; 4 '-dichlorophenyl) ethamine is 1.1%; N-ethanoyl-α-(2 ', 4 '-dichlorophenyl) ethanamide is 0.5%, 2 '; 4 '-Er Lvyixianben is 1.3%, does not detect the pure body of carbonyl reduction.

Comparative example 6

In embodiment 44, except replacing platinum-charcoal as catalyzer, and pressure is remained on 10kg/cm on one side with 5% palladium-charcoal (50% moisture product) ²G reacts outside 5 hours on one side, all implements by embodiment 44, obtains the oily matter of 1.49g with this.

1-(2 '; 4 '-dichlorophenyl) ethamine is 53.8%, and phenyl-ethyl amine is 31%, and 1-(4 '-chloro-phenyl-) ethamine is 16.9%; 1-(2 '-chloro-phenyl-) ethamine is 13.1%; N-1-(2 ', 4 '-dichlorophenyl) ethyl-α-(2 ', 4 '-dichlorophenyl) ethamine is 6.2%; N-ethanoyl-α-(2 '; 4 '-dichlorophenyl) ethanamide is 4.7%, 2 ', 4 '-Er Lvyixianben is 0.5%.

Comparative example 7

In embodiment 48, except using diacetyl oxide 40.6g and pressure being remained on 10kg/cm on one side ²G implements outside the reduction reaction on one side, all implements by embodiment 48, obtains the oily matter of 68g with this.

1-(2 '; 4 '-dichlorophenyl) ethamine is 51%; 1-(4 '-chloro-phenyl-) ethamine is 1%; N-1-(2 ', 4 '-dichlorophenyl) ethyl-α-(2 ', 4 '-dichlorophenyl) ethamine is 1.3%; N-ethanoyl-α-(2 '; 4 '-dichlorophenyl) ethanamide is 42.1%, 2 ', 4 '-Er Lvyixianben is 0.5%.

Comparative example 8

In embodiment 44, except using methyl alcohol 20g, and pressure is remained on 10kg/cm on one side as solvent ²Outside G implements on one side, all implement, obtain the oily matter of 1.52g with this by embodiment 44.1-(2 ', 4 '-dichlorophenyl) ethamine is 12%, N-1-(2 ', 4 '-dichlorophenyl) ethyl-α-(2 ', 4 '-dichlorophenyl) ethamine is 63%, N-ethanoyl-α-(2 ', 4 '-dichlorophenyl) ethanamide is 15%.

Comparative example 9

With 2 ', 4 '-Er Lvyixianben 18.9g, methyl alcohol 35g, two (2-hydroxyethyl) thioether 0.15g, ammonium acetate 0.1g, Raney nickel catalyst (50% moisture product) 1.0g add in the autoclave, behind the nitrogen replacement, add ammoniacal liquor 4.6g, with pressurized with hydrogen to 50kg/cm ²G.

Then be warmed up to after 130 ℃, arrive 80kg/cm with pressurized with hydrogen ²G, again under uniform temp, on one side hydrogen supply pressure is remained on 80kg/cm ²G is Yi Bian reacted 4 hours.Reaction after-filtration catalyzer, the low boiling component in the filtrate is heated up in a steamer in decompression, obtains the oily matter of 19.5g, with vapor-phase chromatography it is analyzed.

1-(2 ', 4 '-dichlorophenyl) ethamine is 24.8%, and 1-(4 '-chloro-phenyl-) ethamine is 53.4%, and not clear composition is 15.9%.

Embodiment 52

In the reactor that Dean-Rodney Stark separator is installed, add ammonium formiate 155.1g, be heated to after 155 ℃, under agitation each with 3 hours to wherein adding phenyl methyl ketone 98.5g and 76% formic acid 49.6g, continue stirring 3 hours down in 160 ℃.In reaction,, suitably repeat operation with phenyl methyl ketone layer (upper strata) Returning reactor with the effluent liquid separatory.

After being cooled to room temperature,, obtain thick N-formyl radical-1-phenyl-ethyl amine 116.1g under reduced pressure by heating up in a steamer low boiling component in the reactant.

It is used gc analysis, and purity is 87.5%.

Embodiment 53

In embodiment 52, except use 1 '-acetonaphthone 139.6g replaces the phenyl methyl ketone, all by embodiment 52 enforcements, obtains thick N-formyl radical-1-naphthyl ethamine 164.5g.Purity is 82.3%.

Embodiment 54

In embodiment 52, replace ammonium formiate except using methane amide 110.7g, with 4 '-chloro-acetophenone 126.7g replaces outside the phenyl methyl ketone, all by embodiment 52 enforcements, obtains thick N-formyl radical-1-(4-chloro-phenyl-) ethamine 150g.Purity is 87.4%.

Embodiment 55

In embodiment 52, except use 2 ', 4 '-Er Lvyixianben 155g replaces outside the phenyl methyl ketone, all by embodiment 52 enforcements, obtains thick N-formyl radical-1-(2,4 dichloro benzene base) ethamine 170.8g.Purity is 78.9%.

Embodiment 56

Ammonia absorber is connected with reactor, in reactor, adds ammonium formiate 206g.Add 76% formic acid 233g in the groove of ammonia absorber, divide with 20g/ to make the tower internal recycle, the connection portion with absorption tower and reactor remains on 80 ℃ of insulations simultaneously.

Reactor is heated with stirring to 155 ℃, splash into 2 to wherein dividing with 0.68g/ ', 4 '-Er Lvyixianben, splash into the tank liquor of ammonia absorber with the 0.48g/ branch, through 3 hours, continue down to stir 7 hours in 155～160 ℃ then, formic acid continues circulation during this period.

After the reaction, low boiling component is heated up in a steamer in decompression, obtains thick N-formyl radical-1-(2,4 dichloro benzene base) ethamine 162.2g of purity 86%.

Through heating up in a steamer the overhead product that low boiling component obtains is 137.9g, and through gc analysis, the result contains methane amide 69.8%, formic acid 12.9%, 2 ', 4 '-Er Lvyixianben 1.7%.

The tank liquor of reaction back ammonia absorber is 229.2g, contains methane amide 4.7%, formic acid 36.7%, and ammonium formiate 0.2%, 2 ', 4 '-Er Lvyixianben 1.7%.

Embodiment 57

The overhead product 137g that will be reclaimed by 27% ammoniacal liquor 56.8g and embodiment 56 and the tank liquor 113g composition mixture decompression of ammonia absorber distillate water 166g, this enriched material is added in the reactor, the tank liquor 116g that in the groove of ammonia absorber, adds the ammonia absorber of 90% formic acid 130g and embodiment 56 recovery, in addition to the above, implement according to embodiment 56.Obtain thick N-formyl radical-1-(2,4 dichloro benzene base) ethamine 165.4g of purity 83.7%.Heating up in a steamer the overhead product that low boiling component obtains is 112.5%, and it contains methane amide 80.1%, formic acid 15.7%, 2 ', 4 '-Er Lvyixianben 1.2%.The tank liquor of reaction back ammonia absorber is 265g, and it contains methane amide 6%, formic acid 31.5%, and ammonium formiate 0.2%, 2 ', 4 '-Er Lvyixianben 3%.

Embodiment 58

In embodiment 52, except with 2 '-*-methoxy acetophenone 123.2g replaces the phenyl methyl ketone, all by embodiment 52 enforcements, obtains thick N-formyl radical-1-(2-p-methoxy-phenyl) ethamine 143.7g.Purity is 90%.

Comparative example 10

In embodiment 52, in ammonium formiate, add acetate benzene and formic acid with 3 hours, insulated and stirred is 3 hours again, and as an alternative, the mixture that will be made up of formic acid and ammonium formiate and phenyl methyl ketone is in 160 ℃ of heated and stirred 6 hours, in addition all by these embodiment 52 enforcements.Obtain the thick N-formyl radical-1-phenyl-ethyl amine 112g of purity 82.7%.

Comparative example 11

In embodiment 55, with in ammonium formiate, added 2 in 3 hours ', 4 '-Er Lvyixianben and formic acid, insulated and stirred is 3 hours again, as an alternative, will by formic acid and ammonium formiate and 2 ', 4 '-mixture that Er Lvyixianben is formed is in 160 ℃ of heated and stirred 6 hours, in addition all by embodiment 55 enforcements.Obtain thick N-formyl radical-1-(2,4 dichloro benzene base) ethamine 178.6g of purity 70.4%.

Comparative example 12

In embodiment 54, with in methane amide, added 4 in 3 hours '-chloro-acetophenone and formic acid, insulated and stirred is 3 hours again, as an alternative, will by methane amide and formic acid and 4 '-mixture that chloro-acetophenone is formed is in 160 ℃ of heated and stirred 6 hours, in addition, implement according to embodiment 54.Obtain purity and be thick N-formyl radical-1-(2,4 dichloro benzene base) ethamine 144.2g of 84.6%.

Embodiment 59

The mixture that the hydrochloric acid 121g of rough N-formyl radical-1-(2,4 dichloro benzene base) ethamine 162g of being obtained by embodiment 56 and water 96g and 36% is formed under agitation refluxed 1 hour.

Then add water 224g, extract 2 times with toluene 80g down in 70 ℃ then, in water layer, add 8% caustic soda aqueous solution 173g again, extract 2 times with 100g toluene down in 60 ℃, then with resulting toluene layer water 80g washing 2 times, then toluene is heated up in a steamer, obtain rough 1-(2,4 dichloro benzene base) the ethamine 128.8g of purity 93.4%.With its underpressure distillation, obtain the highly finished product 118g of purity 99.5%.

Embodiment 60

In methylmagnesium-chloride solution, add 0.6g cupric chloride (II) at 15-25 ℃, then with the about 3 hours dropping 61.3g 2-cyano group-solution of 3-methyl-2-butene acetoacetic ester in 61g toluene under same temperature by 24.2g methyl chloride, 11.7g magnesium and the preparation of 121g tetrahydrofuran (THF).After interpolation is finished, reaction was carried out 2 hours again.With reaction mixture cooling and in the 5-15 ℃ of aqueous sulfuric acid of pouring 173g 15% into.With this mixture heating up to 50～60 ℃, it is left standstill under same temperature and be separated, with 31g toluene aqueous layer extracted 1 time, organic layer merged and with 67g 5% sodium bicarbonate aqueous solution and 31g water washing.The organic layer that merges carries out gc analysis by internal standard with the positive dipropyl of phthalic acid.Calculate 2-cyano group-3, the yield of 3-neohexene acetoacetic ester is 65g (96%).

Embodiment 61

Except replacing the 0.6g cupric chloride (II), according to reacting with the foregoing description 60 similar methods with 3.0g cupric chloride (II).2-cyano group-3, the recovery rate of 3-neohexene acetoacetic ester is 95%.

Compound N of the present invention-[(R)-1-(2, the 4-dichlorophenyl) ethyl]-2-cyano group-3, the 3-dimethyl butane amide can be used as the effective constituent of blight agent for preventing and eliminating and uses, and this agent for preventing and eliminating below being described and handling Oryza seed with this agent for preventing and eliminating is the blight the method for control of feature.

Compound of the present invention, be the N-[(R of opticity that the benzyl position has the absolute steric configuration of (R))-1-(2, the 4-dichlorophenyl) ethyl]-2-cyano group-3, the 3-dimethyl butane amide, for blight, not only in the middle of cauline leaf distribution etc., have the better effectiveness of preventing and kill off, and in seed treatment, also have the experience good effectiveness of preventing and kill off for a long time.

The absolute steric configuration of the benzyl position of amine side is (R), but the optical purity relevant with this position needn't be 100%ee (enantiomeric excess), in the present invention, the optical purity at relevant this position for example is (R) at 75%ee[: (S)=87.5: 12.5] more than be rich in optically active form in (R) body, but preferably the optical purity at relevant this position is (R) at 85%ee[: (S)=92.5: 7.5] more than be rich in optically active form in (R) body.In addition, the α position of The compounds of this invention acid side is easy to carry out racemic modificationization (epimerization), the practical occasion of preventing and kill off in blight, the steric configuration at position does not have a significant impact preventing and kill off effectiveness like this, thereby no matter (R) body or (S) body at this position, but this mixture of arbitrary proportion, but see common use (RS) body from industrial viewpoint.

The compounds of this invention demonstrates good especially preventive effect for the important disease blight (Pyriculariaoryzae) of Oryza, again by mixing with other suitable plant disease control agent, because the effect of multiplying each other, not only make this preventing and kill off become more effective, and, also demonstrate more effective effect to being the preventing and kill off of the Bakanae disease of rice (Gibberella fujikuroi) etc. of other important disease of Oryza.

With the occasion of The compounds of this invention as blight agent for preventing and eliminating effective constituent, also can add other which kind of composition uses like that, but normally mix with assistant agent, make uses such as emulsion, wettable powder, suspension agent, granula, pulvis with other preparation of solid carrier, liquid vehicle, tensio-active agent.In these preparations,, contain 0.1～99% by weight, be preferably 0.2～95% as the The compounds of this invention of effective constituent.

As medicament carrier, for example can enumerate kaolinton, ア Star バ Le ヅ ヤ イ ト Network レ-, divided powder or saccharoids such as wilkinite, acidic white earth, agalmatolite, talcum, diatomite, calcite, corn cob powder, walnut parting, urea, ammonium sulfate, synthetic oxidizing aqueous silicon, as liquid vehicle, it is aromatic hydrocarbon based to enumerate dimethylbenzene, methylnaphthalene etc., alcohols such as Virahol, ethylene glycol, cellosolve, ketones such as acetone, pimelinketone, isophorone, soybean oil, cottonseed wet goods vegetables oil, dimethyl sulfoxide (DMSO), acetonitrile, water etc.

As the tensio-active agent that uses for purposes such as emulsification, dispersion, wet exhibitions, for example can enumerate anion surfactants such as alkyl sulfuric ester salt, alkyl (aryl) sulfonate, dialkyl sulfosuccinates, polyoxy ethyl alkylaryl ether phosphate salt, naphthalenesulfonateformaldehyde formaldehyde water condenses, nonionogenic tensides such as Voranol EP 2001, polyethylene oxide polyoxypropylene block copolymers, sorbitan-fatty acid ester, polyoxyethylene sorbitan fatty acid ester etc.

As the assistant agent that preparation is used, for example can enumerate sulfonated lignin, alginate, polyvinyl alcohol, Sudan Gum-arabic, CMC (Walocel MT 20.000PV), PAP (acid phosphatase isopropyl ester) etc.

These preparations or use, or dilute with water is dispersed on the cauline leaf, or to soil surface and water surface loose powder, shot with former state, or mix to soil surface loose powder, shot, or carry out nursery box and handle, or carry out seed treatment.

As the method for seed treatment, there are seed dip treating, seed spray treatment, seed to wrap up in powder processing etc., when carrying out seed treatment, also can wrap up in powder or coating is carried out live with calcium peroxide etc.

In addition, also can mix use with other plant disease control agent, sterilant, parasiticide, nematocides, weedicide, plant-growth regulator, fertilizer, soil improvement agent etc.

Now enforcement and the compound symbol with blendable other plant disease control agent is expressed as follows simultaneously.

(A) 1,3-dithiolane-2-subunit dipropionic acid diisopropyl ester

[generic name isoprothiolane],

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

[generic name tricyclazole],

(C) 3-aryloxy-1,2-[4-morpholinodithio-1,1-dioxide

[generic name probenazole],

(D) 1,2,5,6-tetrahydrochysene-4H-pyrroles (3,2,1-i j) quinoline-4-ketone

[general name pyroquilon],

(E) (2)-2 '-methyl acetanilide 4,6-dimethyl pyrimidine-2-base hydrazone

[general name ferimzone],

(F) S, the adjacent ethyl ester of S-phenylbenzene idol phosphorus two sulfuric acid

[general name edifenphos],

(G) 4,5,6,7-four Chlorthalidones

[general name phthalide],

(H) kasugamycin

[general name kasugamycin]

(I) α, α, α-three fluoro-3-isopropoxy-toluoyl is for aniline

[general name flutolanil],

(J) 1-(4-benzyl chloride base)-1-cyclopentyl-3-phenylurea

[general name pencycuron],

(K) validamycin

[generic name validamycin],

(L) 3 '-isopropoxy-toluoyl is for aniline

[generic name mepronil],

(M) 6-(3,5-two chloro-4-tolyls)-3 (2H)-pyridazinones

[generic name diclomezine],

(N) N-(1,3-dihydro-1,1, the different benzofurane of 3-trimethylammonium-4-yl)-5-chloro-1,3-dimethyl pyrazole-4-carboxylic acid amide

[generic name furametpyr],

(O) methyl (E)-2-{2-[6-(2-cyano-benzene oxygen) pyrimidine-4-base oxygen base] phenyl }-3-methoxy acrylate, [ICIA5504]

(P) 5-ethyl-5,8-dihydro-8-oxo-1,3-two dislikes luxuriant also [4,5-g] quinoline-7-carboxylic acid

[generic name oxolinic acid],

(Q) (E)-and 4-chloro-α, α, α-three fluoro-N-(1-imidazoles-1-base-2-propoxy-ethylidene)-Ortho Toluidine

[generic name triflumizole],

(R) N-propyl group-N-[2-(2,4, the 6-Trichlorophenoxy) ethyl] imidazoles-1-carboxylic acid amides (カ Le Port キ サ ミ De)

[generic name prochloraz],

(S) 2-[(4-dichlorophenyl)-methyl]-5-(1-first and second bases)-1-(1H-1,2,4-triazol-1-yl methyl) cyclopentanol

[generic name ipconazole],

(T) N-furfuryl group-TMSIM N imidazole-1-base carbonyl-DL-high lactamine penta-4-alkene ester

[generic name pefurazoate],

(U) methyl isophthalic acid-butyl formamyl-benzopyrazoles-2-aminocarbamic acid ester

[generic name benomyl]

(V) 4,4 '-(O-phenylene) two (3-sulfo-allophanic acid dimethyl esters)

[generic name thiophanate-methyl],

(W) 2-(thiazole-4-yl) benzoglyoxaline

[generic name thiobenzimidazole],

(X) two (dimethyl thiocarbamoyl) disulphide

[generic name thiram],

(Y) 4-cyclopropyl-6-methyl-N-phenyl pyridizin-2-amine

[CGA219417, the generic name of suggestion.cyprodinil]、

(Z) 4-(2,2-two fluoro-1, the luxuriant-4-yl of 3-benzene two evils) pyrroles-3-nitrile

[generic name fludioxonil],

Mix the occasion of using at compound of the present invention with the effective constituent of above-mentioned other plant disease control agent, its ratio of mixture is different because of blended plant disease control agent kind etc., but 1 parts by weight with respect to The compounds of this invention, this plant disease control agent is generally 0.001～100 by weight, is preferably 0.2～20.

The example that mixes the sterilant that obtains is expressed as follows with the compound mark,

(a) 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl) sulfinyl-1H-pyrazoles-3-nitrile

[generic name fiproni1],

(b) 1-(6-chloro-3-picolyl-N-nitroimidazole quinoline-2-ylidene amines

[generic name imidacloprid],

(c) N-[2,3-dihydro-2, the 2-3,5-dimethylphenyl furans-7-base-amino sulfo-of oxygen carbonyl (methyl)]-N-sec.-propyl-β-An Jibingsuan ethyl ester

[generic name benfuracarb],

(d) S, S '-(2-dimethylamino trimethylene) two thiocarbamates

[generic name cartap]

(e) dipropyl phosphatase 24-(methyl sulfo-) phenylester

[generic name propaphos]

(f) 2,3-dihydro-2,2-3,5-dimethylphenyl furans-7-base (two butyl amido thio) methyl carbamate

[generic name carbosulfan],

(g) (E)-N-(6-chloro-3-picolyl)-N-ethyl-N '-methyl-2-nitroethylene fork diamines

[generic name nitenpyram],

(h) (E)-4,5-dihydro-6-methyl-4-(3-pyridine methylene amino)-1,2,4-three azines-3 (2H)-ketone

[generic name pymetrozine],

(i) an O-4-nitro-tolyl phosphoro group sulfuric acid O, the O-dimethyl ester

[generic name fenitrothion],

Or the like.

Effective constituent at The compounds of this invention and above-mentioned sterilant is mixed the occasion of using, its ratio of mixture is different because of blended sterilant kind etc., but for the The compounds of this invention 1 of 1 parts by weight, the weight ratio of this sterilant is generally 0.01～100, is preferably 0.2～20.

With the occasion of The compounds of this invention as blight agent for preventing and eliminating effective constituent, its treatment capacity is different because of meteorological conditions, preparation form, processing period, treatment process, processing place etc., but per 1 are is generally 0.05～200g, be preferably 0.1～100g, in the occasion that dilute with waters such as emulsion, wettable powder, suspension agent are used, its application concentration is 0.00005～0.5%, is preferably 0.0001～0.2%, granula, pulvis etc. then not dilutedly former state use.When nursery box was handled, as the effective constituent amount, (30cm * 60cm * 3cm), every case generally can use about 0.1～about 100g, preferablely can be about 0.5～about 10g to the large size nursery box of common usefulness.

When carrying out seed treatment, as the effective constituent amount, every 1kg seed is available about 0.001～about 50g usually, preferablely use about 0.01～about 10g, but when carrying out the seed dip treating, every 1kg seed is short period of time dipping in the high density soup of common about 5000～about 50000ppm of 1～3kg ratio generally, is generally about 5-30 minute.Perhaps generally in general about 20～about 4000ppm lower concentration soup of 1～3kg ratio, to flood for a long time, the time is about 6 hours～and about 48 hours.Below list formulation example commonly used.In addition, part represent parts by weight, The compounds of this invention (1) be usefulness the foregoing description 5 resulting.

Formulation example 1

With (1) 50 part of The compounds of this invention, 3 parts of calcium lignin sulphonates, 2 parts of Sodium Lauryl Sulphate BP/USPs and synthetic oxidizing aqueous silicon are fully pulverized for 45 parts and are mixed, and obtain wettable powder.

Formulation example 2

With (1) 25 part of The compounds of this invention, 3 parts of polyoxyethylene sorbitan monooleates, 3 parts of CMC and 69 parts of mixing of water, the granularity case of wet attrition that makes effective constituent obtains suspension agent below micron.

Formulation example 3

With (1) 2 part of The compounds of this invention, 10 parts in 8 parts of kaolinton and talcum mix through fully pulverizing, and obtain pulvis.

Formulation example 4

With (1) 20 part of The compounds of this invention, 14 parts of polyoxyethylene styryl phenyl ethers, 6 parts of calcium dodecylbenzene sulphonates and 60 parts of thorough mixing of dimethylbenzene make emulsion.

Formulation example 5

With (1) 10 part of The compounds of this invention, 1 part of synthetic oxidizing aqueous silicon, 2 parts of calcium lignin sulphonates, 30 parts of wilkinites and kaolin are fully pulverized for 73 parts and are mixed, add the water thorough mixing after, granulating and drying obtains granula.

Compound (A)～(Z) and (a)～(h) each, and each of these compounds and the mixture of The compounds of this invention (1) also can carry out preparation by above-mentioned formulation example 1～5.

Below the explanation The compounds of this invention is as the isochronous efficiency test example of blight agent for preventing and eliminating.The compounds of this invention (1) obtains by the foregoing description 5, and other plant disease control agent and sterilant are with above-mentioned compound symbolic representation.The compound that is used for compare is in addition represented with following compound mark.I.e. (2) N-[(RS)-1-(2,4 dichloro benzene base) ethyl]-(RS)-and 2-cyano group-3,3-dimethyl butane amide [spy opens the compound (6) of concrete record in the flat 2-76846 communique].

Test example 2 blight preventing iron tests (seed dip treating)

The reagent agent of the wettable powder of making by formulation example 1 is diluted with water to normality, with Oryza seed (Japan is fine) in the ratio of 2kg soup/1kg seed dip treating 10 minutes therein.With the rice after handling air-dry after, with the ratio sowing of 160g seed/case, grew seedlings 20 days.5 Oryza spriggings are filled in 1/5000 are the Wagner basin of water to spreading soil.On one side continuously by ratio processings of leaking of the bottom of Wagner basin in 3cm every day, greenhouse in continue to cultivate on one side.After transplanting for 6 weeks, move in the vinyl plastics room, keeping making it infect blight under the humidification state with other Oryza seedling that blight takes place.The bacterium inoculation by the blight disease index of following standard survey leaf, was obtained the value of preventing and kill off by following formula after 11 days.In addition, the morbidity degree in non-processor district is 58%

Disease index lesion area ratio

0 0

1 1～5％

2 6～25％

4 26～50％

More than 8 51%

N: the number of sheets of investigation

The number of sheets of each disease index 1,2,4,8 of n1～n4=

It the results are shown in table 6.

Table 6

Reagent agent	Effective constituent concentration of treatment (ppm)	The value of preventing and kill off (%)
			(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 compounds of this invention (1) also demonstrates the good effectiveness of preventing and kill off, and is unexpectedly even under exacting terms, and compound exhibits of the present invention goes out and 1/4 dose of comparative compound (2) has the roughly equal effectiveness of preventing and kill off.

Test example 3 blight preventing iron tests (seed spray treatment)

The wettable powder reagent agent of making by embodiment 1 is diluted with water to normality, its dose with the 30ml/1kg seed is blown seed rice (Japan is fine) be coated with processing.The rice of handling is air-dry.Be seeded into then in the plastic channel that sandy loam is housed, in the greenhouse, bred through 20 days.It is indoor that other rice seedling of having fallen ill with blight moves into vinyl plastics then, and keep humidification state, makes it infect wilt.Inoculate after 10 days,, obtain the value of preventing and kill off by the disease index of test example 2 investigation leaves.Morbidity degree in the unprocessed district is 100%.

The result is as shown in table 7.

Table 7

Reagent agent	Effective constituent concentration of treatment (ppm)	The value of preventing and kill off (%)
			(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 Bakanae disease of rice preventing iron tests (seed blows and is coated with processing)

Earlier seed rice (Japan is fine) is infected with the Bakanae disease of rice (Gibberella fujikuroi), will be diluted with water to normality, it is blown by the dose of 30ml/1kg seed this seed rice be coated with processing by the reagent agent that preparation 1 is made wettable powder.With the seed rice of handling air-dry after, sandy loam is inserted in the plastic channel, each groove was cultivated 21 in the greenhouse in the sowing of 50 ratio.The investigation morbidity state is obtained strong seedling rate by following formula.

The results are shown in table 8.

Table 8

Reagent agent	Effective constituent concentration of treatment (ppm)		The value of preventing and kill off (%)
				(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
The bacterium inoculation is untreated			0
				Inoculation is not untreated			100

Test example 5 blight preventing iron tests (cauline leaf distribution)

The sandy loam of packing in plastic channel, sowing seed rice (Japan is fine) was bred in temperature in indoor 20 days.The reagent agent of making suspension agent by preparation 2 is diluted with water to the concentration of regulation, to each rice seedling, spreads on the cauline leaf with the amount of liquid medicine that the blade face is wetting a little (30 liters/10 ares).After the distribution that plant is air-dry, again with the spore suspension spray inoculation of blight germ.After the inoculation 28 ℃ and much darker wet under cultivated 4 days, by the blight disease index of the investigation leaf of test example 2, obtain the value of preventing and kill off.The morbidity degree of distinguishing that is untreated in addition is 100%.

It the results are shown in table 9

Table 9

Reagent agent	Effective constituent concentration of treatment (ppm)	The value of preventing and kill off (%)
			(1)	100	100
50	99
		25		94

Test example 6 blight preventing iron tests (cauline leaf distribution)

Sandy loam is packed in the plastic channel, and sowing seed rice (Japan is fine) was bred through 20 days in the greenhouse, and the reagent agent of making wettable powder by formulation example 1 is diluted with water to normality, and it is spread on the blade face of this rice seedling in the mode of fully adhering to.Carry out the preventive effect test and after soup is air-dry, carry out the residual effect effect test again, in the greenhouse, keep after 7 days, respectively the sporozoite suspension of spray inoculation wilt.The inoculation back kept 10 days down wet more than 24 ℃, by following index investigation preventive effect.

Prevent and kill off index	Preventive effect
		5	Sound
4	Preventive effect is more than 90%
		3	Preventive effect 70～89%
2	Preventive effect 41～69%
		1	Preventive effect 1～40%
0	Preventive effect 0%

Table 9

Reagent agent	Effective constituent concentration of treatment (ppm)	Prevent and kill off index
				The residual effect effect	Preventive effect
		(1)	2.5 0.5			4 2	4 2
(1)+(E)	2.5+5 0.5+3			5 4	5 4
		(1)+(F)	2.5+5 0.5+3			5 3	5 3
(1)+(G)	2.5+5 0.5+3			5 4	5 4
		(1)+(H)	2.5+5 0.5+3			5 4	5 4
(1)+(N)	2.5+500 0.5+100			5 4	5 4
		(1)+(I)	2.5+500 0.5+100			5 4	5 4
(1)+(J)	2.5+500 0.5+100			5 4	5 4
		(1)+(K)	2.5+500 0.5+100			5 4	5 4

Table 10

Reagent agent	Effective constituent concentration of treatment (ppm)	Prevent and kill off index
				The residual effect effect	Preventive effect
		(E)	5 3			1 0	2 1
(F)	5 3			1 0	2 1
		(G)	5 3			2 0	3 1
(H)	5 3			1 0	2 1
		(N)	500 100			0 0	0 0
(I)	500 100			0 0	0 0
		(J)	500 100			0 0	0 0
(K)	500 100			0 0	0 0

Test example 7 Oryza banded sclerotial blight preventing iron tests (cauline leaf distribution)

Sandy loam is packed in the plastic channel, and sowing seed rice (Japan is fine) was bred in the indoor 20 day time of temperature.The reagent agent of making suspension by formulation example 2 is diluted with water to normality, it is carried out cauline leaf to rice seedling blade face in the mode of fully adhering to scatter.After soup is air-dry, the sclerotium of sheath blight fungus is inoculated in each strain.The inoculation back kept 10 days down wet more than 27 ℃.Investigate preventive effect by experimental example 6 to prevent and kill off index.Show the result in table 11.

Table 11

Reagent agent	Effective constituent concentration of treatment (ppm)	Prevent and kill off index
			(1)+(I)	250+10 50+5	4 2
(1)+(J)	250+5 50+1.25	4 2
			(1)+(K)	250+10 50+5	4 2
(1)+(L)	250+30 50+10	4 1
			(1)	250 50	0 0
(I)	10 5	3 1
			(J)	5 1.25	3 1
(K)	10 5	3 1
			(L)	30 10	3 0

Test example 8 blight preventing iron tests (nursery box processing)

The nursery box that (No. 2, ボ Application ソ Le: the little Pu Industry Co., Ltd) Oryza of packing into of will manually earthing up is used (in 30cm * 60cm * 3cm), the about 200g of dried seed rice of per 1 case sowing Oryza (Japan is fine).Sow after 20 days, will be uniformly scattered onto on the soil surface of nursery box by the granula that formulation example 5 is made.Water lightly then, again 5 strains of Oryza seedling are displaced to sandy clay (Bingku county treasured is housed Is produced from the city) and 1/50 are Wagner basin watering in.On one side by ratio processings of leaking continuously in 3cm every day of the bottom of Wagner basin, cultivate in the greenhouse on one side.Dislocation is after 6 weeks, and other rice seedlings of itself and blight morbidity are moved in the vinyl plastics room simultaneously, keeps humidification state to make it to infect wilt.The germ inoculation by the blight disease index of test example 2 investigation leaves, was obtained the value of preventing and kill off after 11 days.The sickness rate of distinguishing that is untreated is 95%.

Show the result in table 12.

Table 12

Reagent agent	Effective constituent treatment capacity (g/ nursery box)	The value of preventing and kill off %
			(1)	3	98
1.5	92
		O.75		80
(B)	2				39

Test example 9 blight preventing iron tests (nursery box processing)

To manually earth up (No. 2, ボ Application ソ Le: little Pu Industry Co., Ltd) pack into Oryza with nursery box (in 30cm * 60cm * 3cm), per 1 case sowing Oryza (Japan is fine) about 200g of dried seed rice.Sow after 20 days, will be uniformly scattered onto on the soil surface of nursery box by the granula that formulation example 5 makes.Water gently then, again with 5 strain rice spriggings to sand loam (Bao mound city, Bingku county product) being housed and watering in 1/500 are the Wagner basin of water.On one side by ratio processings of leaking continuously of the bottom of Wagner basin in 3cm every day, greenhouse in continue carry to train on one side.After transplanting for 4 weeks, move into simultaneously in the vinyl plastics room with other rice seedling that blight takes place again, keep humidification state to make it to infect wilt.The bacterium inoculation by the disease index of test example 2 investigation blights, was obtained the value of preventing and kill off after 11 days.In addition, be untreated the district the morbidity degree be 91%.

The results are shown in table 13.

Table 13

Reagent agent	Effective constituent treatment capacity (g/ nursery box)	The value of preventing and kill off (%)
			(1)	1.5 0.75	98 88
(1)+(a)	1.5+2 0.75+1	100 93
			(1)+(b)	1.5+2 0.75+1	100 90
(1)+(c)	1.5+2.5 0.75+1.25	100 93
			(1)+(N)	1.5+2.5 0.75+1.25	100 93
(a)	2	0
			(b)	2	0
(c)	2.5	0
			(N)	2.5	0

Test example 10 blight preventing iron tests (water surface processing)

Pack into sandy loam in 1/10000 are the Wagner basin and water, the seed rice of 2 leaf phases of dislocation (Japan is fine), in the greenhouse, become through 7 days the region between the heart and the diaphragms, to carry out the water surface in each Wagner basin by the reagent agent that formulation example 5 is made granula then handles, (following note was done to test a) or 14 days (following note is made test b), to the spore suspension of these rice seedling spray inoculation wilts in 7 days in cultivation continuously.The inoculation back was keeping 10 days under the wet condition more than 24 ℃.Investigate preventive effect according to test example 6 to prevent and kill off index.The results are shown in table 14.

Table 14

Reagent agent	Effective constituent treatment capacity g/10 are	Prevent and kill off 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. with the manufacture method of the N-formyl radical-1-aryl methylamine class of general formula [VI] expression,

RArCH-NH-CHO [VI]

In the formula, R represents C ₁-C ₄Alkyl, Ar are represented following group:

In the formula, R ₂Expression hydrogen or chlorine;

This method comprises that aryl ketones and the formic acid with general formula [V] expression injects methane amide and/or ammonium formiate simultaneously:

RArC＝O [V]

In the formula, R and Ar have implication same as described above.

2. the process of claim 1 wherein, as concurrently injected formic acid, is the formic acid that contains the ammonium formiate that obtains by the ammonia that formic acid is absorbed in generate in the reaction system.