AU692601B2 - Process for producing N-(1-(2,4-dichlorophenyl)ethyl)-2- cyano-3,3-dimethylbutanamide - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Sumitomo Chemical Company, Limited ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

a INVENTION TITLE: Process for producing N-[1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide The following statement is a full description of this invention, including the best method of performing it known to me/us:a.

a. a *a a a I- FIELD OF THE INVENTION The present invention relates to a process for producing N-[l-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide which is useful as an active ingredient of plant disease control agents.

BACKGROUND OF THE INVENTION As the process for producing N-[l-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3dimethylbutanamide, there has been known a process comprising converting an ester of 2-cyano-3,3-dimethylbutanoic acid into the corresponding carboxylic acid by hydrolysis with a base, treating the carboxylic acid with thionyl chloride to give the corresponding reactive carboxylic acid chloride, and reacting the reactive carboxylic acid chloride with 1-(2,4-dichlorophenyl)ethylamine in the presence of a base.

*0 This process is, however, disadvantageous that it requires not only the steps 15 of hydrolysis and acid chloride formation but also highly reactive reagents such as thionyl chloride. Accordingly, there has been a great demand for the production by a more simple process.

SUMMARY OF THE INVENTION The present inventors have intensively studied to find a process for producing N-[l-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide in a simple manner.

As a result, they have found that the desired N-[1-(2,4-dichlorophenyl)ethyl]-2-cyano- 3,3-dimethylbutanamide can be simply obtained in high yield, without requiring the steps of hydrolysis and acid chloride formation or highly reactive reagents such as thionyl

I

chloride, by reacting an ester of 2-cyano-3,3-dimethylbutanoic acid directly with 1-(2,4dichlorophenyl)ethylamine, and they have further found improved production processes for these starting materials, esters of 2-cyano-3,3-dimethylbutanoic acid and 1-(2,4dichlorophenyl)ethylamine, thereby completing the present invention.

Thus, the present invention mainly provides a process for producing N-[l-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide (hereinafter referred to as compound which comprises reacting a C 2

-C

4 alkyl ester of 2-cyano-3,3-dimethylbutanoic acid with 1-(2,4-dichlorophenyl)ethylamine at 130" to 250"C (hereinafter referred to as production process 1 of the present invention), and a process for producing -(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide (hereinafter referred to as compound la), which comprises reacting a C 2

-C

4 alkyl ester of 2-cyano- 3,3-dimethylbutanoic acid with (R)-1-(2,4-dichlorophenyl)ethylamine at 130" to 250°C (hereinafter referred to as the production process 2 of the present invention).

The other objects of the present invention will be fully understood by those skilled in the art upon reading the following detailed description.

e.

ese.o

S

S.

S

S

*SS*o 5 5- DETAILED DESCRIPTION OF THE INVENTION The following will describe production process 1 of the present invention.

This process involves reacting a C 2

-C

4 alkyl ester of 2-cyano-3,3-dimethylbutanoic acid (which may be either in racemic form or in optically active form) with 1-(2,4-dichlorophenyl)ethylamine (which may be either in racemic form or in optically active form) without any solvent or in a solvent at 130" to 250'C, preferably 130' to 220"C, usually for 0.5 to 24 hours. Examples of the C 2

-C

4 alkyl group are ethyl, n-propyl, isopropyl, n-butyl and isobutyl. The amount of reagent used in the reaction is 20 5*

S

S

M

usually in the range of 0.9 to 1.2 moles for 1-(2,4-dichlorophenyl)ethylamine to 1 mole of the C 2

-C

4 alkyl ester of 2-cyano-3,3-dimethylbutanoic acid. The solvent used, if necessary, is not particularly limited, so long as it is inert in the reaction and has a boiling point of about 130" to 250°C. Examples of the solvent are hydrocarbon solvents such as xylene, cumene and mesitylene; halogenated aromatic hydrocarbon solvents such as chlorobenzene and dichlorobenzene; ether solvents such as diglyme and triglyme; and mixtures thereof.

After completion of the reaction, the reaction mixture is usually subjected to crystallization by, for example, cooling to room temperature, and the resulting crystals are collected by filtration and washed with a suitable solvent an organic solvent such as methanol, ethanol, isopropanol, hexane or monochlorobenzene; water; or a mixture thereof), followed by drying and, if necessary, purification such as recrystallization. Thus, the desired compound 1 can be isolated.

C

The following will describe production process 2 of the present invention.

S 15 This process involves reacting a C 2

-C

4 alkyl ester of 2-cyano-3,3-dimethylbutanoic acid (which may be either in racemic form or in optically active form) with (R)-l-(2,4-dichlorophenyl)ethylamine (which does not necessarily have an optical purity of 100% e.e. (enatiomeric excess), but may be in optically active form composed mainly of the (R)-isomer, for example, having an optical purity of 75% e.e. or higher) without 20 any solvent or in a solvent at 130" to 250°C, preferably 130' to 220"C, usually for 0.5 to 24 hours. Examples of the C 2

-C

4 alkyl group are ethyl, n-propyl, isopropyl, n-butyl and isobutyl. The amount of reagent used in the reaction is usually in the range of 0.9 to 1.2 moles for (R)-l-(2,4-dichlorophenyl)ethylamine to 1 mole of the C 2

-C

4 alkyl ester of 2-cyano-3,3-dimethylbutanoic acid. The solvent used, if necessary, is not particularly

I

4 limited, so long as it is inert in the reaction and has a boiling point of about 130' to 250C, Examples of the solvent are hydrocarbon solvents such as xylene, cumene and mesitylene; halogenated aromatic hydrocarbon solvents such as chlorobenzene and dichlorobenzene; ether solvents such as diglyme and triglyme; and mixtures thereof.

After completion of the reaction, the reaction mixture is usually subjected to crystallization by, for example, cooling to room temperature, and the resulting crystals are collected by filtration, washed with a suitable solvent an organic solvent such as methanol, ethanol, isopropanol, hexane or monochlorobenzene; water; or a mixture thereof), and dried. Thus, the desired compound la can be isolated. The crystals can also be collected by the following crystallization technique for the purpose of improving their properties.

After completion of the reaction, the solvent is distilled out from the reaction mixture, if necessary, and while keeping the reaction mixture at about 130° to 170°C, an o organic solvent capable of forming an azeotropic mixture with water, such as monochloro- 15 benzene or dichlorobenzene, is poured into the reaction mixture for dissolution. The solution is then cooled to about 70" to 100°C and kept at the same temperature. Another vessel equipped with a thermometer, a condenser for condensation of the distillate and a stirrer is charged with a small amount of seed crystals, water, and, if necessary, a small amount of acid hydrochloric acid, sulfuric acid). The temperature is raised to about 20 100°C, and the above solution (kept at about 70° to 100"C) is slowly poured into the vessel at the same temperature. The crystals of compound la begin to be deposited almost at the same time that the organic solvent is removed by azeotropic distillation with water. The resulting aqueous slurry of compound la is slowly cooled to about 20° to and the crystals are collected by filtration, washed with water, and dried. Thus, I 0 compound la can be obtained as crystalline powder having good filtration properties.

The following will describe the excellent advantages of production process 2 of the present invention.

The compound 1 has one asymmetric carbon atom each on the acid side and on the amine side. Accordingly, there are four kinds of optical isomers, X1-form X2-form Y1-form and Y2-form wherein two symbols S and R in parenthesis represent absolute configurations of the asymmetry carbon atoms on the acid side and on the amine side in this order, and there are two kinds of diastereomers, X-form (racemic form composed of X1-form and X2-form) and Y-form (racemic form composed of YI-form and Y2-form). As shown in Test Example 1 below, the present inventors have found that plant disease control activity can be observed only in Y2-form and XI-form, and further that Y2-form has much stronger plant disease control activity than that of Xl-form, and therefore, Y-form has much stronger plant disease control activity than that of X-form.

15 It has, however, been found that the production of compound 1 from the o** starting material amine in racemic form on an industrial scale has the following disadvantage: if the product is isolated by crystallization, crystals of X-form having weaker plant I: disease control activity are deposited predominantly from among the above two kinds of diastereomers, and the ratio of these diastereomers is liable to be influenced by various 20 factors such as heat and is not always kept constant (which is difficult to control). The present inventors have made various studies and unexpectedly found that in the case of compound la (optically active from) derived from an optically active amine optically active isomer composed mainly of R-form, having an optical purity of 75% e.e.

or higher), crystals of X1-form and those of Y2-form are deposited approximately at L-L equivalent amounts and the ratio of these diastereomers is kept constant with no influence of factors such as heat under the normal conditions for operation. Thus, production process 2 of the present invention has been completed.

The C 2

-C

4 alkyl ester of 2-cyano-3,3-dimethylbutanoic acid, which is one of the starting material compounds used in the present invention, can be obtained with high efficiency according to a production process for the starting materials as described below, although it can also be produced by a conventional process, for example, as described in J. Am. Chem. Soc., vol. 4791 (1950).

The other starting material compound, l-(2,4-dichlorophenyl)ethylamine, can be produced according to a conventional process, for example, as described in Organic Reaction, vol. 15, 301-330 (1949) and JP-A 2-306942/1990.

The following will describe a process for producing a C 2

-C

4 alkyl ester of 2-cyano-3,3-dimethylbutanoic acid, which is one of the starting materials used in the production processes 1 and 2.

15 The C 2

-C

4 alkyl ester of 2-cyano-3,3-dimethylbutanoic acid is obtained by reacting a C 2

-C

4 alkyl ester of 2-cyano-3-methyl-2-butenoic acid with a methyl magnesium halide in the presence of a copper catalyst.

Examples of the C 2

-C

4 alkyl ester of 2-cyano-3-methyl-2-butenoic acid are ethyl 2-cyano-3-methyl-2-butenoate, n-propyl 2-cyano-3-methyl-2-butenoate, isopropyl 20 2-cyano-3-methyl-2-butenoate, n-butyl 2-cyano-3-methyl-2-butenoate and isobutyl 2-cyano-3-methyl-2-butenoate.

Examples of the methyl magnesium halide are methyl magnesium chloride

(CH

3 MgCI), methyl magnesium bromide (CH 3 MgBr) and methyl magnesium iodide

(CH

3 MgI). These compounds can be commercially obtained or can be prepared by 7 reacting a methyl halide with magnesium according to the ordinary process.

As the copper catalyst, a monovalent copper salt is usually used, examples of which are copper chloride (CuCI), copper bromide (CuBr) and copper iodide (Cul). A divalent copper salt is also useful, examples of which are copper (II) chloride (CuC1 2 copper (II) bromide (CuBr 2 and copper (II) iodide (CuI 2 The reaction is usually effected in an organic solvent. Examples of the solvent are ether solvents such as tetrahydrofuran (THF), diethyl ether and dibutyl ether; aromatic hydrocarbon solvents such as toluene, xylene and benzene; and mixtures of ether solvents and aromatic hydrocarbon solvents.

The reaction is usually effected at 10° to 60"C for 0.5 to 10 hours. The amounts of reagents used in the reaction are usually in the range of 1 to 2 moles for the methyl magnesium halide to 1 mole of the C 2

-C

4 alkyl ester of 2-cyano-3-methyl-2butenoic acid and usually in the range of 0.0005 to 0.1 part by weight for the copper •catalyst to 1 part by weight of the C 2

-C

4 alkyl ester of 2-cyano-3-methyl-2-butenoic acid.

15 After completion of the reaction, the reaction mixture is usually treated with, for example, water, aqueous ammonium chloride, diluted sulfuric acid or the like, and the organic layer is concentrated and, if necessary, purified by, for example, distillation or the like. Thus, the desired C2-C 4 alkyl ester of 2-cyano-3,3-dimethylbutanoic acid can be isolated.

20 The C 2

-C

4 alkyl ester of 2-cyano-3-methyl-2-butenoic acid, which is one of the starting materials used in this process, can be efficiently produced according to the following production process.

The following will describe a process for producing a C 2

-C

4 alkyl ester of 2-cyano-3-methyl-2-butenoic acid, which comprises reacting a C 2

-C

4 alkyl ester of cyano-

L

8 acetic acid with acetone in the presence of a catalyst using hexane as a main solvent.

Examples of the C 2

-C

4 alkyl ester of cyanoacetic acid are ethyl cyanoacetate, n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate and isobutyl cyanoacetate, These compounds can be commercially obtained or can be prepared by the ordinary process.

As the catalyst, an optionally substituted aniline and a carboxylic acid are usually used. Examples of the substituent on the optionally substituted aniline are hydroxyl, methyl and methoxy. Examples of the optionally substituted aniline are aminophenol p-aminophenol, o-aminophenol, m-aminophenol) and toluidine p-toluidine, o-toluidine, m-toluidine).

Examples of the carboxylic acid are lower C 1

-C

3 fatty acids acetic acid, formic acid, propionic acid) and benzoic acid.

As the solvent used for the reaction, n-hexane is used as a main solvent. The *9 content of n-hexane used is usually in the range of 50% to 100% by weight, based on the 15 total weight of the solvents. Examples of the solvent which can be used in combination with n-hexane are aromatic hydrocarbon solvents such as toluene and xylene.

The reaction is usually effected at 50° to 100'C for 5 to 20 hours, while removing water formed during the reaction.

The amounts of reagents used in the reaction are usually in the range of 1 to eoa 20 4 moles for acetone and usually in the range of 0.001 to 0.2 mole for the catalyst (usually 0.001 to 0.1 mole for the optionally substituted aniline and usually 0.01 to 0.2 mole for the carboxylic acid), to 1 mole of the C 2

-C

4 alkyl ester of cyanoacetic acid.

After completion of the reaction, the reaction mixture is usually concentrated under reduced or normal pressure and subsequently distilled; or the reaction mixture is

-I

dissolved in a solvent such as ethyl acetate, toluene or xylene and washed with water, and the solution is concentrated under reduced pressure to remove the solvent and, if necessary, purified by distillation or the like. Thus, the desired C 2

-C

4 alkyl ester of 2-cyano-3-methyl-2-butenoic acid can be isolated.

According to this process of the present invention, a lower alkyl ester of 2-cyano-3-methyl-2-butenoic acid can be produced in high yield.

The optically active 1-(2,4-dichlorophenyl)ethylamine used as a starting material in the present invention can be obtained by optical resolution of (RS)-1-(2,4-dichlorophenyl)ethylamine with optically active aspartic acid which is inexpensive and suitable for production on an industrial scale.

The following will describe a process for producing optically active 1-(2,4-dichlorophenyl)ethylamine, which comprises effecting optical resolution of (RS)-1-(2,4-dichlorophenyl)ethylamine with optically active aspartic acid.

o9 The optical resolution usually involves the following steps: 15 dichlorophenyl)ethylamine is mixed with optically active aspartic acid to form a salt; (b) an optically active diastereomer salt is crystallized in a solvent and isolated by filtration or the like; and the salt is treated with a base. The steps a, b and c will hereinafter be explained in more detail.

(Step a) 20 Optically active or aspartic acid is available on an industrial scale, and those having an optical purity of 90% e.e. or higher are usually used. (RS)-1-(2,4-dichlorophenyl)ethylamine can be produced by effecting the Leuckart reaction as described below, using 2,4-dichloroacetophenone as a starting material.

The amount of reagent used in the reaction is usually in the range of 0.1 to

-I

VI

*0 15

I

00 00 0 S .6 0.

0::0 0 0 0.

S. S 1.2 moles, preferably 0.3 to 1 mole, for optically active aspartic acid to 1 mole of (RS)-l-(2,4-dichlorophenyl)ethylamine. The mixing may be carried out in a solvent.

Examples of the solvent used, if necessary, are water, lower alcohols such as methanol and ethanol, and mixtures thereof.

(Step b) The resulting salt is usually dissolved in a solvent by heating at 50° to 120'C, and the solution is usually cooled to 0° to 40"C, thereby causing the deposition of an optically active diastereomer salt. As the solvent, water, lower alcohols such as methanol and ethanol, or mixtures thereof are usually used.

The deposited salt is isolated by filtration or the like, and, if necessary, it may be purified by recrystallization from water, lower alcohols such as methanol and ethanol, or mixtures thereof.

(Step c) The above salt is usually made alkaline at 0° to 40*C by the addition of a base such as sodium hydroxide at a ratio of 1 to 10 moles to 1 mole of the salt, and the liberated amine is extracted with an organic solvent such as toluene, followed by concentration or the like. Thus, the desired optically active 1-(2,4-dichlorophenyl)ethylamine can be isolated.

The configuration and optical rotatory property of the optically active 1-(2,4dichlorophenyl)ethylamine obtained by the production process of the present invention is when L-aspartic acid is used for optical resolution or when D-aspartic acid is used.

In the production process of the present invention, unreacted (RS)-l-(2,4-dichlorophenyl)ethylamine can be recovered from the filtrate after the collection of the salt, I- I 11 and optically active aspartic acid used can be simply recovered from this filtrate and the aqueous layer after the extraction of the amine. Further, optically active aspartic acid thus recovered can be used again.

As the method for optical resolution of 1-phenylethylamines, there are known a method using mandelic acid in an aqueous solvent (JP-A 56-26848/1981) and a method using tartaric acid or malic acid in water as a solvent (Org. Synthesis Coll., vol. 2, 506 (1943)). Even if these methods for optical resolution of 1-phenylethylamines are applied to 1-(2,4-dichloropheny')ethylamine, however, there are disadvantages that optical resolution cannot be successfully attained or only the product having remarkably decreased optical purity is obtained, probably because of the substituent in the ortho-position of the phenyl ring.

As a result from various studies, the present inventors have found that the desired optically active 1-(2,4-dichlorophenyl)ethylamine having high optical purity can e* r)« be produced with high efficiency in an industrially favorable manner by the use of an 15 organic solvent as a solvent for optical resolution and the use of optically active mandelic acid as an agent for optical resolution.

C

The following will describe in detail an industrially favorable process for a d* producing optically active 1-(2,4-dichlorophenyl)ethylamine, which comprises effecting optical resolution of (RS)-l-(2,4-dichlorophenyl)ethylamine with optically active 20 mandelic acid in an organic solvent.

(RS)-l-(2,4-dichlorophenyl)ethylamine is a racemic mixture containing R-form and S-form at the same amounts; however, even a mixture containing one of the optical isomers in excess can be used.

Optically active mandelic acid, which is an agent for optical resolution, may I, I I 1 ih

P

r d be used either in D-form or in L-form. The amount of optically active mandelic acid used is usually in the range of about 0.1 to 1.2 moles, preferably about 0.3 to 1 mole, to I mole of l-(2,4-dichlorophenyl)ethylamine.

Examples of the organic solvent used as a solvent for optical resolution are alcohol solvents such as methanol, ethanol and n-propanol; ketone solvents such as acetone and methyl isobutyl ketone; ester solvents such as ethyl acetate; ether solvents such as methyl tert-butyl ether, dioxane and diethyl ether; aromatic solvents such as toluene, xylene and chlorobenzene; nitrile solvents such as acetonitrile; and mixtures thereof. The organic solvent may contain water. The amount by weight of the solvent used, although it may vary depending upon the kind of solvent used, is usually about 2 to 100 times, preferably about 2 to 10 times, the weight of (RS)-l-(2,4-dichlorophenyl)ethylamine.

0* ge 15

S

C

20

C

S

In the optical resolution, for example, after 1-(2,4-dichlorophenyl)ethylamine is reacted with optically active mandelic acid in an organic solvent as described above to form diastereomer salts, or after the previously prepared diastereomer salts are dissolved in an organic solvent, one of the diastereomer salts is deposited from the solution by leaving without disturbance or by stirring. If necessary, the solution may be cooled or concentrated. The temperature is usually in the range of -20°C to the boiling point of the solvent.

Thereafter, the deposited salt is isolated. The resulting salt may be recrystallized, if necessary. This salt is then decomposed with an alkali, and the resulting organic layer is subjected to phase separation or extracted with an organic solvent. Thus, the desired optically active 1-(2,4-dichlorophenyl)ethylamine can be obtained.

The remaining aqueous layer after the phase separation or extraction of the Is I 13 organic layer is made acidic by the addition of an acid, and then extracted with an organic solvent. Thus, optically active mandelic acid can be recovered.

Further, if the above procedures are repeated for the mother liquor after the isolation of the diastereomer salt, optically active 1-(2,4-dichlorophenyl)ethylamine and optically active mandelic acid can be recovered.

As the alkali used in the decomposition of the diastereomer salt, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarborate or the like is usually used. The amount of such an alkali is usually in the range of about 1 to 5 moles to 1 mole of the salt, As the solvent used for the extraction of an amine formed by the decomposition of the salt, for example, an ester solvent such as ethyl acetate; an ether solvent such as methyl tert-butyl ether, tetrahydrofuran or diethyl ether; an aromatic solvent such as toluene, xylene or chlorobenzene; or the like is usually used. The amount by weight of such a solvent is usually about 0.1 to 5 times the weight of the salt.

Examples of the acid used for the recovery of optically active mandelic acid are mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid. The acid Sis usually used in such a manner that the pH of the aqueous layer becomes 0.5 to 2. In this case, a salt such as sodium chloride may be added, and the amount by weight of such a salt is usually about 0.1 to 0.2 time the weight of the aqueous layer.

Examples of the solvent used for the extraction of optically active mandelic acid are ether solvents such as methyl tert-butyl ether; ester solvents such as ethyl .cetate; and alcohol solvents capable of forming a two-layer system with water, such as n-butanol. The amount by weight of the solvent used is usually about 0.1 to 10 times the weight of the aqueous layer.

r n I 14 According to this process, the desired optically active 1-(2,4-dichlorophenyl)ethylamine having high optical purity can be simply produced with high efficiency by the use of an organic solvent as a solvent and the use of a particular carboxylic acid, optically active mandelic acid, as an agent for optical resolution. In addition, optically active mandelic acid, which is an agent for optical resolution, can be simply recovered and recycled, which is industrially favorable.

The optically active 1-(2,4-dichlorophenyl)ethylamine can also be obtained by an industrially favorable process comprising effecting optical resolution of -(2,4-dichlorophenyl)ethylamine with optically active dibenzoyltartaric acid in an organic solvent.

This process will hereinafter be explained in detail.

(RS)-l-(2,4-dichlorophenyl)ethylamine is a racemic mixture containing R-form and S-forms at the same amounts; however, even a mixture containing one of the optical isomers in excess can be used.

Optically active dibenzoyltartaric acid, which is an agent for optical resolu- 15 tion, may be used either in D-form or in L-form The amount of optically active dibenzoyltartaric acid used is usually in the range of about 0.3 to 1.2 moles, preferably about 0.5 to 1 mole, to 1 mole of (RS)-l-(2,4-dichlorophenyl)ethylamine.

Examples of the organic solvent used as a solvent for optical resolution are alcohol solvents such as methanol, ethanol and n-propanol; ketone solvents such as 20 acetone and methyl isobutyl ketone; ester solvents such as ethyl acetate; ether solvents such as methyl tert-butyl ether, dioxane and diethyl ether; aromatic solvents such as toluene, xylene and chlorobenzene; nitrile solvents such as acetonitrile; and mixtures thereof. The organic solvent may contain water.

The amount by weight of the solvent used, although it may vary depending ~II I r I upon the kind of solvent used, is usually about 2 to 100 times, preferably about 2 to times, the weight of 1-(2,4-dichlorophenyl)ethylamine.

In the optical resolution, for example, after (RS)-l-(2,4-dichlorophenyl)ethylamine is reacted with optically active dibenzoyltartaric acid in an organic solvent as described above to form diastereomer salts, or after the previously prepared diastereomer salts are dissolved in an organic solvent, one of the diastereomer salts is deposited from the solution by leaving without disturbance or by stirring. If necessary, the solution may be cooled or concentrated. The temperature is usually in the range of-20'C to the boiling point of the solvent.

Thereafter, the deposited salt is isolated. The resulting salt may be recrystallized, if necessary. This salt is then decomposed with an alkali, and the resulting organic layer is subjected to phase separation or extracted with an organic solvent. Thus, the desired optically active l-(2,4-dichlorophenyl)ethylamine can be obtained, The remaining aqueous layer after the phase separation or extraction of the *o organic layer is made acidic by the addition of an acid, and extracted with an organic solvent. Thus, optically active dibenzoyltartaric acid can be recovered.

Further, if the above procedures are repeated for the mother liquor after the isolation of the diastereomer salt, optically active 1-(2,4-dichlorophenyl)ethylamine and optically active dibenzoyltartaric acid can be recovered.

As the alkali used in the decomposition of the diastereomer salt, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate or the like is usually used. The amount of such an alkali is usually in the range of about 1 to 5 moles to 1 mole of the salt.

As the solvent used for the extraction of an amine formed by the decomposi-

I

16 tion of the salt, for example, an ester solvent such as ethyl acetate; an ether solvent such as methyl tert-butyl ether, tetrahydrofuran or diethyl ether; an aromatic solvent such as toluene, xylene or chlorobenzene; or the like is usually used. The amount by weight of such a solvent is usually about 0.1 to 5 times the weight of the salt.

Examples of the acid used for the recovery of optically active dibenzoyltartaric acid are mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid. The acid is usually used in such a manner that the pH of the aqueous layer becomes to 2. In this case, a salt such as sodium chloride may be added, and the amount by weight of such a salt is usually about 0.1 to 0.2 time the weight of the aqueous layer.

Examples of the solvent used for the extraction of optically active dibenzoyltartaric acid are ether solvents such as methyl tert-butyl ether; ester solvents such as ethyl acetate; and alcohol solvents capable of forming a two-layer system with water, such as n-butanol. The amount by weight of such a solvent is usually about 0.1 to 10 times the weight of the aqueous layer.

According to this process, the desired optically active 1-(2,4-dichlorophenyl)ethylamine having high optical purity can be simply produced with high efficiency by the 9* use of an organic solvent as a solvent and the use of a particular carboxylic acid, optically active dibenzoyltartaric acid, as an agent for optical resolution. In addition, optically active dibenzoyltartaric acid, which is an agent for optical resolution, can be simply recovered and recycled, which is industrially favorable.

The S-form of l-(2,4-dichlorophenyl)ethylamine remaining in the filtrate after the above optical resolution can be utilized in part as R-form by racemization. As such a process, there have hitherto been known various processes, for example, a process for producing racemic a-phenylethylamine by treatment with sodium naphthalene (JP-A

II

49235/1975); a process for producing a-naphthylethylamine by treatment with sodium hydride (JP-A 54-5967/1979); a process for producing a-phenylethylamine by treatment with sodium carried on alumina (JP-A 50-50328/1975); and a process for producing racemic 1-(4-chlorophenyl)ethylamine by treatment with an alkali metal alkoxide in dimethylsulfoxide (JP-A 4-275258/1992).

When the above known processes were applied to optically active 1-(2,4-dichlorophenyl)ethylamine, however, there occurs a problem that racemizaticn does not completely proceed.

As a result from various studies, the present inventors have found that racemization can be allowed to proceed with high efficiency by condensation of optically active 1-(2,4-dichlorophenyl)ethylamine with 2,4-dichloroacetophenone to give a novel optically active compound, N-(a-methyl-2,4-dichlorobenzylidene)-a-(2,4-dichlorophenyl)ethylamine, which is then treated with an alkali metal alkoxide in dimethylsulfoxide, and they have further found that the desired racemic 1-(2,4-dichlorophenyl)ethylamine S 15 can be simply obtained by hydrolysis of this racemic amine.

The following will describe in detail processes for producing racemic 1-(2,4dichlorophenyl)ethylamine by way of optically active N-(a-methyl-2,4-dichlorobenzylidene)-ac-(2,4-dichlorophenyl)ethylamine.

The optically active N-(a-methyl-2,4-dichlorobenzylidene)-a-(2,4-dichlorophenyl)ethylamine of the present invention can be produced by dehydration condensation of optically active 1-(2,4-dichlorophenyl)ethylamine with 2,4-dichloroacetophenone.

The optically active 1-(2,4-dichlorophenyl)ethylamine may be either in R-form or in S-form, or may also be a mixture containing one of these forms in excess.

The dehydration condensation can be effected according to a known process, I I I 18 for example, the process as described in J. Chem. Soc., 14, 2624 (1984). The 2,4-dichloroacetophenone is usually used at an amount of 0.5 to 2 moles, preferably 0.95 to 1.05 moles, to 1 mole of optically active 1-(2,4-dichlorophenyl)ethylamine.

The reaction is usually effected in the presence of a catalyst in a solvent, but it can be effected even in the presence of a catalyst without any solvent. When a solvent is used, it is not particularly limited, so long as it does not inhibit the reaction. Examples of the solvent are aromatic solvents such as toluene, benzene, xylene and chlorobenzene; ether solvents such as dioxane and methyl tert-butyl ether; aliphatic solvents such as hexane and heptane; and halogenated solvents such as dichloroethane and chloroform.

Preferably, the reaction is effected, while removing water formed by the dehydration condensation from the reaction system.

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

0. Examples of the catalyst for dehydration condensation are Lewis acids such 15 as zinc chloride, zinc bromide, zinc fluoride, titanium tetrachloride, boron trifluoride, boron tribromide, phosphorous trichloride, magnesium bromide, iron chloride, aluminum chloride, tin tetrachloride, titanium alkoxides and copper (II) triflate; sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid and ion exchange resins of the S* sulfonic acid type; and heteropolyacids such as dodecatungstophosphoric acid and 20 dodecatungstosilisic acid. In particular, zinc chloride, titanium alkoxides, titanium tetrachloride, boron trifluoride or p-toluenesulfonic acid is preferably used. More preferred are zinc chloride and titanium alkoxides.

p The amount of catalyst used is usually in the range of 0.001 to 0.1 mole, preferably 0.005 to 0.05 mole, to 1 mole of optically active 1-(2,4-dichlorophenyl)ethyl- 19 amine, The dehydration condensation is usually effected at about 70" to 180°C for about 1 to 20 hours, preferably while removing water formed by the dehydration condensation from the reaction system.

The resulting optically active N-(a-methyl-2,4-dichlorobenzylidene)-a-(2,4dichlorophenyl)ethylamine, after the removal of the catalyst from the reaction mass, may be used as such in the subsequent step, or may be isolated, for example, by distillation of low boiling fractions, or after isolated, may be purified by a technique such as distillation, recrystallization or chromatography.

The racemization of optically active N-(a-methyl-2,4-dichlorobenzylidene)a-(2,4-dichlorophenyl)ethylamine into a racemic compound is carried out by treatment with an alkali metal alkoxide in the presence of dimethylsulfoxide.

As the alkali metal alkoxide, for example, alkali metal alkoxides derived from tertiary alcohols are preferably used, such as potassium tert-butoxide, sodium tertbutoxide, potassium tert-amylate or sodium tert-amylate. The amount of alkali metal See@ alkoxide used is usually in the range of 0.01 to 2 moles, preferably 0.03 to 0.2 moles, to 1 mole of optically active N-(a-methyl-2,4-dichlorobenzylidene)--(2,4-dichlorophenyl)ethylamine.

The amount of dimethylsulfoxide used is usually in the range of 0.1 to S 10 moles, preferably 0.5 to 5 moles, to 1 mole of optically active N-(a-methyl-2,4-dichlorobenzylidene)-a-(2,4-dichlorophenyl)ethylamine. Of course dimethylsulfoxide may be used as a solvent.

The racemization is usually effected in the presence of a solvent. The solvent is not particularly limited, so long as it does not inhibit the reaction. Examples of the

MWMWM

solvent are aromatic solvents such as toluene, benzene, xylene and chlorobenzene; ether solvents such as diethyl ether, methyl tert-butyl ether and dioxane; aliphatic solvents such as hexane and heptane; and dimethylsulfoxide. The amount by weight of the solvent used, although it may vary depending upon the kind of solvent used, is usually 0.3 to 100 times, preferably 0.5 to 10 times, the weight of optically active N-(c-methyl- 2,4-dichlorobenzylidene)-a-(2,4-dichlorophenyl)ethylamine.

The reaction temperature and time for the racemization may vary depending upon the kind and amount of alkali metal alkoxide, and the like. The racemization is usually effected at 0°C to the boiling point of the solvent, preferably 0" to 100°C, more preferably 10° to 50 0 C, for 1 to 48 hours.

The proceeding of the reaction can be monitored by taking a part of the reaction mass, and then measuring the angle of rotation or after hydrolysis, analyzing by high performance liquid chromatography using an optically active column.

The resulting racemic N-(a-methyl-2,4-dichlorobenzylidene)--(2,4-dichloro- 15 phenyl)ethylamine, after the removal of dimethylsulfoxide, alkali metal alkoxide and the like from the reaction mass by washing with an aqueous solution containing an inorganic osalt such as sodium chloride, is usually used as such in the subsequent step. This racemic compound may be isolated, for example, by distillation of low boiling fractions, or after isolated, may be purified by a technique such as distillation, recrystallization or 20 chromatography.

The racemic N-(a-methyl-2,4-dichlorobenzylidene)-a-(2,4-dichlorophenyl)ethylamine can be decomposed into racemic l-(2,4-dichlorophenyl)ethylamine and 2,4-dichloroacetophenone by hydrolysis, for example, according to the ordinary process.

The hydrolysis is usually effected in the presence of an acid such as diluted 21 hydrochloric acid or sulfuric acid using no solvent or using a solvent. In this case, the acid is usually used at an amount of about 1 to 10 equivalents, preferably about 1.05 to equivalents, to 1 equivalent of racemic N-(a-methyl-2,4-dichlorobenzylidene)-a- (2,4-dichlorophenyl)ethylamine, and water is usually used at an amount of about 1 to 1000 moles, preferably about 20 to 100 moles, to 1 mole of racemic N-(a-methyl-2,4-dichlorobenzylidene)-a-(2,4-dichlorophenyl)ethylamine.

When a solvent is used, the amount by weight of the solvent used is usually about 0.1 to 5 times the weight of racemic N-(a-methyl-2,4-dichlorobenzylidene)-a- (2,4-dichlorophenyl)ethylamine. As the solvent, it is not particularly limited, so long as it does not inhibit the reaction. Examples of the solvent are alcohol solvents such as methanol and ethanol; aliphatic solvents such as hexane and heptane; halogenated solvents such as dichloroethane and chloroform; ester solvents such as ethyl acetate; ether solvents such as dioxane and diethyl ether; and aromatic solvents such as toluene, xylene and chlorobenzene.

15 The reaction temperature and reaction time for the hydrolysis may vary Sdepending upon the kind and amount of acid used. The hydrolysis is usually effected at 0C to the boiling point of the solvent, preferably 30° to 70°C, for 10 minutes to 5 hours.

The hydrolysis gives a water-soluble salt of 1-(2,4-dichlorophenyl)ethylamine with the acid, and 2,4-dichloroacetophenone. When the hydrolysis is effected 20 without any solvent, for example, a water-insoluble solvent is added to the reaction mass, and 2,4-dichloroacetophenone is isolated by extraction into the organic layer, after which the aqueous layer is made alkaline by the addition of an aqueous alkali solution such as 0 aqueous sodium hydroxide solution, and then extracted with a water-insoluble solvent, followed by concentration of the organic layer under reduced pressure. Thus, 1-(2,4-disl iv 22 chlorophenyl)ethylamine can be isolated.

When the hydrolysis is effected using a water-soluble solvent such as an alcohol solvent, the alcohol may be distilled out, and then treated in the same manner as described above. When a water-insoluble solvent is used, the reaction mass may be treated in the same manner as described above, except that it is subjected as such to phase separation and 2,4-dichloroacetophenone is extracted into the organic layer.

The 1-(2,4-dichlorophenyl)ethylamine can also be isolated in the following manner: the reaction mass is subjected to steam distillation, so that 2,4-dichloroacetophenone is distilled out as the water azeotrope and separated, and the residue is made alkaline by the addition of an aqueous alkali solution such as aqueous sodium hydroxide solution, and extracted with an water-insoluble solvent, followed by concentration of the organic layer under reduced pressure.

Alternatively, the reaction mass is made alkaline by the addition of an aqueous alkali solution such as aqueous sodium hydroxide solution, and extracted with a 15 water-insoluble solvent to give a mixture of 2,4-dichloroacetophenone and 1-(2,4-di- Schlorophenyl)ethylamine, which can be isolated by an ordinary isolation technique such as column chromatography. The 2,4-dichloroacetophenone recovered by isolation can be recycled.

According to the present invention, racemic 1-(2,4-dichlorophenyl)ethyl- 20 amine, which is useful, can be simply produced with high efficiency by way of optically active N-(a-methyl-2,4-dichlorobenzylidene)-oc-(2,4-dichlorophenyl)ethylamine derived from optically active 1-(2,4-dichlorophenyl)ethylamine which is useless.

As the production process for chloro-substituted phenylalkylamine there has been a process comprising reacting the corresponding chloro-substituted phenylalkylle 1 ketone with ammonia and hydrogen gas under a pressure of 120 atm. in the presence of a Raney nickel catalyst attenuated with a sulfur compound (JP-A 2-73042/1990).

This process has, however, disadvantages that there is found difficulty in operating the facilities requiring high pressure and that alcohol compounds are formed as by-product by reduction of the starting material ketones.

For the industrially favorable production of chloro-substituted phenylalkylamines [II] used in the present invention, the corresponding oxime acetates may be used and subjected to catalytic hydrogenation in the presence of a particular solvent such as an organic carboxylic acid solvent and a particular catalyst such as a platinum catalyst.

Thus, the chloro-substituted phenylalkylamines [II] can be efficiently produced in high yield, even under a low pressure, with almost no alcohol compound formed as a by-product. The present inventors have found this fact and completed the invention.

A chloro-substituted phenylalkylamine of the general formula [II]: S" H2N C1 R2

R

wherein R 1 is lower alkyl and R 2 is hydrogen or chlorine, can be produced by effecting catalytic hydrogenation of a chloro-substituted phenyl alkyl ketone oxime acetate of the general formula OAc N

C

t [I] R2 wherein Ri and R 2 are each as defined above, in the presence of an organic carboxylic acid solvent and a platinum catalyst.

The following will describe this process in detail.

Examples of the group R I in the chioro-substituted phienyl alkyl ketone oxime acetate [II] used in the present invention are lower alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and pentyl. Examples of the group R 2 are hydrogen and chlorine.

Typical examples of the acetate I are oxime acetates such as 2'-chloroacetophenone, 3' -chioroacetophenone, 4'-chloroacetophenone, 2' -dichioroacetophenone, 2' -dichloroacetophenone, 2' ,5 '-dichioroacetophen one, 3' ,4'-dichioroacetophenone, 3',5'-dichloroacetophenone, 2'-chlorophenyl ethyl ketone, 3'-chlorophenyl ethyl ketone, 4'-chlorophenyl ethyl ketone, 2',3'-dichlorophenyl ethyl ketone, 2',4'-dichlorophenyl ethyl ketone, 2',5'-dichlorophenyl ethyl ketone, 3',4'-dichlorophenyl ethyl ketone, 3',5'-dichlorophenyl ethyl ketone, 2'-chlorophenyl i-propyl ketone, 3'-chlorophny i-rplktn,4-hoopey -rplktn,2,4-ihoohnlipoy *fe 15 phnlpoy ketone, chlorophenyl i-propyl ketone, 2',4'-dichlorophenyl i-propylo, p ketone, 2',5'-dichlorophenyl i-propyl ketone, 3',4'-dichlorophenyl i-propyl ketone, 3' ,5 -dichlorophenyl npropyl ketone, 2,'-chlorophenyl n-propyl ketone, '-chlorony '0 pnlpropyl ketone, 4'-chlorophenyl pn-poyl ketone, ','-dchlorolpenyl nepropyl ~ihorpey penty ketone, 2',4'-dichlorophenyl n-proyl ketone, 2,5'-dichlorophenyl npoy eoe pentyl ketone, 3',4'-dichlorophenyl pentyl ketone and 3',5'-dichlorophenyl pentyl ketone.

The acetate I] can be simply produced by treating the corresponding ketone, a chloro-substituted phenyl alkyl ketone of the general formula [IV]: O- Cl R-

[IV]

R2 wherein R 1 is lower alkyl and R 2 is hydrogen or chlorine, with a salt of hydroxylamine with an acid to convert into a keto oxime, a chloro-substituted phenyl alkyl ketone oxime of the general formula [III]: rOH N C1 1 II]

R

2 wherein R 1 and R 2 are each as defined above, followed by treatment with an acylating agent to convert into an acetate.

For the treatment of the ketone [IV] with a salt of hydroxylamine with an 10 acid, examples of the salt of hydroxylamine with an acid are those with mineral acids, such as hydrochloric acid salt, sulfuric acid salt and phosphoric acid salt. The amount of salt used is usually in the range of 1 to 1.1 moles to 1 mole of the ketone [IV].

The reaction is usually effected in a solvent. Examples of the solvent are 0 mixtures of water and alcohol solvents compatible with water, such as methanol and ethanol; and mixtures of water and solvents incompatible with water, such as hexane, heptane, toluene, methylene chloride, dichloroethane and methyl tert-butyl ether. In the latter case, the reaction can be allowed to proceed more smoothly by using a phase transfer catalyst together. The amount by weight of the solvent used is usually about I to times the weight of the ketone [IV].

I

26 The reaction, although it proceeds at room temperature, can also be promoted by heating to about 50° to 60°C. With a progress of the reaction, the mineral acid is liberated, which is neutralized with an aqueous solution of an alkali such as sodium hydroxide, sodium carbonate or ammonia during or after the reaction. The resulting keto oxime [III] can be isolated; for example, when it is obtained as crystals, by distilling out the solvent, washing the collected crystals with water or the like, and then drying, or when it is being dissolved in the organic layer, by subjecting the organic layer to phase separation, washing with water, and distilling out the solvent.

For the treatment of the ketone oxime [III] with an acylating agent to convert into an acetate, examples of the acylating agent are acetic anhydride and acetyl halides such as acetyl chloride and acetyl bromide. The acylating agent is usually used at an amount of 1 to 1,1 moles to 1 mole of the ketone oxime [III]. When the acetate I is subjected as such to catalytic hydrogenation without being isolated, the acylating agent is preferably used at an amount of 1 to 1.05 moles to 1 mole of the ketone oxime [III], S* 15 which makes it possible to reduce the formation of an amide compound of the desired product as a by-product.

The reaction is usually effected in a solvent. Examples of the solvent are Sorganic carboxylic acids such as formic acid, acetic acid and propionic acid; hexane, heptane, toluene, methylene chloride, dichloroethane, and methyl tert-butyl ether. The amount by weight of the solvent used is usually about 1 to 10 times the weight of the ketone oxime [III]. The reaction temperature is usually in the range of 20*C to the boiling point of the solvent, preferably about 50"C to the boiling point of the solvent.

After completion of the reaction, the acetate I can be isolated, for example, by distilling out the solvent and excess of the acylating agent. When an organic 27 carboxylic acid is used as a solvent, the reaction mixture may be subjected as such to catalytic hydrogenation.

This process is characterized in that the acetate I is subjected to catalytic hydrogenation in the presence of an organic carboxylic acid solvent and a platinum catalyst. The platinum catalyst is not particularly limited, and those carried on carriers such as carbon, silica gel and alumina are usually used. The amount of catalyst used, in terms of metal, is usually in the range of about 0.05% to 1% by weight, preferably about 0.1% to 0.2% by weight, based on the weight of the acetate I Examples of the organic carboxylic acid used as a solvent are lower carboxylic acids such as formic acid, acetic acid and propionic acid, and mixtures thereof.

In particular, acetic acid is preferably used. The organic carboxylic acid is usually used at an amount by weight which is about 1 to 100 times, preferably 5 to 10 times, the weight of the acetate I], The catalytic hydrogenation is usually effected at 10' to 50°C, preferably 15 to 40°C, If the temperature is higher than 50°C, there is a tendency to increase the formation of by-products such as dimers and ketone compounds; therefore, it is preferably 50°C or lower.

The pressure for hydrogenation is usually 5 kg/cm 2 G or higher, preferably about 5 to 50 kg/cm2G, although the reaction can be allowed to proceed sufficiently even under a pressure of about 5 to 30 kg/cm 2 G. If the pressure is lower than 5 kg/cm 2

.G,

Sthe reaction becomes slow and there is a tendency to increase the formation of by-products such as dimers and ketone compounds; therefore, the pressure is preferably kg/cm 2 .G or higher.

Thus, the desired amine [II] is formed. After completion of the reaction, the 28 desired product can be isolated, for example, by separating the catalyst, distilling out the organic carboxylic acid, neutralizing with an aqueous solution of a base such as sodium hydroxide, extracting with an organic solvent, and distilling out the organic solvent. If necessary, the desired product may be purifie]j by a purification technique such as distillation and recrystallization. The catalyst recovered by isolation can be recycled.

According to the process of the present invention, the desired 1-(chlorosubstitutedphenylalkyl)amine [II] can be efficiently produced in high yield, even under a low pressure, with almost no alcohol compound formed as a by-product.

It has been known that 1-arylethylamine, which is a starting material used in the present invention, can be obtained by the hydrolysis of an N-(i-arylmethyl)formamide of the general formula [VI]: R Ar CH-NH-CHO

[VI]

wherein R is lower alkyl, optionally substituted aryl or optionally substituted aralkyl, and Ar is optionally substituted aryl. Further, there has been known a process for producing S 15 N-(1-phenylethyl)formamide by heating a mixture of acetophenone, ammonium formate and formic acid J. Am. Chem. Soc., vol. 58, 1808 (1936)). This process is, Showever, not satisfactory because of its low yield.

0 As a result from various studies, the present inventors have found that o0o N-(1-arylmethyl)formamide [VI] can be produced in high yield by pouring an aryl ketone of the general formula RArC=O [V] wherein R and Ar are each as defined above, together with formic acid, into formamide and/ammonium formate.

-~I

The following will describe this process in detail.

The group R in the aryl ketone used represents lower alkyl, optionally substituted aryl or optionally substituted aralkyl. Examples of the lower alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl and pentyl.

Examples of the optionally substituted aryl group are phenyl, naphthyl, and these groups substituted with halogen such as fluorine, chlorine and bromine; nitro; lower alkyl such as described above; lower haloalkyl such as difluoromethyl and trifluoromethyl; lower alkoxy such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, secbutoxy, tert-butoxy and pentoxy; lower haloalkoxy such as difluoromethoxy and trifluoromethoxy; and the like. Examples of the optionally substituted aralkyl group are benzyl, naphthylmethyl, and these groups substituted with halogen such as fluorine, chlorine and bromine; nitro; lower alkyl such as described above; lower haloalkyl such as difluoromethyl and trifluoromethyl; lower alkoxy such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy and pentoxy; lower haloalkoxy such as difluoromethoxy and trifluoromethoxy; and the like.

Examples of the group Ar are aryl optionally substituted with halogen, nitro, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy and the like, such as described above.

Typical examples of the aryl ketone are acetophenone, 2'-chloroacetophenone, 3'-chloroacetophenone, 4'-chloroacetophenone, 4'-fluoroacetophenone, 4'-bromoacetophenone, 2',3'-dichloroacetophenone, 2',4'-dichloroacetophenone, dichloroacetophenone, 2',6'-dichloroacetophenone, 3',4'-dichloroacetophenone, dichloroacetophenone, 3',4'-dibromoacetophenone, 2'-nitroacetophenone, 3'-nitroacetophenone, 4'-nitroacetophenone, 2'-trifluoromethylacetophenone, 3'-trifluoromethylaceto-

I

t 11 V V phenone, 4'-trifluoromethylacetophenone, 2'-methoxyacetophenone, 3'-methoxyacetophenone, 4'-methoxyacetophenone, 2'-trifluoromethoxyacetophenone, 3'-trifluoromethoxyacetophenone, 4'-trifluoromethoxyacetophenone, 2',4'-dimethoxyacetophenone, propiophenone, 2'-chlorophenyl ethyl ketone, 3'-chlorophenyl ethyl ketone, 4'-chlorophenyl ethyl ketone, butyrophenone, 2'-chlorophenyl i-propyl ketone, 3'-chlorophenyl i-propyl ketone, 4'-chlorophenyl i-propyl ketone, 2'-chlorophenyl n-propyl ketone, 3'-chlorophenyl pentyl ketone, 2'-methylacetophenone, 2'-chloro-4'-trifluoroacetophenone, 2'-methoxy-4'-bromoacetophenone, 2'-nitrophenyl i-butyl ketone, 4'-methylphenyl propyl ketone, benzophenone. 4'-chlorobenzophenone, benzyl phenyl ketone, 4'-methylbenzyl phenyl ketone, 1-acetonaphthone and 2-acetonaphthone.

Formamide and ammonium formate, which are starting materials used in the present invention, may be commercially obtained or may be produced by reacting formic acid with ammonia water or anunmmonia gas. The amount of formamide or ammonium formate used, in terms of nitrogen, is usually in the range of about 1 to 10 moles, 15 preferably about 2 to 4 moles, to 1 mole of the aryl ketone The amount of formic acid used is usually in the range of about 0.1 to 10 moles, preferably about 0.5 to 5 moles, more preferably about 0.7 to 4 moles, to 1 mole of the aryl ketone Formic acid, even if it contains water, ammonium formate or the like, can be used.

This process is characterized in that the aryl ketone together with formic acid, is poured into formamide and/or ammonium formate. The aryl ketone and formic acid may be added separately or may be previously mixed together and then added.

The reaction temperature is usually in the range of 150" to 200*C, preferably I I -41 31 155° to 175°C. The aryl ketone together with formic acid, is usually poured for about 0.5 to 10 hours, although it may vary depending upon the production scale and the like. After the addition, stirring is usually continued for about 1 to 10 hours to make the reaction complete.

At that time, ammonia formed from the reaction system is trapped with formic acid to convert into ammonium formate, which is preferably recycled to the reaction system and/or used in the subsequent reaction. This makes possible effective utilization of ammonia formed as a by-product and also reduction in the amount of ammonium formate used.

For example, when formic acid containing ammonium formate, which is obtained by the absorption of formed ammonia in formic acid, is recycled as formic acid to be added to the reaction system, the amount of formic acid returned to the ammonia recovering tower is usually about 10 to 100 moles and the amount of formic acid recycled from the recovered liquor to the reaction system is usually about 0.1 to 10 moles, 15 preferably about 0.5 to 5 moles, more preferably about 0.7 to 4 moles, both to 1 mole of the aryl ketone poured per unit time, Preferably, the pipes leading to the ammonia recovering tower are usually kept at about 800 to 120 0 C. This makes possible prevention of ammonium carbonate S from adhering to the inner walls of the pipes to improve the recovery ratio of ammonia.

20 Thus, the desired N-(l-arylmethyl)formamide [IV] is formed. After completion of the reaction, the desired product can be isolated by distilling out low boiling S" fractions from the reaction mass. If necessary, the desired product may be purified by distillation, recrystallization or other purification techniques. The recovered low boiling fractions contain formamide, which can be used again.

I--I

32 The resulting N-(l-arylmethyl)formamide [IV] can be simply converted into 1-arylmethylamine by hydrolysis with hydrochloric acid, sulfuric acid or the like.

According to the process of the present invention, the desired N-(l-arylmethyl)formamide can be produced in high yield by a simple procedure, pouring aryl ketone together with formic acid, into formamide and/or ammonium formate.

The present invention will be further illustrated by the following examples, which are not to be construed to limit the scope thereof.

Examples 1-9 and Reference Comparative Examples A and B (Process A) A four-necked flask equipped with a Vigreux refining tower, a thermometer and a mechanical stirrer was charged with a C 2

-C

4 alkyl ester of (RS)-2-cyano-3,3dimethylbutanoic acid and 1-(2,4-dichlorophenyl)ethylamine at prescribed amounts. The temperature was raised to 180 0 C, and the reaction was effected at 180" to 190"C for 5 to hours, while distilling out the formed alcohol. After completion of the reaction, the 15 reaction mixture was cooled to room temperature, and the resulting crystals were collected by filtration and washed twice with n-hexane. The crystals thus obtained were dried under reduced pressure, which afforded the desired compound 1 or la.

(Process B) A four-necked flask equipped with a helicoils-containing refining tower 20 (20 cm in height), a thermometer and a mechanical stirrer was charged with a C-C 4 alkyl ester of (RS)-2-cyano-3,3-dimethylbutanoic acid and 1-(2,4-dichlorophenyl)ethylamine at prescribed amounts, to which 50 ml of a prescribed solvent was added. This solution was heated to reflux for 8-20 hours, while distilling out the formed alcohol (about 30 ml) together with the solvent. After completion of the reaction, the reaction mixture was

I

33 cooled to room temperature, to which 50 ml of n-hexane was added, and the resulting crystals were collected by filtration and washed twice with n-hexane. The crystals thus obtained were dried under reduced pressure, which afforded the desired compound 1 or la.

The yield of compound 1 (in racemic form) and the yield of compound la (in optically active form) are shown in Tables 1 and 2, respectively.

Also shown in Table 1 are the results of Reference Comparative Example in which methyl 2-cyano-3,3-dimethylbutanoate was used in place of the C 2

-C

4 alkyl ester of (RS)-2-cyano-3,3-dimethylbutanoic acid in the above process A or B.

TABLE 1 Example Process R* 1

CYBR

2 DCEA Solvent Product Yield* 4 X/y* 1 A Et 20.0 23.6 none 34.6 93.5 88/22 2 B Et 20.0 27.0 xylene 35.8 96.7 67/33 3 A Bu 19.7 20.0 none 28.8 90.8 63/37 4 B Et 20.0 27.7 cumene 34.3 92.7 52/48 Ref. A A Me 20.0 28.2 none 22.6 56.0 79/21 Ref. B B Me 20.0 36.8 xylene 26.3 65.2 71/29 1: The alkyl group in the alkyl ester of (RS)-2-cyano-3,3-dimethylbutanoic acid (Me, Et and Bu represent methyl, ethyl and n-butyl, respectively.) The alkyl ester of (RS)-2-cyano-3,3-dimethylbutanoic acid -(2,4-dichlorophenyl)ethylamine The ratio of the desired product to the alkyl ester of (RS)-2-cyano- 3,3-dimethylbutanoic acid The diastereomer ratio calculated using the area comparison method in the analysis by high performance liquid chromatography The conditions for the analysis by high performance liquid chromatography (HPLC) are as follows: Apparatus: HITACHI L-6200 Column: SUMIPAX YMC-GEL SIL 120A

C

C..

C...r *00 0* *0 0 Co *r C O Co

I

34 Rm, 4 mm diameter x 25 cm. length) Mobile phase: n-hexane/ethanolltrifluoroacetic acid =240: 10: 1 Detection: UV 254 nmn TABLE 2 Example Process R CYBR* 2 [CA*Sol vent Product Yield-- Xi/Y2* (M 5*14_ B E t j 20.0 0*6 zyee 35.3 95. 50/5_;_ A jBu 19,7 none 28.6 90.0 8 A [Et j20.0__ 23.6*7 jnone 33.8 91.3 46/46*12 91 A[ Et 17.0 20.0*8_1none 27.2 8 6.7 44/44* 13 The alkyl group in the alkyl ester of (RS)-2-cyano-3,3-dimethylbutanoic acid (Et and Bu represent ethyl and n-butyl, respectively.) The alkyl ester of (RS)-2-cyano-3,3-dimethylbutanioic acid Optically active 1-(2,4-dichlorophenyl)ethylamidne composed mainly of -formn The ratio of the desired product to the alkyl ester of (RS)-2-cyano- 49 *5:3,3-dimethylbutanoic acid *:The diastereomer ratio calculated using, the area comparison method in the 0 0 0 0analysis by high performance liquid chromatography The conditions for the analysis by high performance liquid chromatography (HPLC) are as follows: Apparatus: HITACHI L-6200 Col umn: SUMIPAX YMC-GEL SIL 120A Jtm, 4 mm. diameter x 25 cm length) SUMICHIRAL OA-4700 g~m, 4.6 mm diameter x 25 cm length) Mobile phase: n-hexane/ethanob/trifluoroacetic acid 240:10: 1 Detection: UV 254 nm (R)-1I-(2,4-dichlorophenyl)ethylamine having an optical purity of 99.8% e.e.

or higher was used.

(R)-1-(2,4-dichlorophenyl)ethylamidne having an optical purity of 84% e.e.

4 or higher was used, 1-(2,4-dichlorophenyl)ethylamine having an optical purity of 76% e.e.

or higher was used.

X2/Y I I X2/Y1I <0.1/<0.1I *11: X2/YI= i *12: X2/Y1 =4/4 *13: X2/Y 6/6 *14: The physical properties of the compound of the present invention obtained in Example 5 are as follows: m.p. 160-161°C, [a]D 20 18.0" (c 1.01, CH 2 Cl 2 Example A four-necked flask equipped with a Vigreux refining tower, a thermometer and a mechanical stirrer was charged with 17.93 g (0.105 mol) of ethyl (RS)-2-cyano- 3,3-dimethylbutanoate, and the temperature was raised to 190 0 C. Then, 20.0 g (0.105 mol) of (R)-1-(2,4-dichlorophenyl)ethylamine (optical purity, 92.4% was added dropwise at the same temperature over 2 hours. The reaction was effected at the same temperature for 17 hours, while distilling out the formed alcohol. After completion of the reaction, the reaction mass was cooled to 140' to 150°C, into which 91.9 g of monochlorobenzene was poured. The solution was then cooled to 80° to 90 0 C and kept 10 at the same temperature.

Another four-necked flask equipped with a thermometer, a Liebig condenser O.L: for condensation of the distillate and a mechanical stirrer was charged with 215 g of C water, 1.14 g of 35% hydrochloric acid and 0.03 g of seed crystals, and the temperature was raised to 97° to 100°C. The above monochlorobenzene solution (kept at about 15 was then added dropwise at the same temperature over 2.25 hours. Almost at the same time that monochlorobenzene was distilled out as an azeotropic mixture with water and monochlorobenzene, the crystals of compound 1 a were deposited, and an aqueous slurry of compound la was obtained. The slurry was cooled to 25°C over 2 hours and then stirred at the same temperature for 30 minutes. The crystals were collected by filtration and washed once with 100 ml of water. The crystals thus obtained were dried under reduced pressure, which afforded 30.0 g of compound la. (91.2% yield; optical isomer

L

36 ratio, X1 X2: Y1 Y2= 47.2: 1.9: 1.8:49.1) Test Example I The respective optical isomers X2-, Y1- and Y2-forms) constituting the racemic compound 1 were isolated and purified by high performance liquid chromatography (HPLC) according to the method as described below, and examined for their plant disease (rice blast) control activity. The results are shown in Table 3.

The conditions for the isolation by HPLC were as follows: Apparatus: HITACHI L-6200 Column: SUMIPAX YMC-GEL SIL 120A pm, 4 mm diameter x 25 cm length) SUMICHIRAL OA-4700 4m, 4.6 mm diameter x 25 cm length) Mobile phase: n-hexane/ethanol/trifluoroacetic acid 240: 10: 1 Detection: UV 254 nm XI-, X2-, Y1- and Y2-forms were eluted in this order. The absolute configuration of each isomer was determined by the X-ray structure analysis of X1-form and Y-form (Y1+ Y2).

10 Testmethod A plastic pot was filled with sandy loam and seeded with rice (Kinki No. 33), °which was grown in a greenhouse for 20 days. A wettable powder formulated from the test compound (by well pulverizing and mixing 50 parts of the test compound, 3 parts of calcium liguninsulfonate and 45 parts of synthetic hydrated silicon oxide) was diluted 15 with water to a prescribed concentration, and the dilution was used for foliar application so as to adhere sufficiently to the rice leaf surface. After the application, the plants were air dried and inoculated by spraying a spore suspension of Pyricularia oryzae. After the inoculation, the plants were placed at 28"C in the dark under high humidity for 4 days and then examined for control activity.

1 1. k 37 The control activity was determined by visual observation of the seveiry, i.e., the extent of colonies and lesions on the leaves, stems and the like, of the test plants at the time of examination, and represented in 6 ranks, for no observation of colonies and lesions; for about 10% observation; for about 30% observation; for about 50% observation; for about 70% observation; and for more than observation with no difference from the seveiry of the untreated plants.

TABLE 3 Concen- Control activity tration xi X2 Y1 Y2 X1 Y2 Racemic Fthalide (ppm) (1 1) (1:1:1:1) 100 4 10 0 5 5 5 4 0 0 15 1 5 4 4 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 31 2 0 0J 4 4 3 0 1.6 2 0 0 4 3 3 0 0.8 1 0 0 3 3 2 0 04 0 0 0 3 2 1 0 0.2 0 0 0 1 0 0 0 The symbols in parentheses represent the absolute configuration of asymmetric carbon atoms in the order (acid side, amine side).

Commercially available agent for comparison Examples 1 1-16 and Reference Comparative Examples 1-2: Production of ethyl 2-cyano-3,3-dimethylbutanoate To a solution of methyl magnesium chloride prepared from 119 g of methyl chloride, 49.6 g of magnesium and 509 g of tetrahydrofuran was added 6.0 g of copper *0 60 B* 6 0 e.

to..

0060 #0*O o**o 00 S 0 4*

•B

B 0 0 .1 0 60 Op I 00O iodide at 35" to 40"C and then added dropwise a solution of 240 g of ethyl 2-cyano- 3-methyl-2-butenoate dissolved in 480 g of toluene at the same temperature over about 1 hour. After completion of the addition, the reaction was further effected at the same temperature for 1 hour. The reaction mixture was cooled to 20" to 30"C and then poured into 1742 g of 20% aqueous ammonium chloride solution at 10" to 20"C. The mixture was allowed to stand without disturbance at room temperature and then subjected to phase separation. The aqueous layer was extracted twice with 480 ml of ethyl acetate, and the organic layers were combined and washed twice with 480 g of saturated saline solution. The combined organic layer was dried i,,n anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was distilled as such (boiling point of the main fraction, 80° to 86°C/12 to 15 mmHg), which afforded the desired product. The yield of ethyl a-cyano-tert-butylacetate after the disti'lation was 249 g 0 In Examples 12-16 and Reference Comparative Examples 1-2, the reaction S 15 was effected in the same manner, except that the kind and amount of catalyst were 0 changed from the above production example. All the results are shown in Table 4. The yo yield in the table is based on the alkyvl ester of 2-cyano-3-methyl-2-butenoic acid.

om*•o 0* 0 *i oO*o* oo *I a 39 TABLE 4 Example Solvent Catalyst *3 Time Yield* THF: toluene (part by wt.)* 2 (hr) 11 1 11 Cul (0.025) Et 1 94 12 1 1*1 CuCl (0.025) Et 1 91 13 1 1*1 CuCl (0.013) Et 1 91 14 1 11 CuCl (0.006) Et 1 91 1 1*1 CuCl (0.002) Et 1 89 16 1 1* CuCi (0.001) Et 1 89 Ref. 1 1: 1* 1 none Et 1 Ref. 2 only THF none Me 2.5 Weight ratio The amount of catalyst (part by weight) to 1 part by weight of the starting material lower alkyl ester of 2-cyano-3-methyl-2-butenoic acid The alkyl group in the starting material lower alkyl ester of 2-cyano-3methyl-2-butenoic acid Yield after the distillation The following are examples for the production of the starting material. In these examples, the reaction rate was determined by the following equation: Reaction rate 100 GC area ratio of the remaining alkyl ester of cyanoacetic acid The conditions for the gas chromatography (GC) were as follows: Apparatus: SHIMAZU GC-7A Column: 10% DEXSIL 300 GC (3 mm diameter x 1 m length) UNIPOTHP 100-200 mesh Column Temperature: raised to 70-150C at a rate of Examples 17-22 and Reference Comparative Example 3: Production of ethyl 2-cyano-3-methyl-butenoate A reaction vessel was charged with 50.0 g of ethyl cyanoacetate, 51.34 g of acetone, 1.99 g of acetic acid, 0.24 g of p-aminophenol and 41 ml of n-hexane, and the

I

I II rsr m r 41 Weight ratio p-Aminophenol and acetic '.cid p-Toluidine and acetic acid p-Aminophenol and benzoic acid p-Aminophenol and propionic acid The following are examples for the optical resolution of 1-(2,4-dichlorophenyl)ethylamine. In these examples, the percentages are all by weight. The optical purity enantiomeric excess) of 1-(2,4-dichlorophenyl)ethylamine was determined by high performance liquid chromatography (HPLC) using an optically active column under the following conditions.

Apparatus: HITACHI L-6200 Column: SUMICHIRAL OA-4100 (6 mm diameter x 25 cm length) Elution solvent: n-hexane/ethanol/trifluoroacetic acid 240 10 1 (volume ratio) Detection: UV 254 nm S"-The absolute configuration (R or S) of optically active 1-(2,4-dichlorophenyl)ethylamine was determined by the X-ray structure analysis of (R)-N-[l-(2,4-dichlorophenyl)ethyl]-(R)-2-cyano-3,3-butanamide, one of the stereoisomers separated from the diastereomer mixture obtained by reacting the -(2,4-dichlorophenyl)ethylamine 10 (99.9% which was obtained by the process of the present invention, with (RS)-2cyano-3,3-dimethylbutanoic acid by the process as described in JP-A 2-76846/1990.

Example 23 To a mixture of 1.2 liters of water and 2.8 liters of 95% ethanol were added goe 53.24 g of L-aspartic acid (Special Grade Reagent available from Wako Pure Chemical Industries, Ltd,; chemical purity, [a]D +24,9" to and 76.5 g of (RS)-1-(2,4-dichlorophenyl)ethylamine, and the mixture was heated to reflux with stirring for 1 hour. While stirring was continued, the solution was air cooled to 40"C and I III LI I L cr" then water cooled to 20'C. The solution was stirred at 20°C for 30 minutes, and the resulting crystals were collected by filtration and washed with 100 ml of chilled ethanol.

The crystals thus obtained were dried to give 27.8 g of (+)-l-(2,4-dichlorophenyl)ethylamine L-aspartate as white crystals. These crystals were treated with 100 ml of aqueous sodium hydroxide solution, and the liberated amine was extracted with 100 ml of toluene. The resulting toluene layer was dried with anhydrous magnesium sulfate and then concentrated with an evaporator, which afforded 19.2 g of (R)-(+)-1-(2,4-dichlorophenyl)ethylamine. The optical purity was 87% e.e.

Example 24 To a mixture of 150 ml of water and 200 ml of 95% ethanol were added 13.31 g of L-aspartic acid (Special Grade Reagent available from Wako Pure Chemical Industries, Ltd.; chemical purity, [aI]D +24.9" to and 38.14 g of (RS)-l-(2,4-dichlorophenyl)ethylamine, and the mixture was heated to reflux with stirring for 1 hour. While stirring was continued, the solution was air cooled to 40'C and 15 then water cooled to 20"C. The solution was stirred at 20'C for 30 minutes, and the resulting crystals were collected by filtration and washed with 50 ml of chilled e:hanol.

The crystals thus obtained were dried to give 14.2 g of (+)-l-(2,4-dichlorophenyl)ethylamine L-aspartate as white crystals. These crystals were treated with 50 ml of aqueous sodium hydroxide solution, and the liberated amine was extracted with 100 ml of toluene. The resulting 'ne layer was dried with anhydrous magnesium sulfate and then concentrated with an evaporator, which afforded 8.3 g of the desired dichlorophenyl)ethylamine. The optical purity was 91% e.e.

Example To a mixture of 1 liter of water and 1 liter of methanol were added 66.6 g of a a a a a a 4 *r r II 43 L-aspartic acid (Special Grade Reagent available from Wako Pure Chemical Industries, Ltd.; chemical purity, [ca]D +24.9" to and 190.07 g of dichlorophenyl)ethylamine, and the mixture was heated to reflux with stirring for 1 hour.

While stirring was continued, the solution was air cooled to 40°C and then water cooled to 20°C. The solution was stirred at 20"C for 30 minutes, and the resulting crystals were collected by filtration and washed with 100 ml of chilled methanol. The crystals thus obtained were dried to give 67.35 g of (+)-l-(2,4-dichlorophenyl)ethylamine L-aspartate as white crystals. These crystals were treated with 200 ml of 20% aqueous sodium hydroxide solution, and the liberated amine was extracted with 200 ml of toluene. The resulting toluene layer was dried with anhydrous magnesium sulfate and then concentrated with an evaporator, which afforded 39.6 g of the desired (R)-(+)-l-(2,4-dichlorophenyl)ethylamine. The optical purity was 92% e.e.

Example 26 To 200 ml of water were added 10.7 g of L-aspartic acid (Special Grade 15 Reagent available from Wako Pure Chemical Industries, Ltd.; chemical purity, >99.0%; [a]D +24.9" to and 15.0 g of (RS)-l-(2,4-dichlorophenyl)ethylamine, and the mixture was heated to reflux with stirring for 1 hour. While stirring was continued, the 6* solution was air cooled to 45°C and then cooled almost evenly to 5°C over 3 hours. The resulting crystals were collected by filtration and washed twice with 30 ml of chilled water. The crystals thus obtained were dried to give 3.7 g of l-(2,4-dichlorophenyl)ethylamine L-aspartate as white crystals. These crystals were treated with 10 ml of a aqueous sodium hydroxide solution, and the liberated amine was extracted with 50 ml of toluene. The resulting toluene layer was dried with anhydrous magnesium sulfate and then concentrated with an evaporator, which afforded 2.15 g of the desired

II-II

A 41 All 44 (2,4-dichlorophenyl)ethylamine. The optical purity was 87% e.e.

Example 27 To a mixture of 1.2 liters of water and 2.8 liters of 95% ethanol were added 53.24 g of L-aspartic acid (Special Grade Reagent available from Wako Pure Chemical Industries, Ltd.; chemical purity, [a]D +24.9" to and 76.5 g of (RS)-l-(2,4-dichlorophenyl)ethylamine, and the mixture was heated to reflux with stirring for 1 hour. While stirring was continued, the solution was air cooled to 40°C and then water cooled to 20°C. The solution was stirred at 23"C for 30 minutes, and the resulting crystals were collected by filtration and washed with 100 ml of chilled ethanol.

The crystals thus obtained were dried to give 25.6 g of (+)-l-(2,4-dichlorophenyl)ethylamine L-aspartate as white crystals. These crystals were recrystallized from 200 ml of aqueous ethanol solution to give 20.4 g of (+)-l-(2,4-dichlorophenyl)ethylamine L-aspartate. These crystals were treated with 100 ml of 20% aqueous sodium hydroxide solution, and the liberated amine was extracted with 100 ml of toluene. The resulting 15 toluene layer was dried with anhydrous magnesium sulfate and then concentrated with an a evaporator, which afforded 11.9 g of the desired l-(2,4-dichlorophenyl)ethylamine. The optical purity was 99.9% e.e. The specific rotation was [G]D 24 +44.86' 1.114).

Example 28 To a mixture of 1.2 liters of water and 2.8 liters of 95% ethanol were added 2 53.24 g of D-aspartic acid (Special Grade Reagent available from Wako Pure Chemical Industries, Ltd.; chemical purity, [ac]D -24.0" to and 76.5 g of (RS)-l-(2,4-dichlorophenyl)ethylamine, and the mixture was heated to reflux with stirring for 1 hour. While stirring was continued, the solution was air cooled to 40'C and r~ then water cooled to 20°C. The solution was stirred at 20°C for 30 minutes, and the resulting crystals were collected by filtration and washed with 100 ml of chilled ethanol.

The crystals thus obtained were dried to give 27.1 g of (-)-l-(2,4-dichlorophenyl)ethylamine D-aspartate as white crystals. These crystals were recrystallized from 200 ml of 50% aqueous ethanol solution to give 22.1 g of (-)-1-(2,4-dichlorophenyl)ethylamine D-aspartate. These crystals were treated with 100 ml of 20% aqueous sodium hydroxide solution, and the liberated amine was extracted with 100 ml of toluene. The resulting toluene layer was dried with anhydrous magnesium sulfate and then concentrated with an evaporator, which afforded 11.9 g of the desired (S)-(-)-1-(2,4-dichlorophenyl)ethylamine. The optical purity was 99.6% e.e. The specific rotation was [a]D 24 -43.87' (c 1.082).

Example 29 A solution of 2 g of (RS)-l-(2,4-dichlorophenyl)ethylamine in 12 ml of ethanol was heated to 70C with stirring, to which a solution of 1.6 g of D-mandelic acid in 12 ml of ethanol was added over about 1 minute, and the mixture was cooled to 25 C with stirring and then allowed to stand at the same temperature with stirring for 12 hours.

SThe deposited crystals were collected by filtration and dried to give 1.4 g of diastereomer salt. These crystals were mixed with 1 g of 20% aqueous sodium hydroxide solution and then extracted twice with 2 ml of toluene. The resulting toluene layer was dried with magnesium sulfate, followed by solvent removal, which afforded 0.77 g of Sdichlorophenyl)ethylamine. The analysis by high performance liquid chromatography using an optically active column revealed that the optical purity was 91% e.e.

Example A solution of 16 g of (RS)-l-(2,4-dichlorophenyl)ethylamine in 10 ml of ~L 111 I I i* 46 ethanol was heated to 70C with stirring, to which a solution of 12.8 g of L-mandelic acid in 40 ml of ethanol was added over about 30 minutes, and the mixture was heated to and stirred at the same temperature for 30 minutes. The mixture was then cooled to over 5 hours, and the deposited crystals were collected by filtration and dried to give 13.2 g of diastereomer salt. These crystals were mixed with 10 g of 20% aqueous sodium hydroxide solution and then extracted twice with 20 ml of toluene. The resulting organic layer was dried with magnesium sulfate, followed by solvent removal, which afforded 7.3 g of (R)-l-(2,4-dichlorophenyl)ethylamine. The optical purity was 82% e.e.

The distillation of low boiling fractions from the mother liquor after the collection of the diastereomer salt gave 15.6 g of the residue. The residue was mixed with 13 g of 20% aqueous sodium hydroxide solution and then extracted twice with 30 ml of toluene. The resulting toluene layer was dried with magnesium sulfate, followed by solvent removal, which afforded 12.7 g of 1-(2,4-dichlorophenyl)ethyl- *000 amine. The optical purity was 70% e.e.

The aqueous layers remaining after the toluene extraction in and (2) were combined together, and the pH was adjusted to 0.7 by the addition of 36% hydrochloric acid. The combined aqueous layer was then extracted three times with 50 ml of ethyl acetate and dried with magnesium sulfate, followed by solvent removal, which afforded 12.3 g of L-mandelic acid.

Example 31 A solution of 16 g of (RS)-l-(2,4-dichlorophenyl)ethylamine in 17 ml of ethyl acetate was heated to 70*C with stirring, to which a solution of 6.4 g of L-mandelic acid in 80 ml of ethyl acetate was added dropwise over about 30 minutes. The tempera- I -I Il-l

SW

ture was raised to 75*C, and stirring was continued at the same temperature for minutes. The mixture was then cooled to 20"C over 5 hours, and the deposited crystals were collected by filtration and dried to give 12.9 g of diastereomer salt. A part of the product was treated in the same manner as described in Example 29, and the optical purity was determined to be 81.2% e.e.

Example 32 A mixture of 19 g of (RS)-l-(2,4-dichlorophenyl)ethylamine, 120 ml of ethanol and 15.2 g of L-mandelic acid was heated to reflux and then cooled to room temperature overnight. The deposited crystals were collected by filtration and dried to give 10.8 g of diastereomer salt. A part of the product was treated in the same manner as described in Example 29, and the optical purity was determined to be 64% e.e.

Example 33 A solution of 90 g of(RS)-l-(2,4-dichlorophenyl)ethylamine in 167 g of methyl tert-butyl ether was heated to 45°C with stirring, to which a solution of 32 g of 15 L-mandelic acid in 197 g of methyl tert-butyl ether was added over about 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. The mixture was then cooled to 20"C over 6 hours, and the deposited crystals were collected by filtration, 0 washed twice with 42 g of methyl tert-butyl ether, and dried to give 84 g of diastereomer o salt. These crystals were mixed with 185 g of 5% aqueous sodium hydroxide solution and then extracted twice with 42 g of methyl tert-butyl ether. The resulting organic layer was dried with magnesium sulfate, followed by solvent removal, which afforded 39.9 g of (R)-1-(2,4-dichlorophenyl)ethylamine. The optical purity was 95.2% e.e.

The filtrate and wash liquid after the collection of the diastereomer salt were combined together and then treated with 18 g of 5% aqueous sodium hydroxide al I- I 48 solution added. The removal of low boiling fractions from the organic layer by distillation gave 50.1 g of(S)-1-(2,4-dichlorophenyl)ethylamine. The optical purity was 77.6% e.e.

The aqueous layers remaining after the decomposition of the salt with aqueous sodium hydroxide solution and the separation of the organic layer in and (2) were combined together, and the pH was adjusted to 1.4 by the addition of 36% hydrochloric acid. The combined aqueous layer was then extracted three times with 150 g of methyl tert-butyl ether and dried with magnesium sulfate, followed by solvent removal, which afforded 31.7 g of L-mandelic acid.

Comparative Example 1 The procedures of Example 32 were repeated, except that 15 g of L-tartaric acid was used in place of L-mandelic acid and 1080 ml of 95% ethanol was further added because L-tartaric acid crystals were remaining in large quantities when 95% ethanol was used only at a volume of 120 ml. Thus, 10.8 g of diastereomer salt was obtained. A part 15 of the product was treated in the same manner as described in Example 29, and the optical purity was determined to be 36% e.e.

Comparative Example 2 The procedures of Example 32 were repeated, except that 13.4 g of L-malic acid was used in place of L-mandelic acid and 360 ml of 95% ethanol was further added because L-malic acid crystals were remaining in large quantities when 95% ethanol was 0* 9 used only at a volume of 120 ml. Thus, 14.5 g of diastereomer salt was obtained. A part of the product was treated in the same manner as described in Example 29, and the optical purity was determined to be 0.8% e.e.

Comparative Example 3 I I I- rl -r -~-rrarrr A I S 49 The procedures of Example 29 were repeated, except that 120 ml of water was used in place of ethanol; however, there occurred separation into the aqueous layer and the organic layer, and no crystals were deposited.

Example 34 A solution of 3.95 g ofD-dibenzoyltartaric acid in 60 ml of 95% ethanol was heated to 60'C, to which a solution of 2 g of (RS)-1-(2,4-dichlorophenyl)ethylamine in 20 ml of 95% ethanol was added, and the mixture was stirred at the same temperature for 5 minutes. The mixture was then cooled to 25'C with stirring and allowed to stand at the same temperature with stirring for 12 hours.

The deposited crystals were collected by filtration, and the crude diastereomer salt obtained was recrystallized from 500 ml of 95% ethanol and dried to give 1.6 g of diastereomer salt. These crystals were mixed with 1.2 g of 20% aqueous sodium a hydroxide solution and then extracted three times with 5 ml of chloroform. The resulting chloroform layer was dried with magnesium sulfate, followed by solvent removal, which afforded 0.66 g of (S)-1-(2,4-dichlorophenyl)ethylamine. The analysis by high perfora mance liquid chromatography using an optically active column revealed that the optical a a purity was 92% e.e.

a The low boiling fractions were distilled out from the mother liquor after ood the collection of the crude diastereomer salt. The residue was mixed with 2.4 g of aqueous sodium hydroxide solution and then extracted three times with 7.5 ml of chloroform. The resulting chloroform layer was dried with magnesium sulfate, followed by a solvent removal, which afforded 1.15 g of (R)-(2,4-dichlorophenyl)ethylamine. The analysis by high performance liquid chromatography using an optically active column revealed that the optical purity was 79% e.e.

-s Example A solution of 4 g of (RS)-1-(2,4-dichlorophenyl)ethylamine in 10 ml of ethanol was heated to 70°C with stirring, to which a solution of 7.88 g of D-dibenzoyltartaric acid in 25 ml of 95% ethanol was added over about 60 minutes. The temperature was raised to 80°C, and stirring was continued at the same temperature for minutes. The mixture was then cooled to 20°C over 5 hours and stirred at the same temperature for 30 minutes. The deposited crystals were collected by filtration, recrystallized from 500 ml of 95% ethanol, and dried to give 3.2 g of diastereomer salt. These crystals were mixed with 5 g of 20% aqueous sodium hydroxide solution and then extracted twice with 20 ml of toluene. The resulting organic layer was dried with magnesium sulfate, followed by solvent removal, which afforded 1.32 g of (S)-l-(2,4-dichlorophenyl)ethylamine. The optical purity was 91% e.e.

S The low boiling fractions were distilled out from the mother liquor after the collection of the crude diastereomer salt. Then, 6.58 g of the residue was mixed with 15 7 g of 20% aqueous sodium hydroxide solution and then extracted with 20 ml of toluene.

0 The toluene layer was dried with magnesium sulfate, followed by solvent removal, which *oO afforded 2.3 g of (R)-(2,4-dichlorophenyl)ethylamine. The optical purity was 91% e.e.

The aqueous layers remaining after the toluene extraction in and (2) a* were combined together, and the pH was adjusted to 0.7 by the addition of 36% hydrochloric acid. The aqueous layer was then mixed with 7 g of sodium chloride, and to the mixture was subjected to salting out at 40° to 60"C and then extracted five times with ml of ethyl acetate, followed by solvent removal, which afforded 6.82 g of D-dibenzoyltartaric acid.

Example 36 I s- i .4 51 To a mixture of 62 g of (S)-l-(2,4-dichlorophenyl)ethylamine (optical isomer ratio, S/R 80.3/19,7), 62 g of 2,4-dichloroacetophenone and 130 g of tol.Iene was added 0.28 g of zinc chloride, and the mixture was refluxed for 20 hours, while removing the formed water from the reaction system.

Then, at 25C, the mixture was washed with 10 g of 5% aqueous sodium hydroxide solution and subjected to phase separation. The resulting toluene layer was subjected to removal of water by azeotropic distillation for 4 hours. A part of the toluene solution was taken and analyzed by gas chromatography. It was found by calculation that the content of N-(cx-methyl-2,4-dichlorobenzylidene)-o-(2,4-dichlorophenyl)ethylamine was 116 g, the content of unreacted 1-(2,4-dichlorophenyl)ethylamine was 1 g and the content of 2,4-dichloroacetophenone was 0.5 g.

Then, at 30°C, to the above water-removed toluene solution was added a solution of 1.2 g of potassium tert-butoxide in 10.1 g of dimethylsulfoxide, and the mixture was stirred at the same temperature for 10 hours and then washed once with 15 233 g of 10% saline solution and twice with 233 g of saturated saline solution.

S(3) To the resulting toluene solution was added 285 g of 5% hydrochloric acid, and the mixture was stirred at 60"C for 1 hour and then allowed to stand without disturbance at the same temperature for 30 minutes, followed by phase separation to give the aqueous layer and the organic layer. To the aqueous layer was added 194 g of toluene, and extraction was effected at 60"C. The resulting toluene layer was combined with the above toluene layer, followed by solvent removal, which afforded 60.7 g of 2 ,4-dichloroacetophenone.

To the aqueous layer after the toluene extraction was added 72 g of 27% *aqueous sodium hydroxide solution, and the mixture was extracted with 580 g of 52 toluene. The removal of toluene by distillation gave 61.7 g of 1-(2,4-dichlorophenyl)ethylamine. A part of the product was taken and analyzed by high performance liquid column chromatography using an optically active column, and the optical isomer ratio S/R was found to be 52.3/47.7.

Example 37 The procedures of Example 36 were repeated, except that (R)-l-(2,4-dichlorophenyl)ethylamine (optical isomer ratio S/R 1/99) was used in place of chlorophenyl)ethylamine. Thus, 59.7 g of 2,4-dichloroacetophenone and 61 g of 1-(2,4dichlorophenyl)ethylamine were obtained. The optical isomer ratio S/R of the latter compound was 45.1/54.9.

Example 38 The reaction was effected in the same manner as described in Example 36 and a toluene solution containing optically active N-(a-methyl-2,4-dichlorobenzylidene)a-(2,4-dichlorophenyl)ethylamine was obtained.

15 Then, the removal of toluene and unreacted starting material gave 111 g of optically active N-(a-methyl-2,4-dichlorobenzylidene)-a-(2,4-dichlorophenyl)ethylamine as white crystals. E/Z 8/92, m.p. 77-85"C .'H-NMR: 1.32 (2d, 3H), 1.51 3H), 2.23 3H), 2.29 (2s, 3H), 4.56 1H), 6.6-7.8 6H) 20 Example 39 The procedures of Example 36 were repeated, except that 111 g of the crystals obtained in Example 38 and 130 g of dry toluene were used in the form of a toluene solution. The resulting toluene solution was then concentrated under reduced pressure, and the low boiling fractions were distilled out at 100°C under 20 mmHg for 53 hours, which afforded 110 g of racemic N-(a-methyl-2,4-dichlorobenzylidene)-a- (2,4-dichlorophenyl)ethylamine as a colorless clear oil. E/Z 8/92 Example The procedures of Example 36 were repeated, except that 110 g of the oil obtained in Example 39 and 130 g of toluene were used in the form of a toluene solution.

Thus, 56.9 g of 2,4-dichloroacetophenone and 57.8 g of 1-(2,4-dichlorophenyl)ethylamine were obtained. The optical isomer ratio S/R of the latter compound was 51.9/48.1.

Example 41 The procedures of Example 36 were repeated, except that 0.45 g of titanium tetraisopropoxide was used in place of zinc chloride. Thus, 59.2 g of 2,4-dichloroacetophenone and 60.8 g of 1-(2,4-dichlorophenyl)ethylamine were obtained. The optical isomer ratio S/R of the latter compound was 53.3/46.7.

t Example 42 15 The procedures of Example 36 were repeated, except that 0.62 g of p-toluenesulfonic acid was used in place of zinc chloride. Thus, 59.1 g of 2,4-dichloroacetophenone and 60.1 g of 1-(2,4-dichlorophenyl)ethylamine was obtained. The optical isomer ratio S/R of the latter compound was 53/47.

*ie Comparative Example 4 The procedures of Example 36 were repeated, except that 20 g of tert-butanol was used in place of dimethylsulfoxide. Thus, 60.3 g of 2,4-dichloroacetophenone and 61.5 g of 1-(2,4-dichlorophenyl)ethylamine was obtained. The optical isomer ratio S/R of the latter compound was 80.3/19.7.

Comparative Example L 3 L- At 80"C, 1.8 g of potassium tert-butoxide was added to a mixture of 6 g of (S)-l-(2,4-dichlorophenyl)ethylamine in 9 g of dimethylsulfoxide, which was the same as that used in Example 36, and the mixture was stirred at the same temperature for hours. After cooling to room temperature, a part of the mixture was taken and analyzed for optical isomer ratio by high performance column chromatography using an optically active column. The optical isomer ratio S/R was 80.3/19.7.

Example 43 Production of chloro-substituted phenyl alkyl ketone oxime To a mixture of 300 g of 2',4'-dichloroacetophenone in 1200 g of methanol were added 122 g of hydroxylamine hydrochloride and 400 g of water, and the mixture was heated to 60'C and then stirred at the same temperature for 3 hours, while adding 27% sodium hydroxide solution to become pH 4 tr The pH was then adjusted to 8 by the addition of 27% sodium aqueous solution, and water and methanol were distilled out under reduced pressure to the total amount of 1200 g The residue was mixed with S, 15 1200 g of water, and the mixture was cooled to 25°C. The deposited crystals were collected by filtration, washed with 1200 g of water, and dried, which afforded 322 g S. *0 (99% yield) of 2',4'-dichloroacetophenone oxime as white crystals with 99.5% purity.

Production of chloro-substituted phenyl alkyl ketone oxime acetate To a mixture of 70 g of 2',4'-dichloroacetophenone oxime and 70 g of n-heptane was added 36.4 g of acetic anhydrate, and the mixture was stirred at 70°C for 2 hours. The reaction mass was sampled in small quantities and analyzed by gas chromatography, and it was found that the starting materials had disappeared.

The reaction mass was cooled to 25°C, and the deposited crystals were collected by filtration, which afforded 60.2 g of 2',4'-dichloroacetophenone oxime acetate as white needle crystals with 100% purity. The filtrate was concentrated under reduced pressure, and the resulting crystals as the residue was washed with 10 g of ice-cooled n-heptane, which afforded 22.5 g of white needle crystals with 99% purity.

Example 44 A 100 ml autoclave was charged with 2 g of 2',4'-dichloroacetophenone oxime acetate (100% purity) obtained in Example 43 20 g of acetic acid and 0.1 g of platinum-carbon (50% water-containing product), and the atmosphere in the autoclave was replaced with hydrogen gas. The temperature was then raised to 30"C, and the pressure of hydrogen gas was increased to 20 kg/cm2G. The reaction was effected at the same temperature for 5 hours, while keeping the pressure at 20 kg/cm 2 .G by supplying hydrogen gas.

After completion of the reaction, the catalyst was removed by filtration, and acetic acid in the filtrate was distilled out under reduced pressure. The residue was mixed a with 5 g of toluene and washed with 18 g of 5% aqueous sodium hydroxide solution, 15 followed by solvent removal from the organic layer, which afforded 1.54 g of an oil.

This oil was analyzed by gas chromatography and found to contain 94.5% dichlorophenyl)ethylamine, 0.97% N-1-(2',4'-dichlorophenyl)ethyl-a-(2',4'-dichlorophenyl)ethylamine, 0.56% N-(a-(2',4'-dichlorophenyl)ethyl)acetamide and 1% 2,4-dichloroacetophenone. The contents of dechlorinated compounds and alcohol compounds to be formed by reduction of carbonyl groups were under the detection limit.

Example The procedures of Example 44 were repeated, except that 2 g of 4'-chloroacetophenone oxime acetate was used in place of 2',4'-dichloroacetophenone oxime acetate. Thus, 1.47 g of an oil was obtained.

I

r 7- This oil was found to contain 98.8% 1-(4'-chlorophenyl)ethylamine and 0.91% N-(a-(4'-chlorophenyl)ethyl)acetamide. Neither dechlorinated compounds nor alcohol compounds to be formed by reduction of carbonyl groups were detected.

Example 46 The procedures of Example 44 were repeated, except that 2 g of 3',4'-dichloroacetophenone oxime acetate was used in place of 2',4'-dichloroacetophenone oxime acetate. Thus, 1.53 g of an oil was obtained.

This oil was found to contain 89.8% 1-(3',4'-dichlorophenyl)ethylamine, 1.4% 1-(4'-chlorophenyl)ethylamine, 2.9% N-1-(3',4'-dichlorophenyl)ethyl--(3',4'-dichlorophenyl)ethylamine and 1.9% N-((x-(2',4'-dichlorophenyl)ethyl)acetamide. No alcohol compounds to be formed by reduction of carbonyl groups were detected.

Example 47 The procedures of Example 44 were repeated, except that 2 g of chloroacetophenone oxime acetate was used in place of 2',4'-dichloroacetophenone 15 oxime acetate. Thus, 1.54 g of an oil was obtained.

This oil was found to contain 88.7% 1-(3',5'-dichlorophenyl)ethylamine, 2% 1-(3'-chlorophenyl)ethylamine, 2.9% N-1-(3',5'-dichlorophenyl)ethyl-cra-(3',5'-dichlorophenyl)ethylamine and 2.9% N-(a-(3',5'-dichlorophenyl)ethyl)acetamide. No alcohol compounds to be formed by reduction of carbonyl groups were detected.

Example 48 To a mixture of 70 g of 2',4'-dichloroacetophenone oxime and 210 g of acetic acid was added 36.4 g of acetic anhydrate, and the mixture was stirred at I 00 0 C for 2 hours. The reaction mass was sampled in small quantities and analyzed by gas chromatography, and it was found that the starting materials had disappeared. A 1000 ml I- e I) ~IClli--llrr~---- .i _~iillr-l.--rr- I, t autoclave was charged with the above reaction mass in the whole quantity, 210 g of acetic acid and 3.9 g of 5% platinum-carbon (50% water-containing product), and the atmosphere in the autoclave was replaced with hydrogen gas. The temperature was then raised to 30"C, and the pressure of hydrogen gas was increased to 20 kg/cm 2 The reaction was effected at the same temperature for 10 hours, while keeping the pressure at kg/cm 2 G by supplying hydrogen gas.

After completion of the reaction, the catalyst was removed by filtration, and acetic acid in the filtrate was distilled out under reduced pressure. The residue was mixed with 100 g of toluene and washed with 180 g of 5% aqueous sodium hydroxide solution, followed by solvent removal from the organic layer, which afforded 65 g of an oil. This oil was analyzed by gas chromatography and found to contain 91% l-(2',4'-dichlorophenyl)ethylamine, 2.9% 1-(4'-chlorophenyl)ethylamine, 1.1% N- -(2',4'-dichlorophenyl)ethyl-a-(2',4'-dichlorophenyl)ethylamine and 1.5% N-(a-(2',4'-dichlorophenyl)ethyl)acetamide. No alcohol compounds to be formed by reduction of carbonyl groups 15 were detected. The distillation of this oil gave 58.5 g of 1-(2',4'-dichlorophenyl)ethylamine with 99% purity, b.p. 130-132 0 C/20 mmHg.

Example 49 The procedures of Example 48 were repeated, except that 0.57 g of platinum-carbon (50% water containing product) and the catalyst in the whole quantity S 20 recovered in Example 48 were used as the catalyst. Thus, 64 g of an oil was obtained.

This oil was found to contain 89.9% 1-(2',4'-dichlorophenyl)ethylamine, 1.8% 1-(4'-chlorophenyl)ethylamine, 3.4% N-1-(2',4'-dichlorophenyl)ethyl-a-(2',4'-dichlorophenyl)ethylamine and 1.6% N-(a-(2',4'-dichlorophenyl)ethyl)acetamide. No alcohol compounds to be formed by reduction of carbonyl groups were detected.

III~ I Exmple The procedures of Example 44 were repeated, except that the pressure was kept at 5 kg/cm 2 Thus, 1.52 g of an oil was obtained.

This oil was found to contain 78.2% Jichlorophenyl)ethylamine, 4.6% 1-(4'-chlorophenyl)ethylamine, 6.1% N-1 -(2',4'-dichlorophenyl)ethy-a-(2',4'-dichlorophenyl)ethylamine, 1.9% N-(a-(2',4'-dichlorophenyl)ethyl)acetamide and 0.4% 2',4'-dichloroacetophenone. No alcohol compounds to be formed by reduction of carbonyl groups were detected.

Example 51 The procedures of Example 44 were repeated, except that the pressure was kept at 10 kg/cm 2 G. Thus, 1.54 g of an oil was obtained.

This oil was found to contain 87.2% 1-(2',4'-dichlorophenyl)ethylamine, 3,7% 1-(4'-chlorophenyl)ethylamine, 1.1% N-1-(2',4'-dichlorophenyl)ethyl-ax-(2',4'-dichlorophenyl)ethylamine, 0.5% N-(a-(2',4'-dichlorophenyl)ethyl)acetamide and 1.3% 15 2',4'-dichloroacetophenone. No alcohol compounds to be formed by reduction of 00* carbonyl groups were detected.

Comparative Example 6 The procedures of Example 44 were repeated, except that the reaction was effected for 5 hours using 0.1 g of 5% palladium-carbon (50% water-containing product) as the catalyst in place of platinum-carbon, while keeping the pressure at 10 kg/cm 2

.G.

0 Thus, 1.49 g of an oil was obtained.

This oil was found to contain 53.8% 1-(2',4'-dichlorophenyl)ethylamine, 31% phenylethylamine, 16.9% l-(4'-chlorophenyl)ethylamine, 13.1% l-(2'-chlorophenyl)ethylamine, 6.2% N-1-(2',4'-dichlorophenyl)ethyl-a-(2',4'-dichlorophenyl)ethyl- L L _b IC 59 amine, 4.7% N-(a-(2',4'-dichlorophenyl)ethyl)acetamide and 0.5% 2',4'-dichloroacetophenone.

Comparative Example 7 The procedures of Example 48 were repeated, except that 40.6 g of acetic anhydride was used and the reduction was effected, while keeping the pressure at kg/cm 2 Thus, 68 g of an oil was obtained.

This oil was found to contain 51% 1-(2',4'-dichlorophenyl)ethylamine, 1% 1-(4'-chlorophenyl)ethylamine, 1.3% N-1-(2',4'-dichlorophenyl)ethyl-a-(2',4'-dichlorophenyl)ethylamine, 42.1% N-(a-(2',4'-dichlorophenyl)ethyl)acetamide and 0.5% dichloroacetophenone.

Comparative Example 8 The procedures of Example 44 were repeated, except that 20 g of methanol and the pressure was kept at 10 kg/cm 2 Thus, 1.52 g of an oil was obtained.

00 This oil was found to contain 12% 1-(2',4'-dichlorophenyl)ethylamine, 63% 15 N-1-(2',4'-dichlorophenyl)ethyl-a-(2',4'-dichlorophenyl)ethylamine and 15% N-(a- (2',4'-dichlorophenyl)ethyl)acetamide.

Comparative Example 9 S An autoclave was charged with 18.9 g of 2',4'-dichloroacetophenone, 35 g of methanol, 0.15 g of bis-(2-hydroxyethyl)sulfide, 0.1 g of ammonium acetate and 1.0 g of Raney nickel (50% water-containing product), and the atmosphere in the autoa clave was replaced with hydrogen gas. Then, 4.6 g of liquid ammonia was added, and the pressure was increased to 50 kg/cm 2 .G by hydrogen gas.

o The temperature was then raised to 130'C, and the pressure was increased to kg/cm 2 .G by hydrogen gas. The reaction was effected at the same temperature for

A*

4 hours, while keeping the pressure at 80 kg/cm 2 .G by supplying hydrogen gas. After completion of the reaction, the catalyst was removed by filtration, and the low boiling fractions in the filtrate were distilled out under reduced pressure. Thus, 19.5 g of an oil was obtained. This oil was analyzed by gas chromatography and found to contain 24.8% 1-(2',4'-dichlorophenyl)ethylamine, 53.4% 1-(4'-chlorophenyl)ethylamine and 15.9% unknown ingredients.

Example 52 In a reaction vessel equipped with a Dean-Stark separator was placed 155.1 g of ammonium formate, followed by heating to 155C. Then, 98.5 g of acetophenone and 49.6 g of 76% formic acid were added with stirring each over 3 hours, and the mixture was further stirred at 160*C for 3 hours. During the reaction, an operation was appropriately repeated that the eluate was subjected to phase separation and the acetophenone layer (upper layer) was returned to the reaction vessel. After cooling to room tempera- 0* ture, the removal of low boiling fractions from the reaction mass under reduced pressure 15 gave 116.1 g of crude N-(1-phenylethyl)formamide. This crude product was analyzed by gas chromatography and found to have a purity of 87.5%.

Example 53 The procedures of Example 52 were repeated, except that 139.6 g of I'-acetonaphthone was used in place of acetophenone. Thus, 164.5 g of crude N-(1-naphthylethyl)formamide with 82.3% purity was obtained.

S

Example 54 The procedures of Example 52 were repeated, except that 110.7 g of form- "C.iC amide was used in place of ammonium formate and 126.7 g of 4'-chloroacetophenone was used in place of acetophenone. Thus, 150 g of crude N-(l-(4-chlorophenyl)ethyl)- LLrl II formamide with 87.4% purity was obtained.

Example The procedures of Example 52 were repeated, except that 155 g of 2',4'-dichloroacetophenone was used in place of acetophenone. Thus, 170.8 g of crude N-(l-(2,4-dichlorophenyl)ethyl)formamide with 78.9% purity was obtained.

Example 56 A reaction vessel was connected with an ammonia absorbing tower and charged with 206 g of ammonium formate. Then, 233 g of 76% formic acid was placed in a pot of the ammonia absorbing tower and allowed to circulate in the tower at a rate of 20 g/min., while keeping the connection part between the absorbing tower and the reaction vessel at 80°C. The reaction vessel was heated to 155°C with stirring, to which 2',4'-dichloroacetophenone and the pot liquid in the ammonia absorbing tower were added dropwise at the respective rates of 0.68 g/min. and 0.48 g/min. over 3 hours, and the mixture was further stirred at 155° to 160'C for 7 hours. At this time, the circulation 15 of formic acid was continued. After completion of the reaction, the removal of low boiling fractions by distillation under reduced pressure gave 162.2 g of crude dichlorophenyl)ethyl)formamide with 86% purity.

The distillate obtained by the removal of low boiling fractions was 137.9 g.

As a result of the analysis by gas chromatography, it was found that 69.8% formamide, 12.9% formic acid and 1.7% 2',4'-dichloroacetophenone were contained. Further, the pot liquid in the ammonia absorbing tower after the reaction was 229.2 g, and it was found that 4.7% formamide, 36.7% formic acid, 0.2% ammonium formate and 1.7% 2',4'-dichloroacetophenone were contained.

Example 57

I

A mixture of 56.8 g of 27% ammonia water, 137 g of the distillate recovered in Example 56 and 113 g of the pot liquid in the ammonia absorbing tower was concentrated by distillation under reduced pressure, and 166 g of water was removed. The concentrate was placed in a reaction vessel, and the procedures of Example 56 were repeated, except that the ammonia absorbing tower was charged with 130 g of formic acid and 116 g of the pot liquid in the ammonia absorbing tower recovered in Example 56. Thus, 165.4 g of crude N-(1-(2,4-dichlorophenyl)ethyl)formamide with 83.7% purity was obtained. The distillate obtained by the removal of low boiling fractions under reduced pressure was 112.5 g, and it was found that 80.1% formamide, 15.7% formic acid and 1.2% 2',4'-dichloroacetophenone were contained. Further, the pot liquid in the ammonia absorbing tower after the reaction was 265 g, and it was found that 6% formamide, 31.5% formic acid, 0.2% ammonium formate and 3% 2',4'-dichloroacetophenone were contained.

Example 58 15 The procedures of Example 52 were repeated, except that 123.2 g of 2'-methoxyacetophenone was used in place of acetophenone. Thus, 143.7 g of crude N-(1-(2-methoxyphenyl)ethyl)formamide with 90% purity was obtained.

Comparative Example The procedures of Example 52 were repeated, except that a mixture of formic 20 acid, ammonium formate and acetophenone was heated at 160'C with stirring for 0 6 hours, in place of the operations that acetophenone and formic acid were added to ammonium formate over 3 hours and the mixture was kept at 160"C with stirring for 3 hours. Thus, 112 g of crude N-(1-phenylethyl)formamide with 82.7% purity was obtained.

L_ II L -I I 'L Comparative Example 11 The procedures of Example 55 were repeated, except that a mixture of formic acid, ammonium formate and 2',4'-dichloroacetophenone was heated at 160°C with stirring for 6 hours, in place of the operations that 2',4'-dichloroacetophenone and formic acid were added to ammonium formate over 3 hours and the mixture was kept at 160°C with stirring for 3 hours. Thus, 178.6 g of crude N-(1-(2,4-dichlorophenyl)ethyl)formamide with 70.4% purity was obtained.

Comparative Example 12 The procedures of Example 54 were repeated, except that a mixture of formamide, formic acid and 4'-chloroacetophenone was heated at 160'C with stirring for 6 hours, in place of the operations that 4'-chloroacetophenone and formic acid were added to formamide over 3 hours and the mixture was kept at 160C with stirring for 3 hours. Thus, 144.2 g of crude N-(1-(2,4-dichlorophenyl)ethyl)formamide with 84.6% purity was obtained.

15 Example 59 A mixture of 162 g of crude N-(I-(2,4-dichlorophenyl)ethyl)formamide 4 o obtained in Example 56, 96 g of water, and 121 g of 36% hydrochloric acid was refluxed S1" with stirring for 1 hour. Then, 224 g of water was added, and the mixture was extracted twice with 80 g of toluene at 70°C. The aqueous layer was mixed with 173 g of 48% 8 9 o 20 aqueous sodium hydroxide solution, and the mixture was extracted twice with 100 g of toluene at 60"C. The resulting toluene layer was washed twice with 80 g of water. The removal of toluene by distillation gave 128.8 g of crude 1-(2,4-dichlorophenyl)ethylamine with 94.3% purity. This crude product was distilled under reduced pressure, which afforded 118 g of the purified product with 99.5% purity.

II r ~II I k* 64 Example To a solution of methyl magnesium chloride prepared from 24.2 g of methyl chloride, 11.7 g of magnesium and 121 g of tetrahydrofuran was added 0.6 g of copper (II) chloride at 15" to 25°C and then added dropwise a solution of 61.3 g of ethyl 2-cyano-3-methyl-2-butenoate dissolved in 61 g of toluene at the same temperature over about 3 hours. After completion of the addition, the reaction was further effected at the same temperature for 2 hours. The reaction mixture was cooled and poured into 173 g of aqueous sulfuric acid solution at 5° to 15"C. The mixture was warmed to 50" to and then allowed to stand without disturbance at the same temperature and then subjected to phase separation. The aqueous layer was extracted once with 31 g of toluene, and the organic layers were combined and washed with 67 g of 5% aqueous sodium hydrogencarbonate and 31 g of water. The combined organic layer was subjected to gas chromatography analvis with di-n-propyl phthalate as an internal o o standard. The yield of ethyl 2-cyano-3,3-dimethylbutanoate was calculated as 65 g Example 61 The reaction was conducted in a similar manner as in Example 60 above, o o except that 3.0 g of copper (II) chloride was used instead of 0.6 g of copper (II) chloride.

The yield of ethyl 2-cyano-3,3-dimethylbutanoate was a 20 N-[(R)-1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide, which is the compound of the present invention, can be used as an active ingredient of rice blast control agents. The following will describe such a control agent and a method for controlling rice blast, which comprises treating rice seeds with the control agent.

The compound of the present invention, particularly optically active

II

1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide with absolute configuration in the benzyl position, has more excellent control activity against rice blast in the foliar application and maintains excellent control activity over a long period of time in the seed treatment.

The absolute configuration in the benzyl position on the amine side is however, the optical purity in this position is not necessarily required to be 100% e.e.

(enatiomeric excess), and the present invention includes any optically active form composed mainly of (R)-form, having an optical purity of 75% e.e. R/S 87.5/12.5) or higher, preferably 85% e.e. R/S 92.5/7.5) or higher, in the benzyl position. On the other hand, the a-position on the acid side in the compound of the present invention is liable to undergo racemization (epimerization), and for practical purposes of controlling rice blast, the absolute configuration in the a-position has no significant influence on the control activity. For this reason, the a-position may have an 0 absolute configuration of either or (S)-form, or a mixture of these forms at any ratio, *000 15 and from an industrial point of view, (RS)-form is usually used.

The compound of the present invention exhibits particularly excellent control activity against rice blast (Pyricularia oryzae) which is a principal disease of rice, and there are additional advantages that a combination of this compound with other suitable plant disease control agents gives, by its synergistical effect, much more effective control not only against rice blast (Pyricularia oryzae) but also against rice "bakanae" disease (Gibberellafujikuroi), which is another principal disease of rice.

When the compound of th present invention is used as an active ingredient of rice blast control agents, it may be used as such without adding any other ingredient; however, it is ur .ily mixed with solid carriers, liquid carriers, surfactants and other ~ol I- ~rrp, f1 auxiliary agents, and formulated into a dosage form such as emulsifiable concentrates, wettable powders, suspensions, granules or dusts. These formulations may contain the compound of the present invention as an active ingredient at a ratio of 0.1 to 99% by weight, preferably 0.2% to 95% by weight.

Examples of the solid carrier are fine powders or granules of kaolin clay, attapulgite clay, bentonite, acid clay, pyrophyllite, talc, diatomaceous earth, calcite, corn rachis powder, walnut shell powder, urea, ammonium sulfate and synthetic hydrated silicon oxide. Examples of the liquid carrier are aromatic hydrocarbons such as xylene and methylnaphthalene; alcohols such as isopropanol, ethylene glycol and cellosolve; ketones such as acetone, cyclohexanone and isophorone; vegetable oils such as soy bean oil and cotton seed oil; dimethylsulfoxide, acetonitrile and water.

Examples of the surfactant used for emulsification, dispersion, wetting and spreading, or the like, are surfactants of the anionic type, such as alkylsulfates, alkyl- (aryl)sulfonates, dialkylsulfosuccinates, polyoxyethylene alkyl aryl ether phosphates and naphthalenesulfonic acid-formalin condensates; and surfactants of the non-ionic type, such as polyoxyethylene alkyl ethers, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters.

Examples of the auxiliary agent are lignin sulfonates, alginates, polyvinyl alcohol, gum arabic, CMC (carboxymethylcellulose) and PAP (isopropyl acid phos- 20 phate).

These formulations may be used as such or after diluted with water, for foliar application, dusting or granular application to the soil surface or water surface, soil incorporation after dusting or granular application to the soil surface, seedling raising box treatment, or seed treatment. The seed treatment includes seed soaking treatment, seed I- I ~e blow treatment and seed dressing treatment. In the seed treatment, seeds, together with calcium peroxide or the like, may be dressed or coated with the formulation, followed by direct sowing.

Further, these formulations may be used in combination with other plant disease control agents, insecticides, acaricides, nematocides, herbicides, plant growth regulators, fertilizers, soil conditioning materials and the like.

Typical examples of the plant disease control agent which can be used in combination are shown below under the respective compound numbers.

Diisopropyl 1,3-dithiolan-2-ylidenemalonate [common name, isoprothiolane], 5-Methyl-1 ,2,4-triazolo[3,4-b]benzothiazol [common name, tricyclazole], 3-Allyloxy-1 ,2-benzisothiazole- 1,1-dioxide [common name, probenazole], 1,2,5,6-Tetrahydro-4H-pyrolo[3,2, I-i j]quinolin-4-one [common name, pyroquilon], (Z)-2'-Methylacetophenone 4,6-dimethylpyrimidin-2-ylhydrazone [common name, ferimzone], O-Ethyl S,S-diphenylphosphorodithioate [common name, edifenphos], 4,5,6,7-Tetrachlorophthalide [common name, phthalide], Kasugamycin, a,a,a-Trifluoro-3-isopropoxy-0-tolanilide [common name, flutolanil], 1-(4-Chlorobenzyl)-l-cyclopentyl-3-phenylurea [common name, pencycuron], Validamycin, 3' -Isopropoxy-O-tolanilide [common name, mepronil], 6- (3,5-Dichloro-4-methylphenyl1)- 3(2H)-pyri dadi none [common name, diclomezine], N-(1 ,3-dihydro- 1, 1,3-trimethylisobenzofuran-4-y l)-5-chloro- 1,3-dimethiylpyrazol-4-carboxamide [common name, furametpyr], Methyl {2-[6-(2-cyanophenoxy)pyrimidin-4-yloxylphenyl }-3-methoxyacrylate [1C1A5504], 5-Ethyl-5 ,8-d ihydro-8-o xo- 1,3-d joxo lo[4,5-g]quin olin e-7-carbo xyli c acid [common name, oxolinic acid], (E)-4-chloro-,(,ca-tifluoro-N-( 1-imidazol- l-yl-2 -propoxyethylide ne)- 0-toluidine [common name, triflumizole], N-propyl-N- [2-(2,4,6-trichloropheiioxy)ethyl]imidazole-l1-carboxamide [comnmon name, prochioraz], 15 2-[(4-Chlorophenyl)methyl]-5-( 1-methylethyl)- 1-(1 H-I ,2,4-triazoI- 1-ylmethyl)cyclopentanol [common name, ipconazole], Pent-4-enyl N-furfuryl-N-imidazol-1I-ylcarbonyl-DL-homoalaninate [common name, pefurazoate], Methyl i -(butylcarbamoyl)benzin-idazol-2-ylcarbamate 20 [common name, benomyl], Dimethyl 4,4'-(0-phenylene)bis(3-thioarophanate) [common name, thiophanate-methyl], 2-(Thiazol-4-yI)benzimnidazol [common name, thiobe- zimidazole]; Bis(dimethylthiocarbamoyl)disulfide [common namne, thiram]; *9*9 9 4-CyclopropYl-6-methyl-N-phenylpyrimidin-2-amine [CGA219417; proposed common namc, cYprodinill, and 4-(2,2-Difluoro-1I,3-benzodioxol-4-yl)pyrrole-3-carbonitrile [common name, fludioxonil].

When the compound of the present invention is used in combination with an active ingredient of the above plant disease control agent, the mixing ratio, although it may vary depending upon the kind of plant disease control agent mixed, is usually in the range of 0.001 to 100 parts by weight, preferably 0.2 to 20 parts by weight, to I part by weight of the compound of the present invention.

Typical examples of the insecticide which can be used in combination are shown below under the respective compound numbers.

5-Amino-I- [2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethyl)sulfinyl- IH-pyrazole-3-carbonitrite [common name, fipronil], 1-(6-Chloro-3-pyridylmethyl)-N-nitroimidazolidin-2-ylidenamine [common name, im-idacloprid], Ethyl N-[2,3-dihydro-2,2-dimethylbenizofuran-7-yloxycarbonyl(methyl)am-inothio]-N-isopropyl-p-alaninate [common name, benfuracarb], S,S'-(2-dimethylaminotrimethylene)bisthiocarbam-ate [comm-on name, cartap], 4-(Methylthio)phenyl dipropyiphosphate [common name, propaphos], 2,3 -Di hydro-2 ,2-d imethylb enz ofu ran -7-y l(d ibu tyl ami nothio )me thy Icarbamnate. [common name, carbosulfan], (E)-N-(6-chloro-3-pyridylfnethyl )-N-ethyl-N' -methyl-2-nitrovinylid enediamine [common name, nitenpyram], 9 9 *9*9 9999 *.9.99 20 99 9999 9 99 09

I

1 4 So o eo oom 0.

CO

15

*C

o*

.C*

C S o ooo 20

C

CC

C

(E)-4,5-dihydro-6-methy1-4-(3-pyridylmethylenamino)-1,2,4-triazin- 3(2H)-one [common name, pymetrozine], and O,0-dimethyl O-4-nitro-m-tolylphosphorothioate [common name, fenitrothion].

When the compound of the present invention is used in combination with an active ingredient of the above insecticide, the mixing ratio, although it may vary depending upon the kind of insecticide mixed, is usually in the range of 0.01 to 100 parts by weight, preferably 0.2 to 20 parts by weight, to 1 part by weight of the compound of the present invention.

When the compound of the present invention is used as an active ingredient of the rice blast control agent, the application amount, although it may vary depending upon the weather condition, dosage form, application time, application method, applied place and the like, is usually in the range of 0.05 to 200 g/are, preferably 0.1 to 100 g/are. When emulsifiable concentrates, wettable powders, suspensions or the like are applied after diluted with water, their application concentration is usually in the range of 0.00005% to preferably 0.0001% to Granules, dusts or the like are applied as such without any dilution. In the seedling raising box treatment, the plant disease control agent can be used at an amount of active ingredient, which is usually in the range of about 0,1 to about 100 g, preferably about 0.5 to about 10 g, per seedling raising box having a size usually used (30 cm x 60 cm x 3 cm).

In the seed treatment, the plant disease control agent can be used at an amount of active ingredient, which is usually in the range of about 0.001 to about 50 g, preferably about 0.01 to about 10 g, per kilogram of seeds. In the seed soaking treatment, seeds are usually soaked in a high concentration chemical solution of about 5000 to about 1 I I 71 50000 ppm at a weight of 1 to 3 kg per kilogram of seeds for a short period of about 5 to about 30 minutes or in a low concentration chemical solution of about 20 to about 4000 ppm at a weight of 1 to 3 kg per kilogram of seeds for a long period of about 6 to about 48 hours.

The following will describe formulation examples in which the parts are all by weight and the compound of the present invention was obtained in Example above.

Formulation Example 1 Fifty parts of the compound of the present invention, 3 parts of calcium lignin sulfonate, 2 parts of sodium lauryl sulfate and 45 parts of synthetic hydrated silicon oxide are well pulverized and mixed to give a wettable powder.

Formulation Example 2 Twenty five parts of the compound of the present invention, 3 parts of polyoxyethylene sorbitan monooleate, 3 parts of CMC and 69 parts of water are mixed 15 and pulverized until the active ingredient has a particle size of 5 pim or less to give a suspension.

Formulation Example 3 Two parts of the compound of the present invention, 8 parts of kaolin Sclay and 10 parts of talc are well pulverized and mixed to give a dust.

Formulation Example 4 Twenty parts of the compound of the present invention, 14 parts of poly-

CC

oxyethylene styryl phenyl ether, 6 parts of calcium dodecylbenzenesulfonate and 60 parts of xylene are well mixed to give an emulsifiable concentrate.

Formulation Example 1 I 1 1 1 ;1 f Ten parts of the compound of the present invention, 1 part of synthetic hydrated silicon oxide, 2 parts of calcium lignin sulfonate, 30 parts of bentonite and 73 parts of kaolin clay are well pulverized and mixed. The mixture is well kneaded with the addition of water, and then granulated and dried to give a granule.

The following test examples demonstrate that the compound of the present invention is useful as an active ingredient of rice blast control agents. In these test examples, the compound of the present invention was obtained in Example 5 above, and other plant disease control agents and insecticides are designated by the above compound numbers and the compound used as a comparative control is designated by the following compound number.

N-[(RS)-1-(2,4-dichlorophenyl)ethyl]-(RS)-2-cyano-3,3-dimethylbutanamide [compound specifically described in JP-A 2-76846/1990].

Test Example 2: Rice blast control test (seed soaking treatment) A wettable powder formulated from the test compound in the same manner as 15 described in Formulation Example 1 was diluted with water to a prescribed concentration.

In this chemical dilution were soaked rices seeds (Nihonbare) at a ratio of 1 kg seeds per 2 kg chemical solution for 10 minutes. The rice seeds treated were air dried, sown in a seedling raising box at a ratio of 160 g seeds per box, and grown for 20 days. Five rice seedlings were then transplanted in a Wagner pot (1/5000 are), which had been filled 20 with soil and flooded with water. The rice seedlings were cultivated in a greenhouse with o the water leaking from the bottom of the Wagner pot at a rate of 3 cm per day. After six weeks from the transplanting, these rice seedlings, together with other rice seedlings taken rice blast, were placed in a vinyl house and maintained at a moistening state to infect them with Pyricularia oryzae. After eleven days from the inoculation, the rice I r I

A.*

73 seedlings were examined for the index of disease attack by leaf rice blast on the following criteria to determine the control value by the following Equations 1 and 2. The disease attack ratio in the non-treated field was 58%. The results are shown in Table 6.

CRITERIA OF DISEASE ATTACK Disease attack index Ratio of lesion area 0 0% 1 2 6% to 4 26% to 8 51% or higher (Equation 1) DisenP. nttak ratin (1 x n 1 x n 2 (4 x n 3 (8 x n 4 x 100 9 9* 9 *9 9 .9.

9

GS

9 *o 9 *0 8xN wherein N is the total number of leaves examined and n I to n 4 are the numbers of leaves having a disease attack index of 1, 2, 4 and 8, respectively.

(Equation 2) Disease attack ratio Disease attack ratio in non-treated field in treated Disease attack ratio in non-treated field Control value x 100 I 74 TABLE 6 Test compound Application concentration of Control value active ingredient (ppm) 10000 86 5000 74 2500 10000 61 (2) 5000 41 10000 0 10000 0 10000 0 As can be seen from Table 6, the compound of the present invention exhibited excellent control activity even under severe conditions, and it was unexpectedly found that the compound of the present invention exhibited almost the same control activity at a fourth concentration as compared with the comparative compound 5 Test Example 3: Rice blast control test (seed blow treatment) A wettable powder formulated from the test compound in the same manner as o described in Formulation Example 1 was diluted with water to a prescribed concentration.

po This chemical dilution was blown on rices seeds (Nihonbare) at a ratio of 1 kg seeds per ml. The rice seeds treated were air dried, sown in a plastic pot filled with sandy loam, p l 10 and grown in a greenhouse for 20 days. The rice seedlings, together with other rice seedlings taken rice blast, were then placed in a vinyl house and maintained at a p moistening state to infect them with Pyricularia oryzae. After ten days from the inoculation, the rice seedlings were examined for the index of disease attack by leaf rice blast to determine the control value. The disease attack ratio in the non-treated field was 100%.

The results are shown in Table 7.

_II

TABLE 7 Test compound Application concentration of Control value active ingredient (ppm) 2000 86 2000 +2000 100 2000+ 2000 100 2000+ 2000 100 2000+ 2000 100 2000+ 2000 100 2000 48 2000 0 2000 0 2000 2000 0 2000 0 a* a..

**a *ooo oao o o a* a a a o ooo ooo oo ii ooo r Test Example 4: Rice "bakanae" disease control test (seed blow treatment) A wettable powder formulated from the test compound in the same manner as described in Formulation Example 1 was diluted with water to a prescribed concentration.

This chemical dilution was blown on rices seeds (Nihonbare) infected with Gibberella 5 fujikuroi at a ratio of 1 kg seeds per 30 ml. The rice seeds treated were air dried, sown in a plastic pot filled with sandy loam at a ratio of 50 seeds per pot, and grown in a greenhouse for 21 days. The rice seedlings were examined for the state of disease attack to determine the good seedling ratio by the following Equation 3. The results are shown in Table 8.

I- I (Equation 3) Good seedling ratio Number of good seedlings in each treated field Number of good seedlings in non-treated non-inoculated field x 100 TABLE 8 Test compound Application concentration of Good seedling ratio active ingredient (ppm) 10000 10000 100 10000+ 10000 100 10000 10000 100 10000 10000 100 10000+ 10000 100 10000 10000 78 10000 88 10000 93 10000 84 10000 inoculated, non-treated non-inoculated, 1 non-treat100 non-treated 0*c*0 *000 0* 0 0c 009e 0*0000 #0 0 0* 00 Test Example 5: Rice blast control test (foliar application) A plastic pot was filled with sandy loam and seeded with rice (Nihonbare), followed by growing in a greenhouse for 20 days. A suspension formulated from the test compound in the same manner as described in Formulation Example 2 was diluted with water to a prescribed concentration. This chemical dilution was used for foliar I s h 77 application to the rice seedlings at such an amount (30 liters/10 are) that the leaf surface got slightly wet. After the application, the plants were air dried and inoculated with a spore suspension of Pyricularia oryzae by spraying. After the inoculation, the plants were grown at 28°C in the dark under high humidity for 4 days and examined for the index of disease attack by leaf rice blast to determine the control value. The disease attack ratio in the non-treated field was 100%. The results are shown in Table 9.

TABLE 9 Test compound Application concentration of Control value active ingredient (ppm) 100 100 50 99 94 C o 6 *9 Test Example 6: Rice blast control test (foliar application) A plastic pot was filled with sandy loam and seeded with rice (Nihonbare), followed by growing in a greenhouse for 20 days. A wettable powder formulated from 10 the test compound in the same manner as described in Example 1 was diluted with water to a prescribed concentration. This chemical dilution was used for foliar application to

C

the rice seedlings so as to adhere sufficiently to the leaf surface. The plants were inoculated with a spore suspension of Pyricularia oryzae by spraying, just after the air So., drying of the chemical dilution in the test on the preventive effect or after the keeping for 7 days in the test on the residual effect. After the inoculation, the plants were kept at 24"C under high humidity for 10 days and examined for the control effect by the following index. The results are shown in Tables 10 and 11.

II I~ It i, 1 78 CRITERIA OF CONTROL EFFECT Control index Control effect good 4 90% or higher 3 70% to 89% 2 41% to 69% 1 1% to 0 0% TABLE .00.

*00 00 6 Test compound Application concentration of Control index (ppm)igrdin Residual effect Preventive effect 2.5 4 4 5 4 4 5 3 3 5 4 4 2.5+5 5 0.5+3 4 4 ()2.5+500 5 100 4 4 2.5+500 5 0.5+ 100 4 4 2.5+500 5 0.5+100 4 4 2.5+500 5 0.5+100 1 4 4 0 to cr,.

.I

9* 0** .o *r 5 *9 .r 9*O* 9r

S

*r 0 TABLE 11 Test compound Application concentration of Control index active ingredient (ppm) Residual effect Preventive effect 1 2 3 0 1 1 2 3 0 1 2 3 3 0 1 1 2 3 0 1 500 0 0 100 0 0 500 0 0 100 0 0 500 0 0 100 0 0 500 0 0 Test Example 7: Rice sheath blight control test (foliar application) A plastic pot was filled with sandy loam and seeded with rice (Nihonbare), followed by growing in a greenhouse for 20 days. A suspension formulated from the test compound in the same manner as described in Formulation Example 2 was diluted 5 with water to a prescribed concentration. This chemical dilution was used for foliar application to the rice seedlings so as to adhere sufficiently to the leaf surface. After air drying of the chemical dilution, sclerotia of Rhizoctonia solani were inoculated on the parts near the roots of the rice seedlings. After the inoculation, the plants were kept at 27 0 C under high humidity for 10 days and examined for the control effect by the control index. The results are shown in Table 12.

-1-4 I L t TABLE 12 Test compound Application concentration of Control index active ingredient (ppm) 250 10 4 50+5 2 250 +5 50+ 1.25 4 250+ 10 50+5 3 250 30 50 10 4 5 4 1.25 4 3 5 1 30 3 a..

a.o a a a.

Test Example 8: Rice blast control test (seedling rasing box treatment) Seedling raising boxes for rice (30 cm x 60 cm x 3 cm) were filled with compost (Bonsol No. 2, available from Koura Sangyo Co., Ltd.) and seeded with dry unhulled rice (Nihonbare) at a ratio of about 200 g per box. After twenty days from the seeding, a granule formulated from the test compound in the same manner as described in Formulation Example 5 was uniformly distributed over the soil surface of the seedbed in the seedling raising boxes. The seedbed was slightly watered, and five rice seedlings were then transplanted in a Wagner pot (1/5000 are), which had been filled with sandy loam (obtained in Takarazuka-shi, Hyogo-ken) and flooded with water. The rice seedlings were cultivated in a greenhouse with the water leaking from the bottom of the ~LII I_

S

*4* *i 4 S 0

S

4* *5 4 5* S S i Wagner pot at a rate of 3 cm per day. After six weeks from the transplanting, these rice seedlings, together with other rice seedlings taken rice blast, were placed in a vinyl house and maintained at a moistening state to infect them with Pyricularia oryzae. After eleven days from the inoculation, the rice seedlings were examined for the index of disease attack by leaf rice blast to determine the control value as described in Test Example 2.

The disease attack ratio in the non-treated field was 95%. The results are shown in Table 13.

TABLE 13 Test compound Application concentration of Control value active ingredient (g/seedling raising box) 3 98 1.5 92 0,75 J 2 39 Test Example 9: Rice blast control test (seedling rasing box treatment) Seedling raising boxes for rice (30 cm x 60 cm x 3 cm) were filled with 10 compost (Bonsol No. 2, available from Koura Sangyo Co., Ltd.) and seeded with dry unhulled rice (Nihonbare) at a ratio of about 200 g per box. After twenty days from the seeding, a granule formulated from the test compound in the same manner as described in Formulation Example 5 was uniformly distributed over the soil surface of the seedbed in the seedling raising boxes. The seedbed was slightly watered, and five rice seedlings were then transplanted in a Wagner pot (1/5000 are), which had been filled with sandy loam (obtained in Takarazuka-shi, Hyogo-ken) and flooded with water. The rice seedlings were cultivated in a greenhouse with the water leaking from the bottom of the

I

82 Wagner pot at a rate of 3 cm per day. After four weeks from the transplanting, these rice seedlings, together with other rice seedlings taken rice blast, were placed in a vinyl house and maintained at a moistening state to infect them with Pyricuiaria oryzae. After eleven days from the inoculation, t'e rice seedlings were examined for the index of disease attack by leaf rice blast to determine the control value as described in Test Example 2.

The disease attack ratio in the non-treated field was 91%. The results are shown in Table 14.

TABLE 14 *0**i Test compound Application concentration of Control value active ingredient (g/seedling raising box) 98 0.75 88 1.5 +2 100 0.75 1 93 1.5 2 100 0.75+ 1 S1.5 2.5 100 0.75+ 1.25 93 1.5 2.5 100 0.75 1.25 93 2 0 2 0 2.5 0 2.5 0

S

S

S

9 S Test Example 10: Rice blast control test (water surface treatment) Wagner pots (1/10000 are) were filled with sandy loam and flooded with water. The rice seedlings (Nihonbare) at the two leaf stage were transplanted in the pots 83 and grown in a greenhouse for 7 days. A granule formulated from the test compound in the same manner as described in Formulation Example 5 was applied to the water surface of each pot. The cultivation was continued for 7 days (hereinafter referred to as test a) or for 14 days (hereinafter referred to as test The rice seedlings were inoculated with a spore suspension of Pyricularia oryzae by spraying. After the inoculation, the plants were kept at 24'C under high humidity for 10 days and examined for the control effect by the control index. The results are shown in Table *r 4*e *r S

*O

.009 *5 S

S

S.

TABLE Test compound Application concentration of Control index active ingredient are) Test a Test b 10 3 3 2.5 1 1 S10+200 5 2.5 +50 4 3 50 5 2.5 +10 4 3 10+100 5 2.5 +30 4 3 10+ 50 5 2.5 10 4 3 200 2 1 50 1 0 2 1 10 1 0 100 2 1 30 1 0 3 2 10 1 0 P:\OPER\MJC\34473-95,CLM- 17/4/98 -83A- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or group of integers or steps.

o o S

Claims (29)

1. A process for producing N-[1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3- dimethylbutanamide, which comprises reacting a C 2 -C 4 alkyl ester of 2-cyano-3,3-di- methylbutanoic acid with 1-(2,4-dichlorophenyl)ethylamine at 130" to 250"C.

2. A process for producing N-[(R)-l-(2,4-dichlorophenyl)ethyl]-2-cyano- 3,3-dimethylbutanamide, which comprises reacting a C 2 -C 4 alkyl ester of 2-cyano-3,3-di- methylbutanoic acid with (R)-l-(2,4-dichlorophenyl)ethylamine at 130' to 250C.

3. A process according to claim 1 or 2, wherein the C 2 -C 4 alkyl ester of 2-cyano-3,3-dimethylbutanoic acid is obtained by reacting a C 2 -C 4 alkyl ester of 2-cyano-3-methyl-2-butenoic acid with a methyl magnesium halide in the presence of a copper catalyst.

4. A process according to claim I or 2, wherein the C 2 -C 4 alkyl ester of 2-cyano-3,3-dimethy!butanoic acid is obtained by reacting a C 2 -C 4 alkyl ester of cyano- acetic acid with acetone in the presence of a catalyst using hexane as a main solvent to 15 give a C 2 -C 4 alkyl ester of 2-cyano-3-methyl-2-butenoic acid and then reacting the C 2 -C 4 alkyl ester of 2-cyano-3-methyl-2-butenoic acid with a methyl magnesium halide in the presence of a copper catalyst.

5. A process according to claim 4, wherein the catalyst is an optionally substituted aniline and a carboxylic acid.

6. A process according to claim 5, wherein the optionally substituted aniline is aminophenol or toluidine and the carboxylic acid is a lower fatty acid or benzoic acid. r o r !0*a a. .00 0

7. A process according to claim 4, wherein the reaction is effected in a solvent containing n-hexane at an amount of 50% by weight or more.

8. A process according to claim 4, wherein the copper catalyst is a mono- valent or divalent copper salt.

9. A process according to claim 8, wherein the copper catalyst is copper (I) chloride, copper bromide, copper iodide, copper (II) chloride, copper (II) bromide or copper (II) iodide. A process according to claim 2, wherein the optically active 1-(2,4-di- chlorophenyl)ethylamine is obtained by optical resolution of -(2,4-dichlorophenyl)- ethylamine with optically active aspartic acid.

11. A process according to claim 2, wherein the optically active 1-(2,4-di- chlorophenyl)ethylamine is obtained by optical resolution of -(2,4-dichlorophenyl)- ethylamine with optically active mandelic acid in an organic solvent.

12. A process according to claim 11, wherein the organic solvent is at least one selected from the group consisting of alcohol solvents, ester solvents and ether solvents. *c C *i C a C 0* -a Ca.. a 20 Ca C

13. A process according to claim 2, wherein the optically active 1-(2,4-di- chlorophenyl)ethylamine is obtained by optical resolution of (RS)-1-(2,4-dichlorophenyl)- ethylamine with optically active dibenzoyltartaric acid in an organic solvent.

14. Optically active N-(a-methyl-2,4-dichlorobenzylidene)-c-(2,4-dichloro- phenyl)ethylamine. A process for producing optically active N-(a-methyl-2,4-dichloro- benzylidene)-ca-(2,4-dichlorophenyl)ethylamine, which comprises effecting condensation of optically active 1-(2,4-dichlorophenyl)ethylamine with 2,4-dichloroacetophenone.

16. A process according to claim 15, wherein at least one selected from the -I I I 86 group consisting of Lewis acids, sulfonic acids and heteropolyacids is used as a catalyst for the condensation,

17. Racemic. N-(Qx-methyl-2,4-dichlorobenzylidene)-c-(2,4-dichlorophenyl)- ethylamine.

18. A process for producing racemic N-(cx-rnethyl-2,4-dichlorobenzylidene)- cx-(2,4-dichlorophenyl)ethylamine, which comprises treating optically active methyl-2,4-dichlorobenzylidene)-cL-(2,4-dichlorophenyl)ethylamidne with an alkali metal alkoxide in the presence of dimethylsulfoxide.

19. A process according to claim 1, 10, 11 or 13, wherein the 1-(2,4-di- chlorophenyl)ethylamine is in racemic form obtained by hydrolyzing racemic N-(ca- r-nethyl-2,4-dichlorobenzylidene)-cx-(2,4-dichlorophenyl)ethylaminie. V00 20. A process according to claim 1, 10, 11 or 13, wherein the l-(2,4-di- chlorophenyl)ethylarnine is in racemic form obtalned by treating optically active N-(cx- 0:methyl-2,4-dichlorobenzylidene)-x- (2,4-dichlorophenyl)ethylaminie with an alkali metal alkoxide in the presence of dimethylsulfoxide to give racem-ic N-(ax-methyl-2,4-dichloro- benzylidene)-cx-(2,4-dichlorophenyl)ethylamine and then hydrolyzing the racernic, N-(ca- methyl-2,4-dichlorobenzylidene)-a-(2,4-dichlorophenyl)ethyI ami le. 2 1. A process according to claim 1, 10, 11 or 13, wherein the 1-(2,4-di- chlorophenyl)ethylamine is in racemic form obtained by effecting condensation of opti- 4. 20 caly active 1-(2,4-dichlorophenyl)ethylamine with 2,4-dichlornazetophenone to give opti- cally active N-(cx-methyl-2,4-dichlorobenzylidene)-cx-(2,4-dichlorophenyl)ethylamine, treating the optically active N-(a-methyl-2,4-dichlorobenzylidene)-cx-(2,4-dichlorophen- yl)ethylamine with an alkali metal alkoxide in the presence of dimethylsulfoxide to give racemic N- (cx-methyl-2,4-dichlorobenzylidene)-cx-(2,4-dichlorophenyl)ethylamine and I i 1 87 then hydrolyzing the racemic N-(a-methyl-2,4-dichlorobenzylidene)--(2,4-dichloro- phenyl)ethylamine.

22. A process for producing a chloro-substituted phenylalkylamine of the general formula [II]: H 2 N CI [II] R R2 wherein RI is lower alkyl and R 2 is hydrogen or chlorine, which comprises effecting catalytic hydrogenation of a chloro-substituted phenyl alkyl ketone oxime acetate of the general formula I OAc *o C R. wherein R 1 and R 2 are each as defined above, in the presence of a platinum catalyst using general formula [II]: H2N CI R2 wherein R is lower alkyl and R2 is hydrogen o chlorine, which comprises treating a chloro-substituted phenyl alkyl ketone oxime of the general formula [III]: t -l 88 O H N Cl R2 wherein R 1 is lower alkyl and R 2 is hydrogen or chlorine, with acetic anhydride to give a chloro-substituted phenyl alkyl ketone oxime acetate of the general formula I OAc N C1 [I] R2 wherein R 1 and R 2 are each as defined above, and then effecting catalytic hydrogenation of the chloro-substituted phenyl alkyl ketone oxime acetate I in the presence of a platinum catalyst using an organic carboxylic acid solvent.

24. A process for producing a chloro-substituted phenylalkylamine of the general formula [II]: HzN* l Cl 10 [II] RR, R2 R wherein R 1 is lower alkyl and R 2 is hydrogen or chlorine, which comprises treating a chloro-substituted phenyl alkyl ketone [IV]: R2 wherein R 1 and R 2 are each as defined above, with a salt of hydroxylamine with an acid 89 to give a chloro-substituted phenyl alkyl ketone oxime of the general formula [III]: sOH N C R2 wherein R 1 and R 2 are each as defined above, treating the chloro-substituted phenyl alkyl ketone oxime [III] with acetic anhydride to give a chloro-substituted phenyl alkyl ketone oxime acetate of the general formula I OAc N C1 [I] R2 wherein R 1 and R 2 are each as defined above, and then effecting catalytic hydrogenation r *oo d. of the chloro-substituted phenyl alkyl ketone oxime acetate I in the presence of a platinum catalyst using an organic carboxylic acid solvent.

25. A process according to claim 23 or 24, wherein the acetic anhydride is used at an amount of 1 to 1.05 moles to 1 mole of the chloro-substituted phenyl alkyl ketone oxime [III],

26. A process according to any one of claims 22 to 24, wherein the platinum o catalyst is used at an amount of 0.05% to 1% by weight, in terms of metal, based on the 15 weight of the chloro-substituted phenyl alkyl ketone oxime acetate I

27. A process according to any one of claims 22 to 26, wherein the organic carboxylic acid is at least one selected from formic acid, acetic acid and propionic acid.

28. A process according to any one of claims 22 to 27, wherein the catalytic hydrogenation is effected at 10' to I I'AOPiAR1MECI 34473.9S. CM 1714/98

29. A process according to any one of claims 22 to 28, wherein the catalytic hydrogenation is effected under a pressure of 5 to 30 kg/cm2-G. A process for producing an N-(l-arylmethyl)formamide of the general formula [VI]: R Ar CH-NH-CHO [VI] wherein R is lower alkyl, optionally substituted aryl or optionally substituted aralkyl, and Ar is optionally substituted aryl, which comprises pouring an aryl ketone of the general formula R Ar C= O IV] wherein R and Ar are each as defined above, together with formic acid, into formamide and/or ammonium formate.

31. A process according to claim 30, wherein formic acid containing ammo- nium formate obtained by allowing formic acid to absorb ammonia formed from the reaction system is used as the formic acid to be poured together.

32. -(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide.

33. A rice blast disease control agent comprising N-[(R)-l-(2,4-dichloro- C phenyl)ethyl]-2-cyano-3,3-dimethylbutanamide as an active ingredient, and a carrier or diluent.

34. A method for controlling rice blast disease, which comprises treating rice seeds with the rice blast disease control agent according to claim 33. A method for controlling rice blast disease, which comprises treating rice seeds with the rice blast disease control agent according to claim 33 and sowing the rice seeds in a seedling raising box. P:\OPER\MJ'34473.95.CIM 17/4/98 -91-

36. (2,4-dichlorophenyl)ethyl]-2-cyano-3, 3-dimethylbutanamide,methods for its manufacture or plant disease control compositions or methods containing it, substantially as hereinbefore described with reference to the Examples. DATED this SEVENTEENTH day of APRIL, 1998 Sumitomo Chemical Company, Limited by DAVIES COLLISON CAVE Patent Attorneys for the Applicants 6 Oa *0 Abstract of the Disclosure: A process for producing 1-(2,4-dichloropheniyl)ethyl]-2-cyano-3,3-di- methylbutanamide, which includes reacting a C 2 -C 4 alkyl ester of 2-cyano-3,3-dimethyl- butanoic acid with 1-(2,4-dichlorophenyl)ethylamine at 1300 to 250*C. 0. 00 *0 *0*0