CH639966A5 - ACYLATION OF LACTON AND THIOLACTONE SUBSTITUTED ANILINE COMPOUNDS IN THE ABSENCE OF AN ACID ACCEPTOR AND APPLICATION OF THE METHOD. - Google Patents

Description

The present invention relates to a process for the preparation of aniline compounds which are substituted with a lactone or a thiolactone and the following formula I.

0

II

/ C ~ r1

Ar-W _

CH-CH-R2 1

l'a '

c CH-R3 // \ /

have in which

Arein is a phenyl radical or a substituted phenyl radical, the substituents being identical or different from one another and having the meaning of 1 to 5 alkyl groups and or alkoxy groups having 1-4 carbon atoms, one or two fluorine atoms, chlorine atoms and / or bromine atoms or a nitro group,

R1 is an alkyl radical, an alkoxyalkyl radical, a hydroxyalkyl radical with 1-4 carbon atoms, which is either unsubstituted or substituted with 1 to 4 fluorine atoms, chlorine atoms or bromine atoms, or a phenyl radical or benzyl radical which is unsubstituted or substituted with identical or different substituents, where the Substituents are selected from the group comprising 1 to 4 alkyl groups each having 1-4 carbon atoms, 1 to 4 alkoxy groups each having 1-4 carbon atoms, 1-4 fluorine atoms, chlorine atoms or bromine atoms and a nitro group,

R: is a hydrogen atom or an alkyl radical with 1-4 carbon atoms,

R 'represents a hydrogen atom, an alkyl group with 1-4 carbon atoms, a phenyl radical or a phenyl radical substituted with 1 or 2 substituents, the substituents of the phenyl radical being identical or different from one another and fluorine atoms, chlorine atoms, bromine atoms and / or alkyl groups having 1- 6 mean carbon atoms, and

Y is an oxygen atom or a sulfur atom.

The compounds of the formula I are therefore y-butyrolactones or y-butyrothiolactones which are substituted by the nitrogen-containing radical mentioned. Those compounds of formula I in which R 'is a halogen-substituted radical are particularly well suited as fungicides.

The prior art is explained in more detail below.

The preparation of aniline compounds by reaction with an acid halide is described in various references. For example, U.S. Patent No. 3,268,584 illustrates the preparation of various a-haloanilines. In the above-mentioned US patent by Olin, the following is emphasized in the third column in lines 31 to 60:

"The a-haloacetanilides of this invention can generally be prepared by halogen-acetylating suitable aromatic amines substituted on the nitrogen atom and substituted in the o-position, which amines can be produced, for example, by the process known in the United States - Patent application No. Serial No. 824455, which was filed on July 2, 1959 and later dropped, is described starting from a primary aromatic amine and a branched chain olefin. A haloacetic anhydride, such as, for example, chloroacetic anhydride, or else a haloacetic acid halide, such as, for example, chloroacetic acid chloride, bromoacetic acid bromide or a similar agent, is preferably used as the haloacetylating agent.

The haloacetylation reaction is preferably carried out in the presence of a suitable liquid reaction medium. The liquid reaction medium must be anhydrous if a haloacetic anhydride is used as the acetylating agent. However, if haloacetic acid halides are used as the acetylating agent, then both anhydrous reaction media and water-containing reaction media can be used. Examples of some suitable reaction media that can be used with either of the two classes of acetylating agents mentioned are the following: benzene, diethyl ether, hexane, methyl ethyl ketone, chlorobenzene, toluene, chloroform and the xylenes. Since an acid or hydrogen chloride is released in the haloacetylation reaction, it is furthermore desirable to have an acid acceptor present in the reaction area, which then neutralizes the acid formed. Suitable acid acceptors for anhydrous solvent systems are, for example, ortho-substituted aromatic amine reagents substituted on the nitrogen atom, which may be present in the reaction zone in an amount which is higher than that which is required for acetylation, and furthermore tertiary amines and pyridines. Acid acceptors which can be used, for example, in water-containing solvent systems are, for example, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates and also alkali metal bicarbonates and alkaline earth metal bicarbonates. »

From the passages cited above in Olin Patent No. 3,268,584, it can be seen that it is desirable that

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an acid acceptor is present in the reaction zone in which the haloacetylation is carried out.

U.S. Patent No. 3,345,151 also relates to a process for the preparation of a-haloacetanilides, and this patent also states that the acetylene reaction should be carried out in the presence of an acid acceptor.

U.S. Patent No. 4,008,066 describes the preparation of compounds of the formula

! R3

/ \ CH2-CO- <

O V <R-

CO-CiI2-Cl

Y

r2

described. This patent also states that the acylation reaction used to prepare the above compounds is preferably carried out in the presence of an acid acceptor, especially when the corresponding chloroacetic acid halides are used as the acylating agent. This United States Patent No. 4008,066 also states that it is possible to change an excess of the aniline compound to be acylated, which excess then acts as an acid acceptor. Example 1 of U.S. Patent No. 4,008,066 describes a process in which the 2,6-dimethylaniline-acetic acid methylamide is acety-lated, the N-methyl- [N'-2,6-dimethyl-phenyl ) -N'-chloroacetylamino] -acetamide forms by carrying out the reaction of dimethylaniline with chloroacetic acid chloride at a temperature of 110 ° C. From the amount of the reactants used in this example, it can be seen that a yield of about 50 mol% has been achieved, with obviously 50% of the aniline compound added in the acylation reaction being bound as the acid acceptor.

Both U.S. Patent No. 4,025,648 and German Laid-Open Patent No. 2,350,944 relate to dimeth-th vlanilins which have a propionic acid methyl group and an a-haloacyl group on the aniline nitrogen atom. Similar things are described in these two references, however, the German patent application relates to acyl groups, which are acetyl groups, while US Pat. No. 4025,648 relates to corresponding compounds 5, in which the acyl group is a propionyl group or a higher acyl group. According to the third column of US Pat. No. 4,025,648 and in the same way according to the last section of page 13 of the German published application, the acylation reaction is preferably carried out in the presence of an acid acceptor in order to produce the acyl-substituted aniline compounds. Examples of acid acceptors which can be used are trialkylamines, pyridine or inorganic bases, such as, for example, the hydroxides or carbonates of the alkali metals. 15 of the aforementioned U.S. Patent No. 4,025,648 further states that it is particularly desirable to use an acid acceptor when the acylation reaction is carried out using a haloacyl halide.

The use of an acid acceptor is not absolutely necessary if an acid anhydride is used to carry out the acylation reaction, because if chloroacetic anhydride is used as the acylating agent, the acid formed in this acylation is chloroacetic acid, which is a much weaker acid than 25 the hydrochloric acid, which is formed when an acid chloride is used to carry out the acylation reaction. For example, Section B of Example 1 of U.S. Patent No. 3,875,228 shows that a yield of about 72 ° "is achieved in the acylation reaction when it is carried out at about 30 ° C and when the 4th in this acylation reaction -Isopropylaminoindan is acetylated with chloroacetic anhydride, in which case no acid acceptor is present.

35

In the present description, the term “acid acceptor” means a material which is added or introduced into the reaction zone, this material being different from the aniline compound used as the starting material. For example, the acid acceptor that is added may be a tertiary amine that is capable of binding the hydrochloric acid that is released in the acylation reaction.

Chan U.S. Patent No. 3,933,860 describes the preparation of haloacetylated aniline compounds after 45 following the following sequence of reactions:

ArNH2 + X-CH (CH2)

0 = C

n

CH-R2

\ / O

(iii)

Ar-NH-CH (CH?) + X-C-R1

! in

& ase

-HX

Ar-NH-CH— (CH2)

n

0 = C CII-R2

V

(IV)

Ar-H.

0 = C ^ ^ CH-R2 (V)

O (IV)

base

-HX

O

n

V

RJ

CH (CH2)

0 ~ C CH-R2

V

(1)

(2)

In the process described in US Pat. No. 3,933,860, the aromatic amine is alkylated in the first stage with the compound of the formula III, the compound of the formula IV being used as the alkylation product

65 receives. In this patent it is mentioned that «the product of the alkylation reaction (1) is generally purified by conventional working methods, for example by extraction, distillation or distillation

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installs before this product is introduced into reaction step (2), ie into the acylation reaction ».

The second stage of the process described there is then the acylation reaction, and in this context it is said there: "The acylation reaction (2) is carried out by customary processes in the presence of an organic amine, such as, for example, a trialkylamine or a pyridine compound. In this acylation reaction, the starting material of the formula IV and the starting material of the formula V and the amine are generally brought together in essentially equimolar amounts in an inert organic solvent at a temperature in the range from 0 ° C. to 100 ° C. Suitable inert organic solvents are, for example, ethyl acetate, methylene chloride, dimethoxyethane, benzene and the like.

As can be seen from the above reaction scheme, the basic structure of the end products of the process described there corresponds to the compounds of the formula I which are prepared by the process according to the invention, provided that Y is an oxygen atom.

The aim of the present invention was to develop an improved process for the preparation of compounds of the formula I.

Surprisingly, it was found that this can be achieved by combining an appropriate acyl halide with an y-butyrolactone or y-butyrothio-lactone substituted with the rest Ar-NH in the absence of an acid acceptor and in the presence of a non-basic solvent.

The present invention therefore relates to a process for the preparation of compounds of the formula I.

0

^ CH-CH-R2 1

1 1 3

, C CH-R3

S N /

O Y.

in which

Ar is a phenyl radical or a substituted phenyl radical, the substituents being identical or different from one another and having 1 to 5 alkyl and / or alkoxy groups with 1-4 carbon atoms, one or two fluorine, chlorine and or bromine atoms or is a nitro group, R 'is an alkyl group. represents an aikoxyalkyl group or a hydroxyalkyl group with 1-4 carbon atoms, which is unsubstituted or with 1-4 fluorine atoms. Chlorine atoms or bromine atoms are substituted, or a phenyl radical or a benzyl radical which are unsubstituted or substituted by substituents which are identical to or different from one another, the substituents being 1 to 4 alkyl groups having 1-4 carbon atoms, 1 to 4 alkoxy groups with 1-4 carbon atoms, 1 to 4 fluorine atoms, chlorine atoms or bromine atoms or a nitro group, R: represents a hydrogen atom or an alkyl group with 1-4 carbon atoms,

R3 represents a hydrogen atom, an alkyl radical with 1-4 carbon atoms, a phenyl radical or a phenyl radical which is substituted by 1 or 2 substituents which are identical to or different from one another, the substituents being fluorine atoms, chlorine atoms, bromine atoms and / or Alkvlgruppen are 1-6 carbon atoms, and

Y represents an oxygen atom or sulfur atom, the process according to the invention being characterized in that, in the absence of an acid acceptor, an acid halide of the formula III

R'C = OX (III)

in which

X is a fluorine atom, a chlorine atom or a bromine atom, and R1 has the same meaning as in formula I,

with a compound of formula 11

H /

Ar-N-CH CH-R'1

I I C11)

C CH-R3

// V /

in which

R2, R3, Ar and Y have the same meaning as in formula I,

brings together, this bringing the compound of the formula III into contact with the compound of the formula II in the presence of a non-basic organic solvent and at a temperature in the range from 50-200 ° C., and thereby the compounds of the formula I are obtained.

According to a preferred embodiment of the process according to the invention, the reaction of the compounds of the formula III with the compounds of the formula II is carried out at a temperature in the range from 65-150 ° C. A preferred non-basic organic solvent for carrying out this reaction is toluene.

Particularly preferred compounds of the formula I prepared by the process according to the invention are those in which Ar is a phenyl radical which is substituted by one or two alkyl groups having 1-4 carbon atoms, R1 is an alkyl radical having 1-4 carbon atoms, which is either unsubstituted or is substituted with 1 to 4 chlorine atoms, R2 and R3 represent hydrogen atoms or methyl groups, and Y is an oxygen atom. The term "hydrogen or methyl" is understood to mean that the radicals R2 and R3 can either be identical to one another or different from one another, i.e. independently of one another either both hydrogen atoms or both methyl groups, or one can represent a hydrogen atom and the other a methyl group. However, in the case of the compounds of the formula 1 prepared by the process according to the invention, both the radical R2 and the radical R3 are preferably hydrogen atoms.

Particularly preferred aryl groups Ar in the compounds prepared by the process according to the invention are those in which Ar has the meaning of a phenyl radical which is substituted by an alkyl group having 1-3 carbon atoms, which is in the 2-position and also by an alkyl group 1-3 carbon atoms is substituted, which is in the 6-position. Very particularly preferred radicals R "are alkyl groups with 1-4 carbon atoms, which are either unsubstituted or substituted by a chlorine atom in the" position. In the acid halides of the formula III used as starting material, X is preferably a chlorine atom.

The process according to the invention can also be used for the preparation of new compounds which fall under the formula I given above. Examples of such compounds are corresponding 3- (N-acyl-N-aryl-

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aminoi-y-butyrolactones and 3- (N-acyl-N-arylamino) -y-butyrothiolactones, which are effective as fungicides.

Preferred solvents which can be used to carry out the process according to the invention are benzene, chlorobenzene, xylene, namely n-xylene, p-xylene and / or o-xylene, 1,2-dimethoxyethane, chloroform and tetrahydrofuran. A particularly preferred solvent is toluene. The solvent used is preferably an ipdi! basic organic solvent which is essentially inert under the reaction conditions used.

The temperatures used to carry out the acylation reaction according to the invention must be in the range from 50 to 200 ° C., preferably in the range from 65 to 150 ° C., and particularly preferably in the range from 75 to 130 ° C. The particular preferred temperature used depends on the particular solvent used. If, for example, benzene is used as the solvent, a temperature in the range from about 70 to about 90 ° C. is particularly preferred, while if xylene is used as the solvent, a temperature in the range from about 120 to about 140 ° C. is very particularly preferred.

The preferred pressure for carrying out the acylation reaction is a pressure which is approximately at or below ambient air pressure or just above it, for example a pressure which is 6.82 x 103 pa -138 x 10! pa (1 psi - 20 psi). Pressures that are below ambient air pressure are preferred for those solvents that boil below about 140 ° C.

According to a preferred embodiment of the process according to the invention, the 3- (N-chloroacetyl-N-2,6-dimeth \ Iphenylamino) -y-butyrolactone is prepared by:

(a) in the absence of an acid acceptor, the chloroacetic acid chloride with the 3- (N-2,6-dimethylphenylamino) y-butyrolactone in the presence of a non-basic organic solvent at a temperature in the range from 65 ° C to 150 ° C, preferably 80 ° C to 150 ° C, reacting, the 3- (N-chloroacetyl-N-2,6-dimethyIphenylamino) -y-butyrolactone forms in this organic solvent, and that fb) the 3- (N-chloroacetyl-N -2,6-dimethylphenylamino) -y-butyrolactone removed from the organic solvent.

The preferred organic solvent in this particular embodiment of the process according to the invention is toluene.

Another object of the present invention is the application of the method according to the invention to the production of 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butvrolactone. This application is characterized in that one

(a) reacting a-bromo-y-butyrolactone with 2,6-dimethylaniline in the presence of water and a non-basic organic solvent at a temperature in the range from 80-160 ° C., the 3- (N-2,6 -Dimethylphenyl-aminoj-y-butyrolactone forms in an organic phase of a two-phase aqueous-organic mixture,

(b) the organic phase is separated from this two-phase mixture,

<c) without the addition of an acid acceptor, the organic phase is brought together with chloroacetic acid chloride at a temperature in the range from 65 to 150 ° C., the 3- (N-chloroacetyl-N-2,6-dimethylphenvlamino) being found in the non-basic solvent - forms y-butyrolactone, and

(d) separating the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrolactone from the organic solvent.

In this application too, the preferred organic solvent is toluene.

5 In this preferred mode of application of the process according to the invention, the alkylation reaction of the starting material used is therefore included in the preparation of the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrolactone. In this context, the term “alkylation” means the reaction step in which the lactone is introduced as a substituent on the nitrogen atom of the aniline-type starting material.

According to a further preferred embodiment of the process according to the invention, the 3- (N-chloroacetyl-15 N-2,6-dimethylphenylamino) -y-butyrothiolactone is prepared by:

(a) in the absence of an acid acceptor chloroacetyl chloride with 3- (N-2,6-dimethylphenylamino) -y-butyrothio-20 lactone in the presence of a non-basic organic solvent at a temperature in the range from 80 ° C to 150 ° C, where 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrothiolactone is obtained in this organic solvent, and 25 (b) the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y -butyrothiolactone removed from the organic solvent.

According to another preferred embodiment of the method according to the invention, the 3- (N-methoxy-acetyl-N-2,6-dimethylphenylamino) -y-butyrothiolactone is prepared by:

(a) in the absence of an acid acceptor, the methoxy-35-acetic acid chloride with the 3- (N-2,6-dimethylphenylamino) -y-

butyrothiolactone in the presence of a non-basic organic solvent at a temperature in the range of 80 to 150 ° C, the 3- (N-methoxyacetyl-N-2,6-dimethyiphe-4o nylamino) -y-butyrothiolactone in the organic solvent forms, and that one

(b) the 3- (N-methoxyacetyl-N-2,6-dimethylphenylamino) -y-butyrothiolactone is removed from the organic solvent.

45 The present invention is based, among other factors, on the fact that the acylation reaction according to the process according to the invention gives unexpectedly high yields when it is carried out in the absence of an acid acceptor, particularly in those cases where 50 is 3- (N-2,6-dimethylphenylamino) ) -y-butyrolactone is reacted with the chloroacetic acid chloride to form the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrolactone. Reasons for using an acid acceptor in an acylation reaction also include those 5S nigen discussed above in connection with the discussion of the prior art. In general, poor yields were obtained when no acid acceptor was used. In this connection, reference is made, for example, to US Pat. No. 4,008,066 hinge-60, according to which the yield is 50% of theory if no acid acceptor is used, and in this case the starting material of the aniline type was obviously bound as the acid acceptor. However, the omission of the acid acceptor leads to various advantages in the special reaction according to the invention, including increased adaptability of the process to a process control of the continuous flow type, which is advantageous in the process carried out on an industrial scale

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and including facilitating the recovery of the products formed, for example a 3- (N-chloroacetyi-N-2,6-dimethylphenylamino) -y-butvrolaeton product so produced. Instead of a salt being formed by the reaction of the acid acceptor with the acid formed in the acylation reaction, and instead of the subsequent removal of the salt by a washing process carried out with water, the acid formed in the process according to the invention is thereby removed from the mixture in the acylation reaction that to a temperature above 50 ° C, preferably above 65 ° C. and usually heated above 80 ° C, and still receives very good yields. These temperatures, which are above 80 ° C, can be viewed as opposed to the temperatures in the range of 37-46 ° C used in the acylation reaction of Example 3, second paragraph of U.S. Patent No. 3,933,860.

Surprisingly, it has also been found that when thiolactone starting materials are used to carry out the alkylation reaction, essentially no yield is obtained if the alkylation reaction is carried out in the presence of a customary acid acceptor, such as in the presence of pyridine, but then if no acid acceptor is added and the process according to the invention is accordingly carried out, good yield is achieved in this alkylation reaction.

Accordingly, according to a particularly preferred embodiment of the process according to the invention, the alkylation reaction according to the invention is applied to butyrothiolac-tones, i.e. to those starting materials in which Y is a smoldering atom in the nomenclature used above.

Among other factors, according to the preferred embodiment of the invention described above, in which the process according to the invention is applied to a reaction sequence in which the alkylation reaction is included. Specifically, high yields are then achieved in the reaction of a-bromo-y-butyrolactone with a dimethyianiline if this reaction is carried out in the presence of water and not, as in the process described in the prior art, only the reaction product is washed with water . If this alkylation reaction is carried out in the presence of water and this water is already present at the start of the reaction, this leads to the advantage that the water contributes to making the overall process more adaptable to a continuous working process carried out on an industrial scale. Instead of a separate washing process carried out with water, the water is already present during the course of the alkylation reaction. It has been shown in this work that no large amounts of “bromo-y-butyrolactone are lost by hydrolysis and that a good yield is achieved in the alkylation reaction carried out in this way.

Preferred conditions for carrying out the alkylation reaction are described in detail in co-inventor Richard N. Reynolds, Jr., U.S. Patent No. 4,165,322, which is not prior art.

When using the process according to the invention for the preparation of 3- (N-chloroacetyl-N-2,6-dimethyl-phenylamino) -y-butyrolactone, the “-bromo-y-butyrolactone with the second , 6-DimethyIanilin in the presence of water in a non-basic organic solvent at a temperature which is in the range of 80-160 ° C, the 3- (N-2.6-

Dimethylphenylamino) -y-butyro! Acton in an organic phase of a two-phase aqueous-organic mixture. It was found that in a particularly preferred embodiment of this production process, the generation of the a-bromo-y-butyrolactone is carried out in the same solvent, which is then used in step (a). This non-basic, organic solvent, preferably toluene, is then expediently retained in all further reaction steps, namely both the alkylation step (a) and the acylation step (c) of this application of the process according to the invention.

The production of the bromolactone can be carried out by combining bromine with the lactone in the presence of a catalyst containing phosphorus.

The present invention will now be illustrated by the following examples.

example 1

Preparation of 3- (N-2,6-dimethylphenylamino) -y-buty-rolactone

A mixture of water and toluene is prepared from the a-bromo-y-butyrolactone and dimethyianiline in a molar ratio of 1 mol lactone to 2.1 mol of the aniline compound, and this mixture is heated to 92 ° C. with stirring for 18 hours . During this heating, the reaction of the lactone with the aniline compound took place, the 3- (N-2,6-dimethyl-phenylaminoj-y-butyrolactone) being obtained in the organic phase. In the aqueous phase, the excess of dimethyianiline was bound to the hydrobromic acid , ie in the form of the hydrogen bromide salt of dimethylaniline, and the aqueous phase which contained the dimethylaniline hydrobromide salt was separated from the organic phase.

The organic phase was washed with an aqueous solution containing 5% hydrochloric acid to remove residual dimethyaniline from it. Then, after this washing process, water was distilled off azeotropically from the organic phase, i.e. of the toluene solution containing the 3- (N-2,6-dimethylphenylamino) -y-butvrolactone. A portion of this solution, which was obtained after removing the water, was freed from the solvent by vacuum suction to give a sample for toxicological analysis. The remaining part of the solution in toluene was retained in order to carry out the acylation of the 3- (N-2,6-dimethylphenylamino) -y-butyrolactone thus produced with the chloroacetic acid chloride by the process described in Example 2.

The composition of the mixture containing toluene before the reaction and after the reaction of the bromobutyrene actone with the dimethyianiline is summarized in Table I below:

Table I

component

Before reaction in weight ".

After the reaction in wt. "

Bromobutyrolactone

19.2

1.5

Dimethyianiline

29.7

-

toluene

22.3

51.2

water

25.7

-

Impurities of the

Bromobutyrolactone

3.2

-

3- (N-2,6-dimethylphenylamino) -

butyrolactone

-

40.8

Impurities of the

3- (N-2,6-dimethylphenylamino) -

butyrolactones

-

6.5

5

St.

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Example 2

Preparation of 3- (N-chloroacetyl-N-2,6-dimethylphenyl-amino) -y-butyrolactone

The toluene solution of 3- (N-2,6-dimethylphenylamino) -y-butyrolactone, which contained about 40.8% by weight of the 3- (N-2,6-dimethylphenylamino) -y-butyrolactone, was subjected to chloroacetylation using 1.3 molar equivalents of chloroacetyl chloride to give 3- (N-chloroacetyI-N-2,6-dimethylphenylamino) -y-butyrolactone, which was carried out by toluene solution of 3rd - (N-2,6-Dimethylphenylamino) -y-butyrolactones with the chloroacetic acid chloride at a temperature of about 105-118 ° C with stirring, and after having added the entire amount of chloroacetic acid chloride to the toluene solution 15 Heated to 110 ° C for minutes.

After this heating step to 110 ° C., the solution was cooled to 20 ° C. and the thick slurry obtained was filtered off. The raw cake was reslurried twice with fresh toluene. To this slurry, 33 wt% toluene,

based on the weight of 3- (N-chloroacetyl-N-2,6-dimethylplienylamino) -y-butyrolactone in the slurry, and then the resulting product was dried in air.

The overall yield of the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrolactone, based on the bromobutyrolactone used as the starting material, was about 66% of the theoretical yield.

Example 3

A mixture of 1.05 moles of 2,6-dimethyl-aniiin and 0.48 moles of "-bromo-y-butyrothiolactone as well as 65 ml of toluene and 65 ml of water was kept at a temperature of about 85 ° C. for 18 hours Reflux cooked. The reaction of the lactone compound with the aniline derivative took place, the corresponding alkylation product being obtained in the organic phase, namely the 3- (N-2,6-dimethylphenylamino) -y-butyrothiolactone. The mixture that after cooking ur. Reflux was poured into 500 ml of dichloromethane and washed with 100 ml of water and 200 ml of an aqueous solution containing 5% HCl. After phase separation, the organic phase containing the alkylation product was subjected to a second washing process, the organic phase being washed with 200 ml of water. The phases were then separated again and the organic phase was dried using magnesium sulfate. After this drying step with the magnesium sulfate, the organic solvent was removed by evaporation at about 75 ° C. About 98 g of a brown viscous material were obtained. The nuclear magnetic resonance spectrum of the crude product obtained indicated that the crude product consisted primarily of the desired alkylated product.

The crude product thus obtained was then mixed with 500 ml of toluene, and a solid by-product formed was removed from the raw material. The toluene was then removed by evaporation, and a yield of about 90 g (85% of theory) of the alkaline product was obtained.

The alkylated product was added to 1000 ml of toluene and heated until the mixture refluxed. Then the chloroacetic acid chloride was added dropwise over a period of about 1 hour. The amount of chloroacetic acid chloride added was 0.4 mole and the amount of the alkylation product present was 0.4 mole in the same way. The reflux was continued until the evolution of hydrochloric acid gas had ceased. After working up, a yield of about 65 g of the acylated product, namely the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrot-hiolactone, was obtained.

Example 4

Preparation of 3- (N-chloroacetyI-N-2,6-dimethylphenyl) -y-butyrothiolactone

A solution of 10 g (0.055 mol) of the a-bromo-y-buty-rothiolactone, 6.68 g (0.055 mol) of the 2,6-dimethyl-aniline and 5.58 g (0.055 mol) of the dimethyl pyridine was heated to 85-90 ° C for 12 hours. The reaction mixture was then cooled and diluted with water and with dichloromethane. The organic phase was separated and filtered through a short silica gel column. The filtrate was evaporated under reduced pressure to give an oil as a residue. This residue was washed with a 5% aqueous hydrochloric acid solution, then washed with water, then dried over magnesium sulfate to obtain 7.2 g of the 3- (N-dimethylphenylamino) y-butyrothiolactone. The infrared spectrum of this thiolactone product showed a strong carbonyl absorption band at 588 microns.

The elementary analysis for this product of the formula Ci: Hi? NOS gave the following values:

% Sulfur: calculated = 14.5 found = 14.2

A solution of 1.52 g (0.0134 mol) of chloroacetic acid chloride in 10 ml of toluene was added dropwise to a solution of 2.97 g (0.0134 mol) of the 3- (N-dimethylphenylamino) -y-butyrothiolactone placed in 100 ml of benzene and left at the reflux temperature. The reaction mixture was heated to reflux until the evolution of hydrogen chloride gas ceased, which was the case after about 3 hours. The mixture was then cooled and evaporated under reduced pressure, giving a brown solid. When this solid was recrystallized from isopropanol, 2.5 g of the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrothio-lactone were obtained in the form of brownish crystals which had a melting point of 138-139 ° C. owned. The infrared spectrum of this product showed two strong bands for car bonyl absorption at 5.88 microns and at 6.02 microns.

The elementary analysis for this product of the empirical formula CuHuClNChS gave the following values:

% Sulfur: calculated = 10.8

found = 10.8

% Chlorine: calculated = 12.0

found = 13.6

Example 5

Preparation of 3- (N-chloroacetyl-N-2-chloro-6-methyl-phenylamino) -y-butyrothiolactone

A solution of 8 g (0.044 mol) of the a-bromo-y-buty-rothiolactone, 6.23 g (0.044 mol) of the 2-chloro-6-methylaniline and 4.7 g (0.044 mol) of the second , 6-Dimethylpyridine was heated to about 95 ° C under a nitrogen atmosphere for about 16 hours. The reaction mixture was then cooled, diluted with 60 ml of dichloromethane and washed with water, then washed with a 10% aqueous hydrochloric acid and then filtered. The filtrate thus obtained was dried over magnesium sulfate and reduced under min

10th

15

20th

25th

30th

35

40

45

50

55

60

65

9

639 966

evaporated pressure to dryness, giving a dark viscous residue. This residue was applied to a short silica gel chromatography column and eluted using dichloromethane. The fractions containing the product were evaporated to give 4.59 g of the 3- (N-2-chloro-6-methyl-phenylamino) -y-butyrothiolactone. In thin layer chromatography, this product showed one large spot. In the infrared spectrum of the product there was a strong absorption of the carbonyl group at 5.88 microns. In the nuclear magnetic resonance spectrum, three proton singlets for the methyl group were found at 2.33 ppm (based on tetramethylsilane).

A solution of 2.15 g (0.019 mol) of the chloroacetic acid chloride in 10 ml of toluene was added dropwise to a refluxing solution of 4.59 g (0.019 mol) of the 3- (N-2-chloro-6-methylphenylamino) -y-butyrothiolactone added in 150 ml of toluene. The reaction mixture was heated to reflux for 7 hours, whereby hydrochloric acid evolved and stirred at 25 ° C for about 16 hours, and then evaporated under reduced pressure to give a dark residue. Two spots appeared on the thin layer chromatography of this residue. The residue was then chromatographed using a silica gel column using a mixture of acetone + dichloromethane as eluent. Those fractions obtained on chromatography which contained the material eluted second on the column were pooled together and the pooled material evaporated to dryness to give the desired product. This product was recrystallized from isopropyl alcohol to give 0.98 g of the product as a brown solid which had a melting point of 133-137 ° C. The infrared spectrum of this product showed two strong absorption bands for the carbonyl group, at 5.84 microns and 5.95 microns. The elementary analysis of this product of the empirical formula C13H13CI2NO2S gave the following values:

15

Examples 7-20

Further compounds were produced by the process according to the invention by using no acid acceptor. The yields were generally 60% or higher for the acylation reaction. The results obtained are summarized in Tables II and III below.

In Table II below, the number of the methyl groups bonded to the benzene nucleus, ie the value n, is given in the third column and then the position of these methyl groups in the benzoyl nucleus in the brackets. Accordingly, for example in example No. 7, the indication 2 (2, 3) means the following: 2 methyl groups in positions 2 and 3.

Table II

Preparation of compounds of the formula

O H

25th

'»Sulfur:

'<> Chlorine:

calculated found calculated found

= 10.0 = 11.0 = 22 3 = 23.6

Example 6

Preparation of 3- (N-methoxymethyl-N-2,6-dimethylphenylamino) -y-butyrothiolactone

A solution of 1.46 g (0.0135 mol) of the methoxy acetic acid chloride in 10 ml of toluene was added dropwise to a refluxing solution of 3 g (0.0135 mol) of the 3- (N-2,6- Dimethylphenylamino) -y-butyrothiolactone added in 200 ml of toluene. The reaction mixture was heated to reflux for 3 hours and then evaporated to give a solid. This solid was recrystallized from a solvent mixture of ether + benzene + hexane in a mixing ratio of 10: 1: 10, 1.8 g of the product being obtained in the form of a brownish solid which had a melting point of 86-87 ° C. The infrared spectrum of the product showed two strong absorption bands for the carbonyl group at 5.85 microns and at 6.03 microns. The elementary analysis for this product of the empirical formula CifHioNCbS showed the following values:

'"Sulfur: calculated = 10.9 found = 11.2

(CH3)

35

Example No.

RE

n (position)

X

Y

7

27210

2 (2.3)

Cl s

8th

27212

2 (2.3)

OCH3

s

9

27484

3 (2,3,6)

Cl

0

10th

27485

3 (2,3,6)

OCH3

0

11

27710

3 (2,3,6)

Cl s

12

27709

3 (2,3,6)

OCH3

s

13

27783

4 (2,3,5,6)

Cl

0

14

27784

4 (2,3,5,6)

OCH3

0

15

27785

4 (2,3,5,6)

Cl s

16

27786

4 (2,3,5,6)

OCH3

s

Table III

Preparation of compounds of the formula

O H

/ -, I

55

60 ■

Example No.

RE

RJ

Rs

X

17th

27108

C2H5

C2H5

Cl

18th

27109

C2H5

C2H5

OCHj

19th

27565

C2H5

CHÎ

Cl

20th

27566

C2H5

CHj

OCHi

It can be seen from the above examples that the amount of alkylated starting material added is preferably one mole per mole of the starting acyl halide material when carrying out the process according to the invention. A slight excess of the acyl halide is preferably used, for example 1.01 to 1.1 moles of the acyl halide, for example chloroacetic acid

639 966

10th

chloride, used per mole of the alkylated starting material. Accordingly, it can be seen that the alkylated starting material is not added in a stoichiometric excess, so that it can serve as an acid acceptor. This was the case with the prior art reactions in which the aniline starting material was used in an amount of about 2 moles per mole of the acyl halide starting product.

Claims (11)

639 966 i PATENT CLAIMS 1. Process for the preparation of compounds of the formula I 0 II ^ C-R1 Ar-Ii CH — CH-R2 ! 1 3 C CH-R3 // \ / in which Ar is a phenyl radical or a substituted phenyl radical, the substituents being identical or different from one another and the meaning of 1 to 5 alkyl groups and / or alkoxy groups having 1-4 carbon atoms, one or two fluorine atoms, chlorine atoms and / or bromine atoms or one Have nitro group, R1 is an alkyl radical, an alkoxyalkyl radical or a hydroxyalkyl radical having 1 to 4 carbon atoms, which is either unsubstituted or substituted by 1 to 4 fluorine atoms, chlorine atoms or bromine atoms, or a phenyl radical or benzyl radical which is unsubstituted or substituted by the same or different substituents, wherein the substituents are selected from the group comprising 1 to 4 alkyl groups each having 1-4 carbon atoms, 1 to 4 alkoxy groups each having 1-4 carbon atoms, 1 to 4 fluorine atoms, chlorine atoms or bromine atoms and a nitro group, R is a hydrogen atom or an alkyl radical with 1-4 carbon atoms, R3 represents a hydrogen atom, an alkyl group with 1-4 carbon atoms, a phenyl radical or a phenyl radical substituted with 1 or 2 substituents, the substituents of the phenyl radical being identical or different from one another and fluorine atoms, chlorine atoms, bromine atoms and / or alkyl groups with 1-6 Mean carbon atoms, and Y is an oxygen atom or a sulfur atom, characterized in that, in the absence of an acid acceptor, an acid halide of the formula III R'C = OX (III) in which X is a fluorine atom, chlorine atom or bromine atom, and R1 has the meaning given in connection with formula I, with a compound of formula II H / Ar-N-CH CK - R 2 ! ! C CH-R3 (II) v. / in which R2. R \ Ar and Y have the same meaning as in formula I, brings together, this bringing the compound of formula 111 into contact with the compound of formula 11 in the presence of a non-basic organic solvent and at a temperature in the range of 50-200 ° C and thereby obtaining the compounds of formula I. 2. The method according to claim I, characterized in that one carries out the reaction at a temperature in the range from 65 ° C to 150 ° C and that toluene is preferably used as the non-basic solvent. 3rd 639 966 nical solvent at a temperature in the range of 80 to 150 ° C, wherein the 3- (N-methoxyacetyl-N-2,6-dimethylphe-nylaminoj-y-butyrothiotecton forms in the organic solvent, and that (b) the 3- (N-methoxyacetyl-N-2,6-dimethylphenylamino) -y-butyrothiolactone is removed from the organic solvent. 3. The method according to claim 1 or 2, characterized in that compounds of formula I are prepared in which Ar is a phenyl radical which is substituted by 1 or 2 alkyl groups having 1-4 carbon atoms, R1 is an alkyl radical or an alkoxyalkyl radical with 1 -4 Carbon atom which is unsubstituted or substituted with 1 to 4 chlorine atoms means that R-1 and R2 are hydrogen atoms or methyl groups and Y represents an oxygen atom or a sulfur atom. 4. The method according to any one of claims I to 3, characterized in that one produces a compound of formula I, in which Y is a sulfur atom. 5. The method according to any one of claims 1 to 4, characterized in that a compound of formula I is prepared in which Ar is a phenyl radical which is substituted by an alkyl group having 1-3 carbon atoms, which is in the 2-position of Phenylrestes and is substituted with an alkyl group with 1-3 carbon atoms, which is in the 6-position, and R 'represents an alkyl group with 1-4 carbon atoms, which is unsubstituted or substituted with a chlorine atom in the «position, and that an appropriate compound, in which X is a chlorine atom, ie the corresponding acid chloride, is used as the acid halide of the formula III. 6. The method according to claim 1, characterized in that the 3- (N-chloroacetyl-N-2,6-dimethyl-phenylamino) -y-butyrolactone is prepared by (a) in the absence of an acid acceptor, reacting the chloroacetic acid chloride with the 3- (N-2,6-dimethylphenylamino) y-butyrolactone in the presence of a non-basic organic solvent at a temperature in the range from 80 ° C. to 150 ° C., the 3- (N-chloroacetyI-N-2,6-dimethylphenylamino) -y-butyrolactone forms in this organic solvent, and that (b) the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrolactone is removed from the organic solvent. 7. The method according to claim 6, characterized in that toluene is used as the organic solvent. 8. The method according to claim 5, characterized in that the 3- (N-chloroacetyl-N-2,6-dimethyl-phenylIamino) -y-butyrothio! Acton is prepared by (a) in the absence of an acid acceptor chloroacetic acid chloride with 3- (N-2,6-dimethylphenylamino) -y-butyrothio-lactone in the presence of a non-basic organic solvent at a temperature in the range from 80 ° C to 150 ° C, wherein in this organic solvent the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrothiolactone is obtained, and (b) the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrothiolactone is removed from the organic solvent. 9. The method according to any one of claims 1 to 4, characterized in that the 3- (N-methoxyacetyl-N-2,6-dimethylphenylamino) -y-butyrothiolactone is prepared by (a) in the absence of an acid acceptor, the methoxy acetic acid chloride with the 3- (N-2,6-dimethyl-phenylamino) -y-butyrothiolactone in the presence of a non-basic orga5 10. Application of the method according to claim 1 to the production of 3- (N-chloroacetyl-N-2,6-dimethyl-phenylamino) -y-butyrolactone, characterized in that (a) reacting a-bromo-y-butyrolactone with 2,6-dimethylaniline in the presence of water and a non-basic organic solvent at a temperature in the range of 80-160 ° C, the 3- (N-2,6- Forms dimethylphenylamino) -y-butyrolactone in an organic phase of a two-phase aqueous-organic mixture, (b) the organic phase is separated from this two-phase mixture, (c) without the addition of an acid acceptor, the organic phase is brought together with chloroacetic acid chloride at a temperature in the range from 65 to 150 ° C., the 3- (N-chloroacetyl-N-2,6-dime-ihviphenylamino) being found in the non-basic solvent. forms y-butyrolactone, and (d) the 3- (N-chloroacetyl-N-2,6-dimethylphenylamino) -y-butyrolactone is separated from the organic solvent. 10th 15 20th 25th 30th 35 40 45 50 55 60 65 11. Application according to claim 10, characterized in that toluene is used as the organic solvent.