CH626333A5 - Process for the preparation of N-(2-methyl-4-chlorophenyl)formamidine derivatives - Google Patents

Description

The present invention relates to a process for the preparation of N- (2-methyl-4-chlorophenyl) formamidine derivatives of the formula I.

N = CH - N

in which

Rj is hydrogen or an alkyl group having 1 to 4 carbon atoms and

R2 represents an alkyl group with 1 to 4 carbon atoms.

The N- (2-methyl-4-chlorophenyl) formamide derivatives of formula I have a strong, selective toxicity against acarians in all stages of development, as described in detail in US Pat. Nos. 3,378,437 and 3,502,720.

According to a process described in the abovementioned patents, the N- (2-methyl-4-chlorophenyl) formamidine derivatives of the formula I are prepared by using an alkyl formamide of the formula II

R-,

40

in which Rt and R2 have the meaning given above and X denotes the group -OPOCl2, OSOC1 or chlorine, the condensation of this intermediate with o-toluidine and the chlorination of the N- (2-methylphenyl) -formamidine derivative obtained to an N- ( 2-methyl-4-chlorophenyl) formamidine derivative of the formula I in a halogenated hydrocarbon.

2. The method according to claim 1, characterized in that 1,2-dichloroethane, 1,1,1-trichloroethane, tetrachloroethane, chlorobenzene, o-dichlorobenzene, carbon tetrachloride or chloroform is used as the halogenated hydrocarbon.

3. The method according to claim 1, characterized in that chloroform is used as the halogenated hydrocarbon.

4. The method according to claim 1, characterized in that phosgene is used as the inorganic acid chloride.

5. The method according to claim 1, characterized in that phosgene with an alkylformamide of the formula II in chloroform in a molar ratio of 0.95 to 0.98: 1 and a temperature of 10 to 30 ° C to a salt-like intermediate of the formula purple , in which X means chlorine, reacting this intermediate product at 20 to 40 ° C with o-toluidine and then chlorinating the hydrochloride of an N- (2-methylphenyl) formamide derivative formed at a temperature of 5 to 25 ° C.

0

II

N - C - H

(II)

R-

in which R 1 and R 2 have the meaning given above, reacting with phosphorus oxychloride to give a salt-like intermediate product which, without isolation, is immediately passed on with 2-amino-5-chlorotoluene to give the desired N- (2-methyl-4-chlorophenyl) formamidine Derivatives of formula I is implemented. The structure of the salt-like intermediate formed by reaction of an alkylformamide of the formula II and phosphorus oxychloride corresponds to H. Bredereck et al. in Chem. Ber. 92, 837 to 849 (1959) of the following formula:

60

65

R,

X ©

N

0 I)

0-p.

= c

"Cl

* C1

Rr

H

CI

0

3rd

626 333

Since other acid halides form analogous products, the salt-like intermediate in the present description is intended to be formula III

1

\

OAc

Cl

O

(III)

H

in which and R2 have the meaning given above and Ac represents an acyl group which corresponds to the acid chloride used.

The disadvantage of the above-mentioned process is that the 2-amino-5-chlorotoluol required for the starting material has to be prepared in a multistage process. This process consists in converting o-toluidine, for example by reaction with acetyl chloride, into an N-acetyl compound, then chlorinating it to 2-acylamino-5-chlorotoluene, which then hydrolyzes 2-amino-5-chlorotoluene -sied. This process has the further disadvantage that large amounts of by-products, namely 2-acetylamino-3-chlorotoluene and 2-acetylamino-3,5-dichlorotoluene, are formed in the chlorination of 2-acetylaminotoluene, which are produced by the desired 2-acetylamino-5 -chlorotoluene and unchlo-rated product must be separated.

In view of these difficulties associated with the production of 2-amino-5-chlorotoluene, it has already been proposed to use N- (2-methyl-4-chlorophenyl) formamidine derivatives of the formula I by chlorination of the corresponding N- (2-methylphenyl) ) -formamidine derivatives, which in turn are obtained by the process already mentioned above by reacting an alkylformamide of the formula II with phosphorus oxychloride and further reacting the salt-like intermediate formed with o-toluidine. According to this method obtained in US Pat. No. 3,911,012, the chlorination of N- (2-methylphenyl) -N, N-dialkylformamidines is preferably carried out in an aqueous reaction medium. It is also mentioned that the chlorination can also be carried out in organic solvents, such as alcohols or glacial acetic acid.

This process is disadvantageous in that the preparation of the salt-like intermediate by reaction of an alkylformamide of the formula II with phosphorus oxychloride and / or the preparation of the N- (2-methylphenyi) -N ', N'-dialkylform-amide and its chlorination in various solvents must be carried out and that consequently at least one of these products must be isolated and converted into another solvent. Furthermore, in the event that the chlorination is carried out in glacial acetic acid, an additional amount of alkali metal hydroxide is required to neutralize the reaction mixture and to isolate the chlorinated product.

It is therefore the object of the present invention to provide a process for the preparation of N- (2-methyl-4-chlorophenyl) formamide derivatives of the formula I, in which all reaction steps, condensation of this intermediate

R-,

0

o-c-ci

V. /

N = C

\ ci

H

Product with o-toluidine to an N- (2-methylphenyl) form amidine derivative and chlorination of the latter to the desired N- (2-methyl-4-chlorophenyl) formamide derivative of formula I, can be carried out in the same solvent 5.

It is in particular the object of the present invention to provide a process for the preparation of N- (2-methyl-4-chlorophenyl) formamidine derivatives of the formula I, in which all reaction steps are carried out in the same solvent in which all those formed Intermediates are soluble, ie that the entire process is carried out in a homogeneous reaction medium.

It has been found that all the reaction steps required for the preparation of N- (2-methyl-4-chlorophenyl) formamidine derivatives of the formula I can be carried out in the same solvent if a halogenated hydrocarbon is used as the solvent.

Accordingly, the process according to the invention for the preparation of N- (2-methyl-3-chlorophenyl) -form-20 amidine derivatives of the formula I consists in the reaction of an alkylformamide of the formula II

25th

H

(II)

in which R! and R2 have the meaning given above, with an inorganic acid chloride from the group Phos-30 phoroxychloride, thionyl chloride and phosgene to give a salt-like intermediate of the formula purple

35

N>

X

Cl

0

(purple)

H

40 in which Rj and R2 have the meaning given above and X denotes the group -OPOCl2, -OSOC1 or chlorine, the condensation of this intermediate with o-toluidine and the chlorination of the N- (2-methylphenyl) -form-amidine derivative obtained to an N - (2-Methyl-4-chlorophenyl) -form-45 amidine derivative of the formula I in a halogenated hydrocarbon.

Suitable halogenated hydrocarbons are, for example, 1,2-dichloroethane, 1,1,1-trichloroethane, tetrachloroethane, chlorobenzene, o-dichlorobenzene, carbon tetrachloride and so chloroform. Among the above halogenated hydrocarbons, chloroform is the preferred solvent.

The preferred inorganic acid chloride is phosgene. The salt-like intermediate product which is initially formed 55 by reaction of phosgene with an alkylformamide of the formula II corresponds to the formula III, in which Ac means the group -COC1. However, this product is unstable and decomposes under the reaction conditions used according to the following equation:

A

j

Cl

= c

\

Cl® +

CO,

H

626 333

4th

The salt-like intermediate of the formula purple is obtained by reacting an alkylformamide of the formula II with one of the aforementioned inorganic acid chlorides, preferably phosgene, in one of the aforementioned halogenated hydrocarbons, preferably chloroform, at a temperature in the range from -10 to +50 ° C, preferably 10 manufactured up to 30 ° C. The molar ratio of inorganic acid chloride to alkylformamide of the formula II is essentially 1: 1. However, each of the reactants can be used in an excess of up to 20 mol%. The molar ratio of phosgene to alkylformamide of the formula II is preferably 0.95 to 0.98: 1.

The condensation of the salt-like intermediate of the formula purple with o-toluidine is carried out at a temperature of 0 to 60 ° C., preferably 20 to 40 ° C. It is advantageous to use an excess of the salt-like intermediate of the formula purple to complete the reaction. The chlorination of the hydrochloride of an N- (2-methylphenyl) formamide derivative obtained by condensation of the salt-like intermediate of the formula lilac with a dialkylform amide of the formula II is carried out at a temperature of 0 to 80 ° C., preferably 5 to 25 ° C. , carried out. The chlorination is preferably carried out with gaseous chlorine. However, other chlorinating agents such as hypochlorites and N-chlorine compounds can also be used. According to a preferred embodiment of the present invention, the N- (2-methyl-4-chlorophenyl) formamidine derivatives of the formula I are obtained by reacting phosgene with an alkylformamide of the formula II in a molar ratio of 0.95 to 0.98: 1 at a temperature of 10 to 30 ° C in chloroform to a salt-like intermediate of the formula purple, in which X is chlorine, condensation of this intermediate at 20 to 40 ° C with o-toluidine and subsequent chlorination of the hydrochloride of an N- (2nd -Methylphenyl) -formamidinderivats prepared at a temperature of 5 to 25 ° C.

The N- (2-methyl-4-chlorophenyl) formamide derivatives of the formula I can be prepared from the reaction mixture in a conventional manner, e.g. by adding an aqueous solution of an alkali metal hydroxide, separating the two layers and evaporating the solvent from the organic layer. On the other hand, when using phosgene or thionyl chloride, it is also possible to evaporate the solvent completely or partially from the reaction mixture and to obtain the crystalline hydrochloride of an N- (2-methyl-4-chlorophenyl) formamide derivative of the formula I, or the product formed Extract hydrochloride of an N- (2-methyl-4-chlorophenyl) formamide derivative of the formula I with water from the reaction mixture. The process according to the invention is particularly suitable for the preparation of N- (2-methyl-4-chlorophenyl) -N ', N'-dimethylformamidine and N- (2-methyl-4-chlorophenyl) -N'-methyl- N'-n-butylformamidine.

The main advantage of the process according to the invention over known processes is that all process steps can be carried out in the same solvent. Additional advantages are obtained when the entire process is carried out in chloroform, which is the preferred solvent according to the present invention, and with phosgene as the inorganic acid chloride, which is also preferred. When carried out in chloroform, the entire process can be carried out in a homogeneous reaction medium since all intermediates and the end products present as hydrochlorides are soluble in the reaction mixture. This is particularly advantageous for the continuous implementation of the process. Furthermore, solvent losses are reduced to a minimum, since chloroform is easily absorbed by dialkylformamides of the formula II.

Therefore, the carbon dioxide escaping from the reaction mixture, which is saturated with chloroform, can be treated with the alkylformamide of the formula II, which is subsequently converted into the salt-like intermediate of the formula purple, 5 in order to absorb the chloroform. This is both an economic and an ecological advantage.

The process according to the invention is explained in more detail by the following examples.

Example 1

At a temperature of 18 to 22 ° C., 99 kg (1000 mol) of phosgene are introduced into a solution of 74.5 kg (1019 mol) of dimethylformamide in 360 kg of dry chloroform, which is located in an enamelled reaction vessel equipped with a stirrer . The carbon dioxide escaping from the reaction mixture is freed of chloroform and traces of phosgene by washing with dimethylformamide. Then 101.3 kg (945 mol) of o-toluidine are introduced into the homogeneous solution within 2 hours at an internal temperature of 22 to 27 ° C. After adding the o-toluidine, the homogeneous solution is stirred for 30 minutes. Thereafter, 67 kg (945 mol) of chlorine are passed in at a temperature of 15 to 20 ° C. for 4 hours. During the addition of chlorine, the pressure in the reaction vessel increases from 1 bar to 251.3 bar. After adding the chlorine, the homogeneous solution is stirred for 1 hour. 150 kg of water are then added, two layers being formed. After separation of the two layers, the aqueous layer is heated to 100 to 105 ° C to remove residual chloroform and excess chlorine-30 hydrogen. Then the pH of the aqueous layer is adjusted to 11 by adding 25% aqueous sodium hydroxide solution, the oily crude product is separated off and purified by fractional distillation. It will

7.7 kg (5% of theory) of N- (2-methylphenyl) -N ', N'-dime-35 thylformamidine with a boiling point of 128-130 ° C./11

Torr,

11.0 kg (5% of theory) N- (2-methyl-6-chlorophenyl) -N ', N'-dimethylformamidine with a boiling point of 144-146 ° C / 11 Torr,

40 147.0 kg (79% of theory) N- (2-methyl-4-chlorophenyl) -N ', N'-dimethylformamidine obtained from the boiling point 159-161 ° C / 11 Torr.

It is also possible to isolate the N- (2-methyl-4-chlorophenyl) -45 N ', N'-dimethylformamidine as the hydrochloride. For this purpose, after the chlorination, a third of the chloroform present in the reaction mixture is distilled off and replaced by the appropriate volume of xylene. The separated hydrochloride is filtered off, washed with xylene and dried.

Example 2

In a solution of 54.1 kg (740 mol) of dry dimethylformamide in 280 kg of chlorobenzene, which is located in an enamelled reaction vessel equipped with a stirrer, 71 kg (718 mol) of phosgene are added at 25 to 30 ° C. for 5 Hours initiated. After adding the phosgene, the reaction mixture is stirred at 25 to 30 ° C. for 30 minutes. Then 74 kg (690 mol) of o-toluidine 60 are added at 45 to 50 ° C. over 2 hours. After adding the o-toluidine, the reaction mixture is stirred at 75 to 80 ° C. for 1 hour. The mixture, cooled to 30 ° C., is then mixed with a solution of 1 kg of triethanolamine in 1 kg of chlorobenzene. The pressure in the reaction vessel is then reduced to 200 Torr re-65 and 52.5 kg (740 mol) of chlorine are introduced at 30 to 35 ° C. for 6 hours in the following manner: First, enough chlorine is introduced that the pressure in the reaction vessel is raised 1140 torr rises. Then the chlorine addition is interrupted

5

626 333

and the mixture was stirred for 1 hour. The pressure is then reduced again to 200 torr and the remaining chlorine is introduced. After all the chlorine has been added, the reaction mixture is stirred at 30 to 35 ° C. for 2 hours. Then the suspension obtained from

After pressure equalization, N- (2-methyl-4-chlorophenyl) -N ', N'-dimethylformamidine hydrochloride is mixed with 150 kg of water, the temperature being kept below 50 ° C. by cooling. The excess chlorine is then destroyed by adding an aqueous sodium bisulfite solution. After separation of the layers, the pH of the aqueous layer is adjusted to 11 by adding 25% aqueous sodium hydroxide solution, the oily crude product is separated off and purified by fractional distillation. 115 kg (84.7% of theory) of N- (2-methyl-4-chlorophenyl) -N ', N'-dimethylformamidine with a boiling point of 141-143 ° C./0.5 torr are obtained.

Example 3

A mixture of 235 kg of chloroform, 45.5 kg (395 mol) of N-methyl-N-n-butylformamide and 40 kg (373 mol) of o-toluidine is heated to 60 ° C. in an enamelled reaction vessel equipped with a stirrer. 52 kg (437 mol) of thionyl chloride are added to this solution at 60 ° C. in the course of one hour and the mixture is stirred for a further 1 1/2 hours. After adding 0.4 kg of iodine, 37.5 kg (529 mol) of chlorine are introduced into the reaction mixture, which has cooled to 5 to 10 ° C., over the course of 4 hours. After the addition of chlorine has ended, the mixture is stirred at 20 ° C. for 12 hours and then excess chlorine and dissolved hydrogen chloride are blown out with nitrogen. The reaction mixture is then poured onto 140 kg of ice and 15 kg of 24% sodium disulfite solution while stirring, the temperature being kept at 15 ° C. The mixture obtained is then adjusted to pH 10 to 11 by adding 30% aqueous sodium hydroxide solution and stirred for one hour. The organic layer is then separated off, washed with 70 kg of water and the solvent is distilled off in vacuo. The crude product thus obtained is purified by vacuum distillation. 85 kg of N- (2-methyl-4-chlorophenyl) -N'-methyl-N'-butylformamine are obtained with a boiling point of 130-135 ° C./0.5 torr. The product has the following composition:

86% N- (2-methyl-4-chlorophenyl) -N'-methyl-N'-n-butyl-formamidine

1% N- (2-methylphenyl) -N'-methyl-N'-n-butylform amidine

7.2% N- (2-methyl-6-chlorophenyl) -N'-methyl-N'-n-butylformamidine

2% N- (2-methyl-4,6-dichlorophenyl) -N'-methyl-N'-n-butylformamide 0.2% 2-amino-5-chlorotoluene 0.2% N-methyl-Nn-butylformamide 5 3% unknown by-products.

This composition gives a pure yield of 43.1 kg (87.2% of theory) of N- (2-methyl-4-chlorophenyl) -N'-methyl-N'-n-butylformamidine.

Example 4

A mixture of 1150 kg of o-dichlorobenzene and 249 kg of dry dimethylformamide is placed in an enamelled reaction vessel provided with a stirrer and 370 kg of phosgene are introduced at a temperature of 20 to 40 ° C. 15 After the addition of the phosgene has ended, the pressure in the reaction vessel is reduced to 200 torr to remove unreacted phosgene. 300 kg of o-toluidine are then added, cooling being used to ensure that the temperature does not exceed 60.degree. The reaction mixture is then heated to 80 ° C. and kept at this temperature for 2 hours.

Then 25 kg of triethanolamine are added and 235 kg of chlorine are introduced at 20 to 40 ° C. The hydrogen chloride formed during the chlorination is absorbed in a solution of Na-25 trium hydroxide and sodium thiosulfate. After stirring for 2 hours, 650 kg of water are added with cooling. The excess chlorine is removed by adding sodium bisulfite. After the organic layer has been separated off, 280 kg of toluene are added to the aqueous phase and the whole is stirred for 10 minutes. After the toluene has been separated off, 400 kg of fresh toluene are added and the pH of the mixture is adjusted to 10 by adding 820 kg of 30% strength aqueous sodium hydroxide solution. The aqueous sodium hydroxide solution is added in such a way that the temperature of the entire mixture does not exceed 35 to 40 ° C.

After adding the sodium hydroxide solution, the entire mixture is stirred at 35 to 40 ° C. for 2 hours. After separating the two layers, the organic layer is worked up by distillation. A water-containing fraction is first obtained under a slightly reduced pressure. The toluene is then distilled off in vacuo. The temperature is then increased, 10 kg of a third fraction being obtained, which essentially consists of o-dichlorobenzene. The distillation is stopped when a bottom temperature 45 of 145 ° C and a top temperature of 85 to 90 ° C is reached. The crude N- (2-methyl-4-chlorophenyl) -N ', N'-dimethylformamidine obtained as a residue is purified by vacuum distillation. There are 455 kg (82.6% of theory) of N- (2-methyl-4-chlorophenyl) -N ', N'-dimethylformamidine from the Sie-50 depunkt 159-161 ° C / 11 Torr.

s

Claims (4)

626 333 2nd PATENT CLAIMS 1. Process for the preparation of N- (2-methyl-4-chlorophenyl) formamidine derivatives of the formula I. 'R1 CL_ / q V- N = CH - N (I) :H. N - 0 II C - H (II) R2 in which Rj and R2 have the meaning given above, with an inorganic acid chloride from the group phosphorus oxychloride, thionyl chloride and phosgene to give a salt-like intermediate of the formula purple R, _ © . N> X Cl 0 (purple) »2 H 6. Process according to Claims 1 and 5, characterized in that N, N-dimethylformamide is used as the alkyl amide of the formula II. 7. Process according to Claims 1 and 5, characterized in that N-methyl-N-n-butylformamide is used as the alkyl formamide of the formula II. 10th in which Ri is hydrogen or an alkyl group having 1 to 4 carbon atoms and R2 is an alkyl group having 1 to 4 carbon atoms, by reacting an N-alkylformamide with an inorganic acid chloride, condensing the intermediate obtained with o-toluidine and chlorinating the N- (2-methylphenyl) formamide derivative formed in this way, characterized in that the Implementation of an alkyl formamide of the formula II 30th 35