CS255227B1 - Process for preparing 2,6-dichlorodiphenylamine - Google Patents

Abstract

The solution concerns the preparation of 2,6-dichlorodiphenylamine, which is carried out in five synthesis stages: by reacting 2,6-dichloroaniline with benzoyl chloride, 2,6-dichloroanilide of benzoic acid is prepared, which is converted by the action of thionyl chloride into N-(2,6-diochlorophenyl)-benzimidoyl chloride, whose reaction with alkali metal phenolate in a two-phase system in the presence of a phase transfer catalyst produces N-(2,6-dichlorophenyl)-benziminophenyl ether, which undergoes thermal rearrangement to N-benzoyl-2,6-dichlorodiphenylamine, which, upon saponification, provides 2,6- -dichlorodiphenylamine. The above method of preparing 2,6-dichlorodiphenylamine is technologically easy to implement, allows achieving high yields of the desired product, ensures high product quality even when using standard purification procedures and uses commonly available raw materials. The obtained 2,6-dichlorodiphenylamine is a key intermediate for the preparation of diclofenac sodium salt, a widely used drug with analgesic and anti-inflammatory effects.

Description

The present invention provides a process for the preparation of 2,6-dichlorodiphenylamine of formula I,

Cl

Cl, which is a key intermediate for the preparation of o- (2,6-dichloroanilino) -phenylacetic acid, whose sodium salt (diclofenac sodium) is a widespread drug with an anti-pain and anti-inflammatory effect. '

A known process for the preparation of 2,6-dichlorodiphenylamine based on the Gomberg reaction of bromobenzene (or iodobenzene) with 2,6-dichloro-N-acetanilide according to the following equation:

Cl wherein X represents a bromine or iodine atom is the subject or part of a number of patents such as Brit. U.S. Pat. 1 132 318, GDR Pat. 141,306, Jap. U.S. Pat. 57 167 947 and others. The inventors have found that the course of the Gomberg reaction is complicated by the following dispioporational (2a, 2b) and side (2c) reactions

whereby the resulting 2-bromo- (or 2-iodo) 6-chloro-N-acetanilide and 2-bromo- (or 2-iodo) 6-chloro-N-acetyldiphenylamine significantly contaminate both the key component and the reaction product ( 1).

However, the preparation of diclophenea of pharmacopoeial purity requires 2,6-dichlorodiphenylamine completely free of 2-bromo- (or 2-iodo-) 6-chlorodiphenylamine, which, due to their chemical affinity, is very difficult and unprofitable.

The above-mentioned disadvantages of the hitherto known processes are eliminated by the process for the preparation of 2,6-dichlorodiphenyl amine according to the invention, which consists in a five-step transformation of 2,6-dichloroaniline into 2,6-dichlorodiphenylamine. In the first synthesis stage, 2,6-dichloroaniline is acylated with benzoyl chloride in a temperature range of 50 to 200 ° C, optionally in the presence of an aprotic or protophilic solvent (toluene, ethylbenzene, xylene, industrial naphtha, chlorinated aliphatic or aromatic hydrocarbons, diphenylether, etc.). it is preferred to carry out the reaction in

25522 constant temperature of the boiling solvent. The resulting benzoic acid 2,6-diohloroanilide is reacted with thionyl chloride in a temperature range of 50 to 125 ° C in the second synthesis stage, optionally in the presence of an aprotic or protophilic solvent (toluene, ethylbenzene, xylene, industrial gasoline, chlorinated aliphatic or aromatic hydrocarbons, diphenyl ether etc. ), preferably at a constant boiling point of thionyl chloride or the solvent used, to give N- (2,6-dichlorophenyl) -benzimidoyl chloride. A solution of N- (2,6-dichlorophenyl) -benzimidoyl chloride in an aprotic or protophilic, water-immiscible solvent (toluene, ethylbenzene, xylene, industrial gasoline, chlorinated aliphatic or aromatic hydrocarbons, diphenyl ether, etc.) is reacted in a third synthesis stage with an alkali metal phenolate in aqueous solution in the presence of quaternary ammonium salts as a phase transfer catalyst (tetrabutylammonium chloride, triethylbenzylammonium chloride, etc.) in the temperature range of 5 to 75 ° C.

The obtained N- (2,6-dichlorophenyl) -benziminophenyl ether is thermally rearranged in the fourth synthesis stage at 200 to 330 ° C, optionally in the presence of high boiling solvents (chlorinated aromatic hydrocarbons, aliphatic glycols and polyols, diphenyl ether and the like) in N-benzoyl -2,6-dichlorophenylamine. In the fifth synthesis step, the saponification of N-benzoyl-2,6-dichlorodiphenylamine with an aqueous-alcoholic alkali metal hydroxide solution or aqueous alkali metal hydroxide solution in the presence of quaternary ammonium salts as 2,6-dichlorodiphenylamine phase transfer catalyst in a total yield of about 75%, the saponification of N-benzoyl-2,6-dichlorodiphenylamine takes place in the temperature range of 40 to 105 ° C, optionally in the presence of a water-immiscible solvent (toluene, ethylbenzene, xylene, industrial gasoline, chlorinated aliphatic or aromatic hydrocarbons, etc.).

The process for preparing 2,6-dichlorodiphenylamine according to the invention has the following advantages over known processes:

- the product obtained is chemically very pure,

- product yields are clearly higher and very stable (i.e., they do not depend very much on deviations from the optimal reaction mode),

- the intermediates prepared in the individual synthesis stages are usable directly in the raw state,

- raw, apparatus and manipulation undemanding process allows increased labor productivity and better utilization of technological equipment.

In the following example, the process for preparing the 2,6-dichlorodiphenylamine of the present invention is illustrated in more detail, but the present invention is not limited in any way.

Example

162.0 g (1 mol) of 2,6-dichloroaniline are dissolved in 250 ml of toluene, 140.6 g (1 mol) of benzoyl chloride are added and the resulting homogeneous reaction mixture is refluxed for 3 hours. The product crystallized by cooling the reaction mixture to 20 ° C is filtered off with suction, concentrating the toluene mother liquors to a volume of about 50 ml and cooling them to 20 ° C to crystallize a further portion of the product. Drying the combined fractions of the isolated crystalline product to constant weight gave 250 g, i.e. 94.0% of the theory of 2,6-diohloroanilide benzoic acid as white needles, m.p. 149-150 ° C, min.

99% (determined by gas chromatography).

A heterogeneous mixture of benzoic acid 2,6-dichloroanilide (240.0 g, 0.90 mol) and thionyl chloride (150 ml) was maintained under stirring for 2 hours, during which time the reaction mixture was homogenized to evolve with hydrogen chloride and sulfur dioxide. From the homogeneous reaction mixture, unreacted thionyl chloride is distilled off first under atmospheric and later under reduced pressure, which can be used in another batch. The remaining crude N- (2,6-dichlorophenyl) -benzimidoyl chloride was purified by vacuum distillation: collection of the fraction, b.p. 200 DEG-230 DEG C. at a pressure of 1.2 kPa, 240 g (93.7% of theory of a slightly yellowish oily product) are obtained.

which crystallizes on standing. Purified by distillation N- (2,6-dichlorophenyl) -benzimidoyl chloride shows m.p. Deň: 32 ° C.

To a solution of 227.1 g (0.80 mol) of N- (2,6-dichlorophenyl) -benzimidoyl chloride in 600 ml of dichloromethane is added an aqueous solution of sodium phenolate prepared by dissolving 75.3 g (0.80 mol) of phenol in 90 ml. 30% aqueous sodium hydroxide solution. A solution of 10.0 g of triethylbenzylammonium chloride in 100 ml of dichloromethane was added to the vigorously stirred biphasic reaction mixture at 20 ° C over 5 minutes and the reaction mixture was allowed to stir at 35 ° C for 3 hours. The specifically heavier organic layer is separated, washed with 5% aqueous sodium hydroxide solution, x with distilled water and dried on standing with anhydrous sodium sulfate. Distillation of dichloromethane yielded 260 g (95.0%) of the crude N- (2,6-dichlorophenyl) -benziminophenyl ether of 93-95% purity (determined by gas chromatography) as a yellow oil which solidified on standing. Crystallization of the crude product from petroleum ether gave 230 g of N- (2,6-dichlorophenyl) -benziminophenyl ether, a yellow crystalline solid, m.p. 71 ° C purity 98-99% (determined by gas chromatography).

Melt 222.5 g (0.65 mol) of N- (2,6-dichlorophenyl) -benziminophenyl ether is heated to 300 ° C with stirring and maintained at this temperature for 15 minutes: by thermal rearrangement, crude N- is obtained in quantitative yield. benzoyl-2,6-dichlorodiphenylamine, which solidifies resinous by cooling the melt to room temperature. Crystallization of the crude product from ethanol-water gave 200 g (89.9%) of white crystalline N-benzoyl-2,6-dichlorodiphenylamine, mp, 130-132 ° C, 98-99% purity (determined by gas chromatography).

To a solution of 80.0 g (2.00 mol) of sodium hydroxide in 300 ml of methanol-water (1: 1) was added 205.4 g (0.60 mol) of N-benzoyl-2,6-dichlorodiphenylamine and the resulting heterogeneous the reaction mixture is kept under reflux for 3 hours. Methanol was distilled off from the resulting homogenized reaction mixture at atmospheric pressure and the cooled strongly alkaline biphasic system was extracted with 500 ml of dichloromethane. The combined organic extracts were washed with 2% aqueous sodium hydroxide solution and dried by standing with sodium sulphate.

By distilling off the dichloromethane from the dried organic extract, 134 g, i.

93.7% of theory of crude 2,6-dichlorodiphenylamine of 97 to 98% purity (determined by gas chromatography) as a brown oil which solidifies on standing. The crude 2,6-dichlorodiphenylamine was purified by vacuum distillation, collecting the 145-157 ° C fraction at 160 Pa to give 120 g of a honey-yellow viscous oil which solidified on standing at room temperature. Distilled 2,6-dichlorodiphenylamine shows m.p. 56-58 ° C and is at least 99% pure (as determined by gas chromatography).

SUBJECT OF THE INVENTION

Claims (1)

SUBJECT OF THE INVENTION A process for preparing 2,6-dichlorodiphenylamine of formula I Cl Cl, characterized in that 2,6-dichloroaniline is reacted with benzoyl chloride in a temperature range of 50 to 200 ° C, optionally in the presence of an aprotic or protophilic solvent to form the 2,6-dichloroanilide benzoic acid of formula II Cl Cl which is converted to N- (2,6-dichlorophenyl) -benzimidoyl chloride of formula III pi by treatment with thionyl chloride in the temperature range of 50 to 125 ° C, optionally in the presence of an aprotic or protophilic solvent, by reacting with an alkali metal phenolate in a two-phase system - water or aprotic or protophilic solvent - the solid phase in the presence of a quaternary ammonium salt type phase transfer catalyst results in a temperature range of 5 to 75 ° C N- (2,6-dichlorophenyl) -benziminophenyl ether of formula IV which by thermal rearrangement at 200 to 330 ° C, optionally in the presence of high-boiling heat exchangers, provides N-benzoyl-2,6-dichlorodiphenylamine of formula V, and by alkaline hydrolysis of the benzoyl group in the presence of an aliphatic alcohol or phase transfer catalyst liberates 2,6-dichlorodiphenylamine of formula I.