CS254744B1 - Process for preparing 2,6-dichlorodiphenylamine - Google Patents

Abstract

The solution concerns the preparation of 2,6-dichlorodiphenylamine, which is carried out in three synthesis stages: the reaction of N-phenylbenzimidoyl chloride with 2,6-dichlorophenolate of an alkali metal in a two-phase system in the presence of a phase transfer catalyst produces N-phenylbenzimino-2,6- -dichlorodiphenylamine, which, upon saponification, provides 2,6-dichlorodiphenylamine. The method of preparing 2,6-dichlorodiphenylamine. The method of preparing 2,6-dichlorodiphenylamine is technologically easy to implement, allows high yields of the desired product to be achieved, ensures its high quality and uses readily available raw materials and intermediates; 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

O- ^nh -5 (1), 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

I (1) wherein X represents a bromine or iodine atom is the subject or part of a number of patents, such as Brit. 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 disproportionation (2a, 2b) and side (2c) reactions

NH-COCH

Cl

Cl +

(2a) / CO-CH 3 ⁺

O 'ci

(2b)

(2c) the resulting 2-bromo- (or 2-iodo) 6-chloro-N-acetanilide and 2-bromo- (or 2-iodo) 6-chloro-N-acetyldiphenylamine significantly contaminate the key component i reaction product (1). However, the preparation of diclofenac sodium 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-dichlorodiphenylamine according to the invention, which consists in a three-step transformation of 2,6-dichlorophenol into 2,6-dichlorodiphenylamine. In the first synthesis stage, the alkali metal 2,6-dichlorophenolate is reacted with N-phenylbenzimidoyl chloride in a two-phase water-aprotic or protophilic water-immiscible solvent (toluene, ethylbenzene, xylene, industrial gasoline, chlorinated aliphatic or aromatic hydrocarbons, diphenyl ether etc.). quaternary ammonium salts as phase transfer catalysts (tetrabutylammonium iodide, tripthylbenzylammonium chloride and the like) in the temperature range of 5 to 80 ° C. The prepared N-phenylbenzimino-2,6-dichlorophenyl ether obtained by separation of the organic phase is thermally rearranged in the second synthesis stage at 175 to 300 ° C, optionally in the presence of a high boiling solvent or heat transfer medium (chlorinated aromatic hydrocarbons, aliphatic glycols and polyols, diphenyl ether and the like) in N-benzoyl-2,6-dichlorodiphenylamine.

In the third synthesis step, by 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 a quaternary ammonium salt as a phase transfer catalyst (tetrabutylammonium sulfate, triethylbenzylammonium chloride, etc.) 2,6-dichlorodiphenylamine total yield over 80% of theory; 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 are very stable (i.e., they are little dependent on deviations from the optimal reaction mode);

the intermediates prepared in the individual synthesis steps 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 2,6-dichlorodiphenylamine of the invention is illustrated in more detail; however, this example does not limit the scope of the invention in any way.

Example

To a solution of 151.0 g (0.70 mol) of N-phenylbenzimidoyl chloride in 400 ml of dichloromethane is added an aqueous solution of sodium 2,6-dichlorophenolate, prepared by dissolving 114.2 g (0.70 mol)

2,6-dichlorophenol in 80 ml of 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 30 ° C for 1 hour. The specifically heavier organic layer was separated, washed with 1 x 5% aqueous sodium hydroxide solution, 2 x distilled water and dried on standing with anhydrous sodium sulfate.

Distilling off the dichloromethane yielded 228 g (95.2%) of the crude N-phenylbenzimino-2,6-dichlorophenyl ether of about 95% purity (determined by gas chromatography), an ocher-colored oily substance which solidified on standing. Crystallization of the crude product from petroleum ether gave 210 g of N-phenylbenzimino-2,6-dichlorodiphenyl ether, a yellowish crystalline solid, m.p. 73.5-75.0 ° C, 98-99% purity (determined by gas chromatography).

A melt of 210 g (0.60 mol) of 98% N-phenylbenzimino-2,6-dichlorodiphenyl ether was heated to 250 ° C with stirring and held at this temperature for 15 minutes; by thermal rearrangement, the crude N-benzoyl-2,6-dichlorodiphenylamine is obtained in quantitative yield, which solidifies resinously by cooling the melt to room temperature. Crystallization of the crude product from ethanol-water gave 193 g, i. 91.9% of theory of white crystalline N-benzoyl-2,6-dichlorophenylamine m.p. 130 DEG-132 DEG C., purity 98 to 99% (determined by gas chromatography).

To a solution of 80 g (2.0 mol) of sodium hydroxide in 200 ml of distilled water was added 192 g (0.55 mol) of 98% N-benzoyl-2,6-dichlorodiphenylamine and a solution of 10.0 g of triethylbenzylammonium chloride in 300 ml of toluene. The resulting heterogeneous reaction mixture was stirred vigorously at 50 ° C for 2 hours, the specifically lighter organic phase was separated, washed with 1% aqueous sodium hydroxide solution and toluene with residual moisture removed. distills off; By distilling off toluene, 124 g (94.7%) of the crude 2,6-dichlorodiphenylamine of 97-98% purity (determined by gas chromatography) were obtained as a brown oil which solidified on standing. The crude 2,6-dichlorodiphenylamine is purified by vacuum distillation; collecting 145-155 ° C at 160 Pa yielded 115 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).

Claims (1)

SUBJECT OF THE INVENTION Process for the preparation of 2,6-dichlorodiphenylamine of formula I, Cl (I) Cl characterized by reacting N-phenylbenzimidoyl chloride with an alkali metal 2,6-diohlorophenolate in a biphasic water-aprotic or protophilic solvent or solid phase-aprotic or protophilic solvent in the presence of a quaternary ammonium salt type phase transfer catalyst in a temperature range of 5 to 80 ° C to give N-phenylbenzimino-2,6-dichlorophenyl ether of formula II which, by thermal rearrangement at 175 to 300 ° C, optionally in the presence of high boiling solvents or heat exchangers, yields N-benzoyl-2,6- dichlorodiphenylamine of formula III, (III) and the latter by alkaline hydrolysis of the benzoyl group in the presence of an aliphatic alcohol or a quaternary ammonium salt type phase transfer catalyst liberates 2,6-dichlorodiphenylamine of formula I.