CS264483B1 - Process for the preparation of N- (2-chlorobenzoyl) -4-chloroanilide - Google Patents

Abstract

The solution concerns the preparation of N-(2-chlorobenzoyl)-4-chloroanilide from 4-chloroaniline and 2-chlorobenzoyl chloride in a toluene environment in the presence of an organic base, preferably pyridine in a reducing environment, ensured by the presence of hydrogen or sodium metabisulfite in the reaction mixture. This prevents oxidative changes in the aromatic amino group, which are manifested by the coloration of the product of the next stage of synthesis, namely 2-amino-2',5-dichlorobenzophenone. This ketone is the starting material for the production of 7-chloro-5-(2-chlorophenyl)-1,4-benzodiazepin-2-one.

Description

The present invention relates to a process for the preparation of N- (2-chlorobenzoyl) -4-chloroanilide which is the starting material for the preparation of 2-amino-2 ', 5-dichlorobenzophenone. This ketone is virtually the only substance useful for the construction of the 1,4-benzodiazepine nucleus of the hypnotic Triazolam / 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-s-triazolo (4,3a) -1,4 -benzodiazepine /. Introduction of 1,4-benzodiazepine-derived psychopharmaceuticals (5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones)

In the 1960s, decisive progress was made in the treatment of a number of mental disorders. Individual pharmacologically active substances were substituted on the basic skeleton of 1,4-benzodiazepine both on the accumulated core A with halogens or nitro groups and on the core C with halogen. In this way, important specialties from world-renowned companies such as Valium and Librium Roche (Diazepam and Oxazepam Spofa) came into routine medical practice. In the 1970s, substances with centrally depressant activity, hypnotics, sedatives or anxiolytics were again derived from the basic skeleton. The construction of the 1,4-benzodiazepine core was accomplished by a number of routes, given by the steric possibilities defined by the substitution groups. The basic work in the field of 1,4-benzodiazepines is Sternbach et al., J. Org. Chem. 27, 3781-88 (1962). The synthesis of the 1,4-benzodiazepine core of Triazolam, introduced by Upjohn in the late 1960s, is practically always based on 2-amino-2,5-dichlorobenzophenone. The preparation of this ketone utilizes the Friedel-Crafts reaction of 4-chloroaniline with 2-chlorobenzoic acid chloride by catalysing zinc chloride at temperatures of 200-240 ° C. The first step is the rapid acylation of the aromatic amino group with 2-chlorobenzoic acid chloride at 190 ° C. This reaction, followed by heating the reaction mixture to 240 [deg.] C. with zinc chloride, produces pitch-like products resulting from changes in the free aromatic amino group upon vigorous acylation in the pre-stage of the Friedel-Crafts reaction. Despite their low percentage, it is sufficient to color the products of subsequent synthesis stages so that they must be cleaned with high losses.

The invention relates to a process for the preparation of N- (2-chlorobenzoyl) -4-chloroaniline by aoylation of 4-chloroaniline with 2-chlorobenzoyl chloride in toluene in the presence of an organic base, preferably pyridine in a reducing medium. This is maintained by the presence of sodium bisulfite or sodium pyrosulfite in the reaction mixture. The anilide thus prepared is used for the Friedel-Craft owl reaction at temperatures of about 200 ° C. The reaction product, after hydrolysis and purification, crystallizes from aqueous solutions of aliphatic alcohols that specifically separate the color impurities retained after filtering the solution through the surfactant material. There was thus obtained 2-amino-2 ', 5-dichlorobenzophenone as yellow crystals. The product is uniform in thin-layer chromatography and its melting point 86-89 ° C indicates a high degree of purity. AND

Example 1

127.5 g (1 M) of 4-chloroaniline are mixed with 500 ml of toluene, 2 g of sodium metabisulphite and 83 g of pyridine. While stirring, 180.0 g (1.03 M) of 2-chlorobenzoyl chloride are added at 20 to 50 ° C. After refluxing for 3 hours, the reaction mixture is slightly cooled and treated with 500 ml of petrol and 500 ml of water. The suspension is cooled to room temperature, the product is filtered off with suction and washed with water and petrol. 246.0 g of a white crystalline solid are obtained. Mp 130-133 ° C. 266.0 g (1 M) of the N- (2-chlorobenzoyl) -4-chloroaniline thus obtained are mixed with 227.5 g of 2-chlorobenzoyl chloride (1.3 M) and 136 g of anhydrous zinc chloride. The mixture was heated to 200 ° C + 5 ° C for 2 hours. After cooling to about 130 DEG C., 500 ml of water and 20 ml of sulfuric acid conc. The product is stirred at 100 ° C in a quenched reaction mixture, filtered off with suction and washed with hot water. Yield 500 g. Hydrolysis of the product was carried out with a mixture of 500 ml of water, sulfuric acid conc. and acetic acid at 115-120 ° C. Time required 12 hours. The reaction was quenched with 3 L of water, the crude 2-amino-2 ', 5-dichlorobenzophenone was filtered off with suction and washed with hot water. Yield 151.8 g (57.2% of theory) based on 4-chloroaniline. The product is dissolved at temperatures of 20 to 50 ° C in ten times the volume of methanol. The solution is diluted with 10% water (solvent) and, after coagulation of dark impurities, is filtered through 20% of the amount of activated charcoal per ketone weight. The filtrate was diluted 10-fold with water and the yellow, crystalline 2β-diphenyl-2 ', 5-dichlorobenzophenone was filtered off with suction and washed with water. Yield 111.5 g represents 42% of the theoretical amount per 4-chloroaniline employed.

Example 2

The design is identical, but a reducing atmosphere of acylation is provided by the addition of 2 g of sodium bisulfite. Ethanol was used for crystallization in the same amounts as in Example 1. The yields of the examples were identical.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of N- (2-chlorobenzoyl) -4-chloroaniline by acylating 4-chloroaniline with 2-chloroenzoyl chloride, characterized in that the reaction is carried out in toluene in the presence of an organic base, preferably pyridine, in a reducing medium. 2. A process according to claim 1 wherein the reducing medium of the reaction is maintained with sodium bisulfite or sodium metabisulfite.