NO133890B - - Google Patents

Description

The present invention relates to a process for the preparation of r"N-(disthylaminoethyl)-2-methoxy-<1>+-amino-5-chloro-benzamide by chlorination of an O-alkylated, N-substituted p-aminosalicylic acid ester and subsequent reaction with diethylaminoethylamine.

With the previously used method, one has started

with p-aminosalicylic acid, whose carboxyl group was esterified and whose hydroxyl group was alkylated, after which the ^-amino group was blocked by acetylation through reaction with acetic anhydride. After introducing the other substituents, this acetyl group was again cleaved off.

It has now been found that the stated benzamide can be obtained by the usual methods with significantly improved yield if, by blocking the <*>+-amino group, this is not acetylated, but after an esterification and O-alkylation of p-aminosalicylic acid, the k- amino group is substituted with a p-toluene-sulfuric acid residue for the chlorination, which after reaction with diethylaminoethylamine is split off again.

According to a preferred embodiment of the method, 2-methoxy-<1>+-aminobenzoic acid methyl ester is reacted with p-toluene sulphochloride, while cleavage of this p-toluenesul&nic acid residue is simply carried out by heating N-Cdiethylaminoethyl)-2-methoxy-<1>+- (p-toluene-sulfamido)-5-chloro-benzamide in concentrated sulfuric acid.

The turnover in the individual process steps takes place according to the following reaction scheme:

LOOOOOOVE

Implementation example

2- methoxyv-^- aminobenzoic acid methyl ester (I)

In a 2-liter flask equipped with a stirrer, thermometer and dropping funnel, 35 g (0.229 mol) of p-amino-salicylic acid was dissolved in 700 ml of acetone. As soon as a solution was present, 33.6 g (0.6 mol) of potassium carbonate was introduced into 6 portions over the course of 2.5 hours, during which the reaction mixture was vigorously stirred.

5l ml (C.5"+ mol) of dimethylsulphate was then added dropwise to the mixture, after which the mixture was stirred for 3 hours at room temperature. Acetone was distilled off in a vacuum while gently heating on a water bath.

700 ml of water was then added, the product was separated, washed with water and dried at 50°C. 36 g (87%) of compound (I) with melting point 158°C were obtained.

2- methoxy-^- ( p- toluene- sulf amido-)- benzoic acid- methyl ester (II)

36 g (0.198 mol) (I), h2 g (0.26 mol) p-toluene sulfochloride, <*>+00 ml toluene and 2 g triethanola min.

20 ml of distillate was very slowly distilled off in the course of

<*>+ hours at a temperature in the reaction mixture of 115°C

The mixture was cooled and allowed to crystallize overnight.

The reaction product was filtered off, washed several times with 200 ml of a solution of 20% hydrochloric acid, then with water to a neutral pH of the wash water. After drying in an oven at 50°C, $ h g (81.3%)- of compound (II) with melting point 1<+3°C was obtained.

2- methoxy- 1!— ( p- toluene- sulf aml do )- 5- chloro- benzo acid- methyl ester (III)

Into a 250 ml flask equipped with stirrups and a dropping funnel were introduced 2^.5 g (0.0732 mol) of compound (II) and 50 ml of acetic acid. To the suspension thus obtained, a solution of 552 g (0.0732 mol) chlorine in 137 ml acetic acid was added dropwise over the course of 1/2 hour at room temperature. The mixture was stirred for 3 hours and allowed to stand overnight.

The reaction mixture was poured into 1.5 liters of water, filtered, the product washed with water and alcohol and dried at 50°C. 2.5 g (90%) of compound (III) with melting point 177°C was obtained.

N-(diethylaminoethyl)-2-methoxy-!+-(p-toluene-sulfa amido)-5-chloro-benzamide ( IV)

Into a 250 ml flask equipped with stirrups and skirts, was introduced 1^5 ml of toluene, 21.5 g (0.0583 mol) of compound (III) and 20.7 g (0.0583 mol x 3) of diethylaminoethylamine which was heated to back-flow for 2.5 hours.

The reaction mixture was cooled, filtered and the precipitate was washed with toluene and dried at 50°C. 26 g (98.5%) of compound (IV) with a melting point of 1M+°C were obtained.

N-(diethylaminoethyl)- 2- methoxy-^— amino- 5- chlorobenzamide (V)

10 g of compound (W) and 15 ml of concentrated sulfuric acid of 96% were introduced into a reaction flask, after which the mixture was heated over the course of 1 hour in a water bath at 60 - 70°C. The mixture was then cooled and transferred to crushed ice. The pH was adjusted to 10 with 35 ml of sodium hydroxide solution. The precipitate obtained was filtered off, washed with water and dried.

After recrystallization in isopropanol, 5 g (76%) of compound (V) with melting point 1^5 - 1<!>+6°C were obtained.

N-(diethylaminoethyl)-2-methoxy-1+-amino-5-chloro-benzamide is a very effective agent in the treatment of stomach and intestinal diseases as well as for managing and influencing the digestive process.

Claims (1)

Procedure for the preparation of N-(diethylaminoethyl)-2- methoxy-^-amino-5-chloro-benzamide of the formula by chlorination of an O-alkylated, N-substituted p-aminosalicylic acid ester and subsequent reaction with diethylaminoethylamine, characterized in that the ^--amino group in an esterified and O-alkylated p-aminosalicylic acid, for chlorination, is substituted with a p-toluene sulfonic acid residue , which after the reaction with diethylamino- . ethylamine is again split off.