PROCESS FOR THE PREPARATION OF N-(1-ETHYL 2-PYRROLIDYL METHYL)-2-METHOXY-5-SULFAMOYL BENZAMIDE

PROCEDE POUR LA PREPARATION DE LA N-(1-ETHYL-2-PYRROLIDYLMETHYL)-2-METHOXY-5-SULFAMOYLBENZAMIDE

English Abstract

ABSTRACT OF THE DISCLOSURE
There is provided a novel process for preparing the
N-(1ethyl-2-pyrrolidylmethyl)-2-methoxy-5-sulphamoyl benzamide
by the selective reduction of the tertiary amide group of N-
(1-acetyl-2-pyrrolidylmethyl)-2-methoxy-5-sulphamoyl benzamide.
The product obtained is a useful antiemetic.

Claims

The embodiments of the invention in which an exclu-
sive property or privilege is claimed are defined as follows:
1. A new method of preparing N-(1-ethyl-2-pyrrol-
idylmethyl)-2-methoxy-5-sulphamoyl benzamide, its salts of
addition with pharmaceutically acceptable inorganic or organic
acids and its quaternary ammonium salts, which comprises
selectively reducing the tertiary amide group of N-(1-acetyl-2-
pyrrolidylmethyl)-2-methoxy-5-sulphamoyl benzamide to form the
desired N-(1-ethyl-2-pyrrolidylmethyl)-2-methoxy-5-sulphamoyl
benzamide.

Description

~o~
The invention relates to a new method of preparing N-
(l-ethyl-2-pyrrolidylmethyl)-2-methoxy-5-sulphamoyl benzamide,
its salts of addition with pharmaceutically acceptable inor-
ganic or organic acids, and quaternary ammonium salts obtained
by reacting the benzamide with an agent for introducing a
univalent aliphatic or aromatic hydrocarbon radical.
The method of the invention comprises selectively
reducing the tertiary amide group of N-(l-acetyl-2-pyrrolidyl-
methyl)-2-methoxy-5-sulphamoyl benzamide without affecting the
secondary amide function, to give N-(l-ethyl-2-pyrrolidyl-
methyl)-2-methoxy-5-sulphamoyl benzamide.
The N-~l-ethyl-2-pyrrolidylmethyl)-2-methoxy-5-
sulphamoyl benzamide is a useful antiemetic sold under the
generic name Metoclopramide.
The process accordlng to the invention is illustrated
in the following diagram:
CO-~H-~H2--~J
¦ reduction
~/ ~ OCH3 CO-CH3 - _
H2N02SI~J
Co-NH-cH2~;~
~ ~ OCH3 C2H5
H2N02S-~
The reduction envisaged in the method of the
invention is effected by an alkali metal borohydride and a
halide of a polyvalent metal such as aluminium chloride,
gallium chloride, titanium tetrachloride, and the like.
-- 1 --

~ 36~f~
The solYents used are adapted to solubilize the
catalysts used, such as d;ethylene glycol dimethyl ether or
diylyme.
The ~ollowing example is given to illustrate the
invention without imposing any restrictions on it.
EXAMPLE
N-(l-ethyl-2-pyrrolidylmethyl)-2-methoxy-5-sulphamoyl benzam;de
3.55 g of ~-(1-acetyl-2-pyrrolidylmethyl~-2-methoxy-
5-sulphamoyl benzamide, 35 ml of diethylene glycol dimethyl
ether and 0.51 9 of sodium borohydride were placed in a 250 ml
flask.
The mixture was agitated for ~ive minutes at 20C,
then a solution of 0.8 g o~ aluminium chloride in 10 ml of
diethylene glycol dimethyl ether was dropped in.
The mixture was heated for three hours at 110C.
After cooling, the suspension formed was poured into a solution
of 10 ml of hydrochloric acid (density 1.18) in 50 ml oF water.
The mixture was heated for ~ive minutes to boiling point then
cooled and the solvents were evaporated under vacuum. The
crystallized residue obtained was dissolved in water and the
solution formed was made alkaline with ammonia. When the
mixture had been extracted three times with 50 ml oF ethyl
acetate and the solvent evaporated, the resldue obtained was
recrystallized in ethanol.
1.4 g of N-(l-ethyl-2-pyrrolidylmethyl)-2-methoxy-5-
sulphamoyl benzamide was obtained (M.P. 178-180C).