PROCESS FOR THE PREPARATION OF N-(DIETHYLAMINOETHYL)-2-METHOXY-5-METHYLSULFONYL BENZAMIDE

PREPARATION DE BENZAMIDE N-(DIETHYLAMINOETHYLE)-2-METHOXY-5-METHYLSULFONYLE

English Abstract

A B S T R A C T


Process for preparing N-(diethylainoethyl)-2-
methoxy-5-methylsulfonylbenzamide which comprises reacting
2-methoxy-5-methylsulfonylbenzaldehyde with N,N-diethylamino-
ethylhydroxylamine to form the 2-methoxy-5-methylsulfonyl-
benxaldehyde-(N,N-diethylaminoethyl)-nitrone And hydrolyzing
the latter compound to form the desired benzamide which is
useful as an antimetic and as an agent for modifying the
digestive process.

Claims

The embodiments of the invention in which an exclu-
sive property or privilege is claimed are defined as follows:

1. A novel process for the preparation of the 2-
methoxy-5-methylsulfonylbenzaldehyde-(N,N-diethylaminoethyl)-
nitrone corresponding to the formula:

Image

characterized in that 2-methoxy-5-methylsulfonylbenzaldehyde is
reacted with N,N-diethylaminoethylhydroxylamine to produce the
2-methoxy-5-methylsulfonylbenzaldehyde-(N,N-diethylaminoethyl)-
nitrone.


2. The process of Claim 1, wherein the nitrone
compound obtained is hydrolyzed by means of an acid to produce
the N-(diethylaminoethyl)-2-methoxy-5-methylsulfonylbenzamide.

3. 2-Methoxy-5-methylsulfonylbenzaldehyde-(N,N-
diethylaminoethyl)-nitrone, when prepared by the process
defined in Claim 1 or by an obvious chemical equivalent.

Description

1~37~9~
The present invention concerns a novel process for ~ .
the preparation of N-(diethylaminoethyl)-2-methoxy-5-methyl-
sulfonylbenzamide (IV), its salts of addition with pharmaceuti- :cally acceptable mineral or organic acids, and the quaternary .:
ammonium salts produced by reacting said benzamide (IV~ with
an alkylating agent.
The benzamide (IV) is produced by reacting 2-methoxy-
; 5-methylsulfonylbenzaldehyde (I) with N,N-diethylaminnethyl-
hydroxylamine (II), so as to produce 2-methoxy-5-methyl-
sulfonylbenzaldehyde-(N,N-diethylaminoethyl)-nitrone (III)
which is hydrolyzed by means of an acid to produce the desired :
benzamide (IV). ~.
This benzamide has attractive pharmacologlcal
. properties as an antiemetic and as an agent for mod1fy~ng
the digestive process. :;~
The diagram of the reaction is as follows:

2 5~ N-CH2-CH2-Cl NH2H > 2 5 ~N-CH2-CH2- HoH


CHO 2 5/ R-CH2-CH2-RHOH CH-R-CH2-CH2-R~ 2 S

~ OCH3 ~ OCH3
H3CQ2S ~ (I~ H3CO2S ~ (III~

, O

CH N CH2 CH2 N~C H CO-NH-CH2-cH2-N~c H ~:

OCH3 ~ OC~13
hydrolYsi AS~ H3Co2s~J
(III) ~IV
~ ' ' '.
-- 1 --

`, . . .
: ...... . , `. . . ~ ~ . .

~ 7~94 .

The following example illustrates but does not limit
the present invention.
EXAMPLE I -~
N-(diethylaminoethyl)-2-methoxy-5-methylsulfonylbenzamide
STAGE I: N?N-diethylaminoethylhydroxylamine
Into a 1 litre balloon flask provided with a stirrer,
a thermometer and a condenser there are introduced 41.7 g
(0.6 mol) of hydroxylaminehydrochloride, 82.4 y (0.48 mol) oF
N,N-diethylamino-2-chloroethanehydrochloride, 86 g of sodium
carbonate, 600 ml of 70% ethanol and 50 ml of water.
This is then heated For 8 hours under reflux, and
left at rest overnight.
The alcohol is evaporated under vacuum and the
product is extracted three times with 200 ml oF ether, aFter
salting out the residue with potassium carbonate.
The organic phase is dried on potassium carbonate,
and then filtered, and the ether is evaporated; the product is
distilled under vacuum.
29 g (yield: 45%) of N,N-diethylaminoethylhydroxyl-
amine is produced (boiling point/10 mm: 102-106C).
STAGE II: 2-methoxy-5-methylsulfonylbenzaldehyde-(N,N-diethyl-
- aminoethyl)-nitrone
6.40 9 (0.03 mol) of 2-methoxy-5-methylsulfonyl- -
; benzaldehyde, 3.96 g (0.03 mol) of N,N-diethylaminoethyl-
hydroxylamine and 90 ml of dioxan are introduced into a 250 ml
balloon flask provided with a stirrer, a thermometer and a
condenser.
The mixture is heated under reflux For 5 hours, and
left at rest For 2 days and then the solvent is evaporated
under vacuum.
.~ '


:. .

1~ 94
-The residue is suspended in 20 ml of water and
rendered alkaline with sodium hydroxide. The suspension is
left to crystallize, and then filtration is effected. The
crystallized substance is washed with water and dried in a
drying oven at 50C.
5 g (yield: 50%) of 2-methoxy-5-methy1sulfonyl-
benzaldehyde-(N,N-diethylaminoethyl)-nitrone (melting point:
110C) is produced.
STAGE III: N-(diethylaminoethyl)-2-methoxy-5-methylsulfonyl-
benzamide
:
5 g (0.015 mol) of 2-methoxy-5-methylsulfonyl-
benzaldehyde-~N,N-diethylaminoethyl)-nitrone, 15 ml of acetic
acid and 15 ml of acetic anhydr~de are placed in a 500 ml
;beaker. The m~xture is heated for 10 m~nutes to 80 - 90C.
Cooling is then effected, and then 50 ml of water and some 20%
sodiu~ hydroxide is added, until the pH-value is 10. The
solution is left to crystallize, followed by filtration,
washing with water and drying in a drying oven at 50C. The
substance obtained is dissolved in 150 ml of ethanol and
20 hydrochloric ethanol is added until the pH-value is 1. The ;
solution is left to crystallize, followed by filtration, and
then the product is washed with a little ethanol and dried in
a drying oven at 50C.
2.5 9 (yield: 46%) of N-(diethylaminoethyl)-2-
methoxy-5-methylsulfonylbenzamide hydrochloride(melting point:
199-200C) is produced.

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