Preparation of n-2-diethylamino-ethyl-2 1 methoxy -4-amino- 5-chlorobenzamide

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PATENTS AND REGISTRATION OFFICE

PUBLISHING LETTER No. 366 298 in C 07 c 103/82

Patent Application. No 14276/71 Received on 9 XI 1971 Validity Day on 9 XI 1971

Ans. generally available on 5 II 1973

Ans. laid out and the petition published 22 IV 1974 Priority requested from 4 VIII 1971 (CH, 11 443)

FRATMANN SA, CH ^ NE-BOURGERIES, CH

Inventor: EA Denzler, Ziirich

Agent: J Wallin

Process for the preparation of N- (diethylaminoethyl) -2-methoxy-4-amino-5-chlorobenzamide

The invention relates to a process for the preparation of N- (diethylaminoethyl) -2-methoxy-4-amino-5-chlorobenzamide by chlorination of an o-alkylated, N-substituted p-aminosalicylic acid ester and subsequent reaction with diethylaminoethylamine.

This is generally done in such a way as to start from the p-amino salicylic acid, whose carboxyl group is esterified and whose hydroxyl group is alkylated, after which the 4-amino group is blocked by acylation by reaction with acetic anhydride. for execution = those of the subsequent steps. This acetyl group is then cleaved again after introduction of the other substituents.

It has now been found that the yield can be significantly improved in the preparation of the benzamide initially described. by the usual procedure, if the blocker of the 4-amino group does not acetylate it, but substitutes it otherwise.

Such a method is characterized according to the invention in that, after an esterification and o-alkylation of p-amino salicylic acid, before the chlorination, the 4-amino group is substituted with a p-toluenesulfonic acid residue, which is reactivated after the reaction with diethylaminoethylamine.

According to a preferred approach, the 2-methoxy-4-aminobenzoic acid methyl ester can be reacted with p-toluenesulfochloride, while the cleavage of this p-toluenesulfonic acid residue can be easily achieved by heating N- (diethylaminoethyl) -2-methoxy-4- toluene sulfonamido-5-chlorobenzamide in concentrated sulfuric acid.

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

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4EXEMPEL

2zmgtoxi342aminobensoesyrametylester __ (I) _

In a 2 liter flask with stirrer, thermometer and drip funnel, 35 g (0.229 mol) of p-aminosalicylic acid was dissolved in 700 ml of acetone.

As soon as solution occurred, 33.6 g (0.6 mole) of potassium carbonate was introduced into six portions of 2.5 hours, maintaining extremely vigorous stirring of the reaction mixture.

Then, 51 ml (0.54 mol) of dimethyl sulfate was added dropwise and stirred further for 3 hours at normal room temperature. Then the acetone was distilled off in vacuo to facilitate heating in a water bath.

Then 700 ml of water was added, suctioned, washed with water, dried in a drying cabinet at 50 ° C. Thus, 36 g (= 87%) of (I) was obtained, mp 158 ° C.

2-methoxy-4- (o-toluenesulfamidobenzoic acid methyl ester (II)

Into a 1 liter reaction vessel with stirrer, thermometer and distillation column was added 36 g (0.198 mol) of (I), 42 g (0.26 mol) of p-toluenesulfochloride, 400 ml of toluene and 2 g of triethanolamine. Thereafter, 20 ml of distillate was distilled extremely slowly over 4 hours, the temperature of the reaction mixture being 115 ° C.

The whole thing was then allowed to cool and crystallize overnight. The reaction product was filtered off, washed several times with 200 ml of a 20% hydrochloric acid solution, then with water to neutral pH of the wash water. After drying in a drying cabinet at 50 ° C, 54 g (81.3%) of (II) having a melting point of 143 ° C were obtained.

2Lu! Gtoxi24-Xo-toluene sulphamido _353klor2bensoesyrametylester_JIII}} _

Into a 250 ml flask equipped with a stirrer and dropping funnel was introduced 24.5 g (= 0.0732 mol) of (II) and 50 ml of acetic acid.

In the suspension thus obtained, a solution of 5.2 g (0.0732 mol) of chlorine in 137 ml of acetic acid was added dropwise at 0.5 hours at normal temperature.

The whole was stirred for another 3 hours and then allowed to stand overnight.

Then, the reaction mixture was poured into 1.5 liters of water, filtered, washed with water and alcohol was dried at 50 ° C.

24.5 g (90%) of (III) were obtained, mp 177 ° C. Ullöietylaminoetyliy methoxy ^ - ^^ p ^ toljUensulfainido ^ -S-chlorobenzamide ^ IZ).

Into a 250 ml flask equipped with a stirrer and cooler were charged 145 ml of toluene, 21.5 g (0.0583 mol) of (III) and 20.7 g (0.0583 molx 3) of diethylaminoethylamine and the whole was heated for 2 hours. , 5 hours under reflux.

The whole was allowed to cool, filtered and the precipitate washed with toluene, then dried in a drying cabinet at 50 ° C. 26 g (98.5%) of (IV) were obtained, mp 144 ° C.

NilÉietylaminoetyli22 ~ metoxi242amino-53klor2bensarnid __ (V) _

Into a reaction flask was introduced 10 g of (IV) and 15 ml of 96% concentrated sulfuric acid and this mixture was heated for 1 hour on a water bath to 60 ° -70 ° C. Then the mixture was cooled and poured on crushed ice. With 35 ml of 40% sodium hydroxide, the pH of the mixture was adjusted to 10: The precipitate formed was filtered off, washed with water and dried in a drying cabinet.

After recrystallization from isopropanol, 5 g (76%) of (V) was obtained, mp 145-146 ° C.

The N- (diethylaminoethyl) -2-methoxy-4-amino-5-chlorobenzamide is a very effective agent for the treatment of gastrointestinal disorders and for the regulation and influence of the digestion process.