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

<td>POLAND REPUBLIC CHINA</td><td>PATENT DESCRIPTION</td><td> 84572</td>

<td></td><td>Additional Patent</td><td>MKP C07c 103/28</td>

<td></td><td>uo pa ven 1 u. 111</td><td></td>

<td>| § | r</td><td>Submitted: 30.03.72 (P. 154414)</td><td></td>

<td></td><td>Priority: 04.08.71 Switzerland</td><td>Int.Cl.^{and 2 * 4} C07C 103/28</td>

<td>OFFICE PATENT</td><td>The application was announced: 31.05.73</td><td></td>

<td>PRL .4. '</td><td>Patent description published: 15.12.1976</td><td></td>

Inventor: Patent holder: Fratmann AG, Chene-Bougeries (Switzerland)

Production method

N- / diethylaminootyl / -2-methoxy-4-amino-5-chlorobenzamide and

The present invention relates to a process for the preparation of N- (diethylaminoethyl) -2-methoxy-4-amino-5-chlorobenzamide, which is a valuable therapeutic agent for gastrointestinal disorders as well as regulating and affecting digestive processes. 5

A known method for the preparation of N- (diethylaminoethyl) -2-methoxy-4-amino-5-chlorobenzamide from p-aminosalicylic acid consists in the esterification of the carboxyl group of p-aminosalicylic acid, subsequent alkylation of the hydroxyl group and protection of ₁₀baking the amino group positioned by acetylation with acetic anhydride. The obtained compound is subjected to appropriate reactions to introduce the desired substituents and then cleaved the acetyl group₁₈from the final product obtained.

It has been found that N- (diethylaminoethyl) -2-methoxy-4-amino-5-chlorobenzamide can be prepared in a much higher yield if the amino group is not protected by acetylation with acetic acid ₂but with substitution in another way, preferably with a p-toluenesulfonic acid residue.

Process of the invention for the preparation of N- (diethylaminoethyl) -2-methoxy-4-amino-5-chlorobenzamide by chlorination of an N-substituted ester ₂₅2-methoxy-4-aminobenzoic acid and substitution with diethylaminoethylamine consists in the esterification of the carboxyl group and methylation of the hydroxyl group of p-aminosalicylic acid, and then the amino group in position 4 is protected with a residue of p-toluenesulfonic acid, the obtained compound is chlorinated and substitution with diethylaminoethylamine, followed by cleavage of the protective group.

The reactions leading to the final product are illustrated in the diagram in the figure.

The process according to the invention makes it possible to obtain the final product with a much higher yield than hitherto obtained with a very simple procedure and easy cleavage of the p-tol-ueno-sulfonic acid residue, preferably by heating of N- (diethylaminoethyl) -2-methoxy-4- (p-toluenesulfamido) - 5-chlorobenzamide in concentrated sulfuric acid.

The following examples illustrate the method of the invention.

Example. Preparation of 2-methoxy-4-aminobenzoic acid methyl ester. In a 2-liter flask equipped with a stirrer, a thermometer and a dropping funnel are dissolved in 700 ml of acetone 35 g (0.229 M) of p-aminosalicylic acid, and immediately after dissolution of the ingredients with intensive stirring, introduced in 2.5 hours in 6 portions. 33.6 g (0.6 M) of potassium carbonate. Then 51 ml (0.54 M) dimethyl sulfate is added dropwise to the reaction mixture and stirred for a further 3 hours at room temperature, then the flask is placed in a slightly warm water bath and under reduced pressure

572

572 acetone is distilled off, 700 ml of water are added, filtered, washed with water and dried in an oven at 50 ° C.

36 g of acid methyl ester are obtained

2-methoxy-4-aminobenzoate with a melting point of 158 ° C, which corresponds to 87% of the reaction yield.

Preparation of 2-methoxy-4- (p-toluenesulfamido) -benzoic acid methyl ester.

36 g (0.198 M) of the 2-methoxy-4-aminobenzoic acid methyl ester obtained above and 42 g (0.26 M) of p-toluenesulfonic acid chloride, 400 g, are introduced into a 1 liter reactor equipped with a stirrer, a thermometer and a distillation column. ml of toluene and 2 g of triethanolamine, at a temperature of 115 ° C, distillate 20 ml are distilled very slowly over 4 hours. The distillation residue is cooled and left for a period of several hours to crystallize the product. The separated crystals are filtered off and washed several times with 200 ml of a 20% hydrochloric acid solution, then with water until a neutral filtrate is obtained, after which the product is dried in an oven at 50^ABOUTC. 54 g of 2-methoxy-4- (p-toluenesulfamido) -benzoic acid methyl ester are obtained with a melting point of 143 ° C., which corresponds to 81.3% of theory.

Preparation of 2-methoxy-4-t-toluenesulfuric acid methyl ester ^ c ^ m ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^

Into a 250 ml flask equipped with a stirrer and a dropping funnel are introduced 24.5 g (0.0732 M) of the 2-metaxy-4- (p-toluenesulifamido) benzoic acid methyl ester obtained above and 50 ml of acetic acid a solution of 5.2 g (0.0732 M) chlorine in 137 ml acetic acid is added dropwise over half an hour at room temperature, followed by stirring for 3 hours, and then allowed to stand for a dozen or so hours. The reaction mixture is poured into 2.5 liters of water, the precipitate is filtered off, washed with water and alcohol and dried at 50 ° C.

24.5 g of methoxy-4- (p-toluenesulfamido) -benzoate ester are obtained, melting at 177 ° C., which corresponds to 90% of the reaction yield. Preparation of N- (diethylaminoethyl) -2-methoxy-4- (p-toluenesulfamido) -5-chlorobenzamide.

Into a 250 ml flask equipped with a stirrer and condenser, 145 ml of toluene, 21.5 g (0.0583 M) of the above-prepared 2-methoxy-4 - / - p-toluenesulfamido / benzoic acid methyl ester and 20.7 g (0.0583 Μ X 3) diethylaminoethylamine and the mixture is refluxed for 2.5 hours, then cooled, filtered, washed with toluene and dried in an oven at 50 ° C.

26 g of N- (diethylaminoethyl) -2-methoxy-4- (p-toluenesulfamido) -5-chlorobenzamide are obtained with a melting point of 144 ° C., which corresponds to a 98.5% yield of the reaction.

Preparation of N - (diethylaminoethyl) -2-methoxy-4-amino-5-chlorobenzamide.

10 g of the above N- (diethylaminoethyl) -2-methoxy-4- (p-toluenesulfamido) -5-chlorobenzamide and 15 ml of 96% sulfuric acid are introduced into the reaction flask. The mixture is heated for 1 hour in a water bath at 60-70 ° C, then cooled, poured onto crushed ice and neutralized to pH 10 with 35 ml of 40% sodium hydroxide. The resulting precipitate is filtered, washed with water and dried in a dryer.

After recrystallization from isopropyl alcohol, 5 g of N- / diethylaminoethyl / -2-methoxy-4-amino-5-chlorobenzamide are obtained, mp 145-146 ° C, which corresponds to 76% of the reaction yield.

N- / diethylaminoethyl / -2-methoxy-4-amino-5-chlorobenzamide is a very effective agent in the treatment of gastrointestinal disorders and also serves to regulate and affect digestive processes.