SU645557A3 - Method of obtaining bezamide derivatives or salts thereof - Google Patents

Description

subjected to interaction with the amine of General formula III

HaNW, in

where W is above,

at a temperature of from room temperature to 160 ° C, and the target product is isolated in the form of a base or salt, the process is better carried out in the presence of a solvent, in the case of D - hydroxy group, the process is usually carried out in the presence of condensing, its means, for example, silicon tetrachloride, phosphorus pentoxide or carbodiimide.

As solvents which are inert during the amidation reaction, for example, alcohols, polyhydric alcohols, benzene, toluene, dioxane, chloroform, diethylene glycol dimethyl ether are used. An excess of the amine used as the raw material can also be used as a solvent. Upon amidation, the reaction mixture is preferably heated, for example, to the boiling point of the solvent used in this process.

Mineral or organic acids can be used to form salts, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, W, Abelic, acetic, tartaric, citric, methanesulfonic, or acid halides or alkyl sulfates, with the formation of quaternary ammonium salts.

Example I. (2-Hydroxyethyl) -2-pyrrolidinylmethyl -2-methoxy-5-sulfamoylbenzamide.

In a 250 ml flask, 48 g of 2-methoxy-5-sulphamoyl-benzoic acid ethyl ester, 17 g of water and 32 g of 1- (2-hydroxyethyl) -2-aminomethylpyrrolidine are introduced. The mixture is heated in a water bath until the sample taken is completely dissolved in dilute acetic acid. After cooling, the solution is diluted with 300 ml of water. The precipitated crystals are sucked off, washed with water, dried at 40 ° C. The resulting benzamide is purified, converted to acetate, followed by separation of the free base.

39 g of (2-hydroxyethyl) 2-pyrrolidinylmethyl -2-methoxy-5-sulfamoylbenzamide are obtained; yield 59%; m.p. 135-136 ° C.

Example 2. (3-hydroxypropyl) -2-pyrrolidinylmethyl -2-methoxy-5-ethylsulfonylbenzamide hydrochloride.

38.8 g of 2-methoxy-5-ethylsulfonylbenzoic acid methyl ester, 13.5 ml of water and 28.4 g of 1- (3oxypropyl) -2-aminomethylpyrrolidine are introduced into a 250 ml flask. The mixture is heated for 10 hours at 85-90 ° C. The residue after evaporation is dissolved in 300 ml of ethanol and the solution is acidified with an alcoholic solution of hydrogen chloride to pH 1. After tetrahydrofuran is added, the precipitated crystals are removed, washed and dried in a drying cabinet at 50 ° C. By recrystallization from propyl alcohol, 35 g of (3-hydroxypropyl) -2-pyrrolidinylmethyl -2-methoxy-5-ethylsulfonylbenzamide hydrochloride are obtained; yield 55.5%; m.p. 184-186 ° C.

Example 3. N- (1-Acetyl-2-pyrrolidinylmethyl) -2-methoxy - 5 - sulfamoylbenzamide. Analogously to example 2 of 48 g ethyl

2-methoxy-5-sulfamoyl benzoate and 31.5 g of K-acetyl-2-aminomethylpyrrolidine, 34.5 g of M- (G-acetyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide; yield 52.5%; m.p. 204 ° C.

Example 4. M-1Y-ethyl-M- (2-hydroxyethyl) aminoethyl -2-methoxy-4-amino-5-chlorobenzamide.

6.1 g of 2-methoxy4-amino-5-chlorobenzoic acid and 8 g are added to a 250 ml flask.

H-ethyl-, L-2-hydroxyethylethylenediamine. The mixture is heated to, then 6.5 g of phosphoric anhydride are introduced. The mixture is heated to 110 ° C, then the temperature is quickly raised to 150-160 ° C. Give at this temperature

a half-hour exposure, cooled to 100 ° C and poured 100 ml of water. After complete dissolution, sodium hydroxide is added. The mixture is cooled, the precipitated precipitate is filtered off, which is washed with water and

dried

6.6 g of LNH-ethyl-, L- (2-hydroxyethyl) -aminoethyl -2-methoxy-4-amino-5-chlorobenzamide are obtained; yield 69.8%; m.p. 111-112 ° C.

Example 5. N - 1 - (2 - Benzhydroloxyethyl) -2 - pyrrolidinylmethyl -2-methoxy-5sulfamoylbenzamide.

99 g of 1- (2-benzhydroloxyethyl) -2-aminomethylpyrrolidine and 500 ml of methyl ethyl ketone are introduced into a 4-liter flask. The mixture is cooled to 15 ° C and a solution of 80 g of 2-methoxy-5-sulphamoylbenzoyl chloride is poured into 1500 ml of methyl ethyl ketone. The mixture is stirred for 2 hours at room temperature. The precipitate formed is filtered off, washed with a small amount of methyl ethyl ketone and dried. The hydrochloride obtained is added to it when heated with ammonia and allowed to crystallize upon cooling. The crystals are filtered, washed, dried in a drying oven at 50 ° C. After recrystallization from ethanol, filtration through activated carbon and drying, 88 g of N - 1 - (2 - benzhydryloxyethyl) -2 - pyrrolidinylmethyl -2-methoxy-5sulfamoylbenzamide are obtained; yield 52.6%; m.p. 124 ° C.

Example 6. 1 - (2-Methoxy-4-nitrobenzamidopropyl) -4-hydroxyethylpiperazine. 45 g of 1- (2-hydroxyethyl) - 4 - (3 - aminopropyl) - piperazine, 180 ml of chloroform are introduced into a liter flask, a solution of 51 g of 2-methoxy-4-nitrobenzoyl chloride is added at 5-10 ° C. At the end of the fling, the mixture is brought to room temperature and heated

within 1 h to 40-45 ° C. After the water was added, chloroform was distilled off, the resulting solution was filtered through activated carbon, and the benzamide base was precipitated by adding 50 g of potash. After decantation, the substance is dissolved in methyl chloride and the aqueous solution is extracted with methylene chloride.

After drying the extract over potash, the solvents are distilled off under vacuum. The benzamide is obtained in the form of an oil, which is clear, ayut by transfer to the hydrochloride and treatment with ammonia. 59 g of 1- (2-methoxy-4-nitrobenzamidopropyl) -4-hydroxyethylpiperazine are obtained in the form of an oil; yield 67.2%. Purity (by titration in a non-aqueous medium with perchloric acid) 97.8%.

Example 7. N-1 - (2-hydroxyethyl) -2-pyrrolidinylmethyl -2-methoxy-5-ethylsulfonylbenzamide hydrochloride.

In a 500 ml flask, 39 g of 1- (2-hydroxyethyl) -2-aminomethylpyrrolidine, 250 ml of methyl ethyl ketone are added, and maintaining the temperature in the range from 5 to 10 ° C, 70 g of 2-methoxy-5-ethylsulfonylbenzoyl chloride are added. Stir overnight. The precipitated crystals are sucked off, washed with methylethyl ketone and dried at 45 ° C. Recrystallized from 200 ml of ethanol at 95 ° C. 73 g of (2oxyethyl) -2-pyrrolidinylmethyl -2-methoxy5-ethylsulfonylbenzamide hydrochloride are obtained; yield 66.5%; m.p. 175-178 ° C.

Example 8. M-N-ethyl-L- (2-hydroxyethyl) aminoethyl -2-methoxy - 5-sulphamoylbenzamide.

In a 250 ml flask, 78 g of 2-methoxy-5-sulfamoyl-benzoic acid ethyl ester, 27 ml of water and 51 g of M-ethyl-M-hydroxyethylethylenediamine are introduced. The mixture is heated for 10 hours in a water bath. After diluting the solution, the benzamide base crystallizes out. It is cleaned by transfer to the hydrochloride and by reprecipitation of the base after ammonia tides. The precipitated crystals are sucked off, washed with water until the chlorine ions are removed, and dried in a drying cabinet at 40 ° C. 66 g of L-M-ethyl-L- (2oxyethyl) -aminoethyl-2-methoxy-5-sulphamoylbenzamide are obtained; yield 64%; m.p. 149-150 ° C.

Example 9. (3-hydroxypropyl) -2-pyrrolidinylmethyl -2-methoxy-5sulfamoylbenzamide hydrochloride.

In a 250 ml flask, 38.9 g of 2-methoxy-5-sulfamoyl-benzoic acid ethyl ester, 13.5 ml of water and 28.4 g of N-1- (3-hydroxypropyl) -2-aminomethylpyrrolidine are introduced. The mixture is heated for 10 hours at 80 ° C. After cooling, 100 ml of benzene are poured in and the solvents are distilled off. The mixture is cooled, njJKjjrHBia 500 ml water1. The precipitated crystals are filtered, washed with water, dried in a closet at 50 ° C. 40 g of (3-Oxypropyl) -2-pyrrolidinylmethyl -2-meth-6-x-5-sulfamoyl-benzamide are obtained. Yield 72%.

Benzamide is converted to hydrochloride by dissolving to absolute. treated with 50 ml of a 25% ethanolic solution of hydrogen chloride. The resulting crystals are recrystallized from methanol. 38 g of (3-hydroxypropyl) -2-pyrrolidinylmethyl -2-hydroxy-5-sulphamoylbenzamide hydrochloride are obtained; yield 62.2%; m.p. 226-.

Example 10. Diphosphate 1- (2-metho-i-4-aminobenzamidopropyl) -4-hydroxyethylpiperazine.

2.8 g of 2-methoxy4-aminobenzoic acid, 3.4 g of 1- (2-hydroxyethyl) -4- (3-aminopropyl) piperazine, 60 ml of pyridine and 2.3 g of silicon tetrachloride are introduced into a 250 ml flask. . The mixture is heated at reflux temperature for 3 hours. Pyridine is distilled off under vacuum. 30 ml of water are poured, then hydrochloric acid to pH 1. The mixture is heated to boiling, filtered, checking that the solution remains acidic, then ammonia is poured in when heated. After cooling, it is decanted. 3.9 g of 1- (2-methoxy-4-aminobenzamidopropyl) -4-hydroxyethylpiperazine are obtained; yield 69.6%. The degree of purity (titration in non-aqueous medium) is 97.5%.

The resulting base is dissolved in alcohol and converted to phosphate by the addition of phosphoric acid. The resulting diphosphate crystallizes with 3 water molecules. The diphosphate of 1- (2-methoxy-4-aminobenzamidopropyl) - -oxyethylpiperazine is obtained; m.p. 144-145 ° C.

Claims (4)

1. The method of obtaining benzamide derivatives of the general formula 40CONHW Oa. where A is alkyl with 1-5 C atoms; Y is hydrogen, amino, or nitro; Z is hydrogen, halogen, or the sulfamoyl group or Ci-Cs alkylsulfonyl. W - choose from the group -CH, CH, N (CjH5) CHjCHaOH, -CHiCHjCH W -NCHjCHiOH, -sn t m. ./ wherein R is acetyl, alkanol with 2-3 C atoms or their benzhydrol ether, or their combination, characterized in that the compound of the general formula V6455 (J05 „5, where D is a halogen, hydroxy or alkoxy group, and A, Y, Z is indicated above, is reacted with an amine of general formula III10.: H NW - 2 where W is higher, at a temperature of from room temperature to 160 ° C, and the desired product is isolated as a base or salt. 57 8 2. Method software P. 1, characterized by the fact that the process is conducted in the presence of a solvent. 3. The method according to paragraphs. 1 and 2, that is, in the case of D being a hydroxy group, the process is carried out in the presence of a condensing agent. 4. The method according to paragraphs. 1-3, characterized in that silicon tetrachloride, phosphorus pentoxide or carbodiimide are used as the condensing medium ™ a. Sources of information taken into account in the examination 1. Swiss patent number 468377, cl. From 07d 27/04, published 1969.