IL42400A - Preparation of 2-alkoxy or alkenyloxy-4,5-substituted-aminoalkylbenzamides and certain new intermediates therefor - Google Patents

Description

The preparation of alkenyloxy substituted amlnoalkyl and certain new intermediates therefor SOCIETE ET INDUSTRIELLES DE i 40497 The present invention concerns a new method of preparing or alkenyloxy corresponding to the following general their salts with pharmaceutically acceptable mineral or organic and their quaternary ammonium salts produced by reaction with an aliphatic or aromatic alkylating In the above is a hydrogen atom or a methyl is a or alkenyl X is a hydrogen atom or a acylamino or amino Y is a hydrogen or halogen atom or a group of formula in which is an monoalkylamino dialkylamino haloalkyl alkyl n is 2 or and A is a radical of the formula in which and are identical or different lower alkyl a saturated heterocyclic ring an alkyleneimino or a heterocyclic radical having the in which R is a alkyl alkenyl radical and m prepared reacting a diamine the general formula in which n and Λ are as defined with carbon disulphide to s treating the latter in a basic medium with a substance capable of reacting with sulphur to give a volatile or insoluble to produce an isothiocyanate of formula and condensing the latter with a benzoic acid of formula in which Y and are as defined above in the presence of a basic The benzoic acids defined their preparation are described in patent specification number Dithiocarbamic acids having the r and isothiocyanates having the are novel compo In the preferred e bddiments of the B is a methyl X is a hydrogen atom or an amino Y is a trifluoromethylsulphonyl or sulphamoyl group or a chlorine is a hydrogen atom or a methyl n is 1 and is a or pyrrolidyl The benzamides thus produced can he used in particular in the pharmaceutical field as agents and psychotropic The following which are are provided in order to give a better understanding of the technical characteristics and the advantages of the present EXAMPLE I STAGE acid 82 g of carbon disulphide was in a balloon flask at ambient to a solution g of pyrrolidine in J00 of After stirring for one the precipitate washed and dried in a drying oven at g of acid was obtained 208 STAGE 2 isothiocyanate 5 S 40 ml of water and of sodium hydroxide were introduced into a balloon A solution of g of lead acetate in of water was The mixture was heated at boiling point for a of an After the lead sulphide precipitate was The substance produced was purified by conversion to the chloride and precipitation of the by the addition of The precipitate was dried without washed with water and in a drying oven at g of was produced EXAMPLES II oxalate Stages 1 and 2 are the same as described above in Example STAGE sulphonylbenzamide oxalate II5 g of acid and ml of dioxan were introduced into a balloon The mixture was heated at a temperature of After the addition of the mixture was put under reflux for The solvent was distilled unde and the substance produced was with with 1500 ml of The mixture was then extracted with methylene The organic which was washed and dried on magnesium was methylsulphonylbenzamide which was produced in this way was dissolved in 1 litre of sulphuric Added to this solution and was a solution of S of oxalic acid in 2 litres of Stirring of the suspension having been continvied for a quarter of an the organic phase was decanted and the residue was dissolved in ml of acetone in the hot After filtration of the the solvent was concentrated to 100 After the precipitate obtained vas washed and 30 g of methylsulphonylbenzamide oxalate 146 was by recrystallisation from ml of acid 70 g of I64 ml of water dropwise and at a temperature of g of carbon were introduced into a balloon The mixture was etirred for three hours at ambient The precipitate was washed with water and then left overnight in the dried in a oven at 88 g of piperidyldithiocarbamic acid was produced 166 STAGE isothiocyanate ml of and 20 g of sodium hydroxide in pellet was introduced into a balloon Added to this solution were 100 of 200 ml of water 53 g of The mixture was subjected to continued stirring until the ature of the reaction reached ambient The mixture was then filtered and the filtrate extracted by of After drying of the solution on magnesium filtration and distillation of the the oil produced was purified by distillation vacuum 108 0 g of was produced STAGE g of isothiocyana 600 ml of dioxan and 108 g of acid were introduced into a balloon The mixture was at reflux for two hours and then left at rest The solvent was then distilled under vacuum and the residue was dissolved in 1200 ml of After the addition of 200 ml of hydrochloric the solution was The crystals formed in the filtrate were filtered then dissolved in ammonia precipitated by hydrochloric The precipitate obtained was washed with water and dried in a drying oven at In order to extract the substance ml of After having been extracted with ml of the solution gave a crystalline which was filtered and dried in a drying oven at This operation was repeated The whole of the crystalline substances was purified by dissolution in 20 hydrochloric The solution made alkaline at its boiling point by After the precipitate was washed with water and dried in a drying oven at 13 g of was produced STAGE acid 100 ml of water and 71 g of were introduced into a balloon ml of carbon disulphide were added to this with stirring at a temperature of After the introduction of carbon disulphide had been of the reaction medium was continued for one The precipitate was washed with water and then dried in the 97 g of dithiocarbamic acid was produced higher than C STAGE isotliiocyanate 5OO ml of water and 206 g acid were introduced into balloon g of sodium hydroxide in pellet form and a solution of g of lead acetate in 4OO of water were added with Stirring was continued for hours and after separating the precipitated lead filtrate was extracted with sulphuric The organic solution was dried on anhydrous magnesium sulphate and and the solvent was S piperidylmethyl isothiocyahate was produced 37 STAGE phosphate 200 ml of acid and 16 g of isotliiocyanate were introduced into a balloon The mixture was heated at reflux temperature for one hour and then the solvent was distilled under 0 ml of hydrochloric acid was to the and the mixture was heated under reflux for two After ammonia was added to produce an alkaline pH and the mixture was extracted with methylene After drying of the organic phases with carbonate and the solvent was The residue produced was dissolved in ml of acetone and a solution of 3 of phosphoric acid in 6 ml of acetone was The precipitate formed was then washed with alcohol and 20 g of benzamide phosphate was produced 186 EXAMPLE V acid This substance was prepared in a manner similar to that described by the action of ethyl chloroformate and sodium hydroxide on acid point at STAGE 300 ml of acid and 20 g of isothiocyanate were introduced into a balloon The mixture was heated at reflux ature for three quarters of an After the solvent was distilled under Added to the residue was 60 ml of After the mixture had been acidified to a alue of the precipitate formed was The filtrate was concentrated vacuum to 100 ml and then made alkaline with ammonia The crystals produced were washed with water and at then recrystallised from 120 ml of g of was produced EXAMPLE VI I STAGS 1 acid This acid was produced in a manner similar to that described by the action of carbon disulphide on 125 STAGE substance was produced by the action of ethyl chloroformate and on point at 3 STAGE ml of dioxan and isothiocyanate were introduced into a balloon The mixture was heated at reflux ature for two After the solvent was distilled under The residue was treated with ammonia and the mixture raised to boiling The crystals produced by cooling were washed with dried in a drying oven at and recrystallised from benzamide was produced 1 VII STAGE 1 acid This acid was synthesized in a mariner to that described above by the action of carbon disulphide on dine 134 STAGS isothiocyanate This compound was produced in accordance with the method described hereinbefore by the action lead acetate and sodium hydroxide on acid hydrochloride The condensation of g of acid and g of isothiocyanate in using procedure described in the preceding followed by a treatment with hydrochloric permitted the preparation 17 hydrochloride 188 EXAMPLE VIII honyIbenzamide STAGE acid 100 g of 234 of water at a temperature of of carbon were introduced into a balloon The mixture was subjected to stirring half an the precipitate formed was water and dried in the g of acid was produced melting STAGE 2 iperidinoethyl isothiocyanate ml of water and g of hydroxide in pellet form were introduced into a balloon Added to this solution were 100 g of dithiocarbamic 200 ml of 55 g of ethyl Stirring of the mixture was maintained one hour until the of the reaction medium The mixture was then filtered and the filtrate was extracted with ml of After drying of the solution on magnesium filtration and distillation of the the oil produced was purified by distillation under vacuum 108 44 g of isothiocyanate was produced STAGE g of acid and 550 ml of T dioxan were introduced into a balloon The temperature of the mixture was raised to 60 then a solution of 35 g of piperidinoethyl isothiocyanate in 140 ml of dioxan was The mixture was heated for six hours and thirty minutes at reflux After the solvent was distilled under vacuum and the residue was treated with 250 ml of normal The suspension obtained was extracted with 600 ml of After drying of the organic solution on magnesium the solvent was distilled under The crystals produced were dissolved at boiling temperature in of After hydrochloric ethanol was added till the was The precipitate produced was washed with 200 ml of water and dried in a drying oven at The expected hydrochloride was purified by dissolution in 250 ml of hydrochloric The solution produced was extracted with 200 of ether and rendered alkaline by sodium The precipitate obtained was washed with water and dried in a drying oven at 18 g of was produced point IX chloride Stages 1 and 2 are the same as those described in Example STAGE The mixture was heated for six hours under After the dioxan was nder The residue was dissolved in ml of sodium and then the mixture was extracted with ml of After drying of the organic solution on magnesium sulphate and the solvent was evaporated under vacuum and the residue was dissolved in 50 ml of to this solution until the was 1 was hydrochloric After filtration of the crystals formed washing with 20 ml of ether and drying at g of benzamide salt was By recrystallisation from ml of g of hydrochloride was produced 189 EXAMPLE X STAGE 1 ethylaminoethyldithiocarbamic acid g of carbon disulphide was in a balloon flask at ambient to a solution formed by 116 g of diethylethylenediamine in ml of After stirring for one the precipitate formed was and dried in a drying oven at 157 g of dithiocarbamic as produced STAGS 2 isothiocyanate of diethylaminoethyldithiocarbamic acid was introduced into balloon A solution of g of sodium hydroxide in 1 litre of followed by a solution of 353 g of lead acetate in 1 litre of The mixture was heated to boiling ature after the lead sulphide formed was The filtrate was extracted with 600 ml of The organic solution was and evaporated to 120 g of diethylaminoethyl isothiocyanate was STAGE The mirbure of g of I6 g of diethylaminoethyl isothiocyanate and 0 ml of dioxan was heated reflux for eight hours in a balloon er the solvent was evaporated under vacuum ml of sodium hydroxide was The mixture was heated reflux for one The precipitate was washed and dried in n oven at chlorobenzamide was produced After recrystallization g of the compound pected was produced EXACTLE XI ethyl Stages 1 and 2 are the as those described in STAGE amino ethyl g of acid and 80 ml of dioxan were introduced into a balloon The mixture was heated to and the solution of 64 g of sothiocyanate in 20 of dioxan was The mixture was heated at reflux temperature for four After the was evaporated and the residue treated with 100 ml of sodium The crystallised substance was washed with water dried in a oven at of 123 was EXAMPLE XII Similarly as in the preceding after treatment with HCl gave the hydrochloride and after treatment with HCl gave the hydrochloride were The starting compounds were and diethylaminoethyl isothiocyanat and acid and diethylaminoethyl insufficientOCRQuality

Claims (2)

1. CLAIMS 1. A method of preparing a 2-alkoxy or alkenyloxy 4,5- suhstituted benssamide of the general formula: I » -(CH) -A s in which is a hydrogen atom or a methyl group, B is a alkyl or * alkenyl radical, X is a hydrogen atom or a nitro, carboxylic acylamino «4»ylamiA9/or amino group, Y is a hydrogen or halogen atom or a group of formula SOgKg in which Hg is an amino, monoalkylamino, dialkylamino, haloalkyl or alkyl group, £ is 0, 1, 2 or 3, and A is a radical of the formula identical or different lower alkyl groups, a nitrogen-attached saturated heterocyclic ring (i.e. an alkyleneimino group), or a heterocyclic radical having the formula: t R in which B is a alkenyl radical and m is 0, 1, 2, 3 or 4, that comprises reacting a diamine having the general formula *1 H2N(CH)£A in which R-^, n and Λ are as defined above with carbon disulphide to produce a dithiocarbamic acid of formula . " ?! ■ HS-C-HtT-(CH) Λ S treating the latter in a basic medium with a substance capable of reacting with sulphur to give a volatile or insoluble compound, to . produce an isothiocyanate of formula Rl S = C = N(CH)nA and condensing the latter on a 2-alkoxy-4» 5-substituted benzoic acid formula in which X, Y and B are as defined above in the presence of a basic medium.

2. Λ method as claimed in claim 1, including the further step of converting the product to an acid-addition salt by reaction with a pharmaceutically acceptable mineral or organic acid or to a quaternary ammonium salt by reaction with an aliphatic or an aromatic alkylating agent, 5, Λ method as claimed in claim 1 substantially as hereinbefore described in any one of the foregoing Examples, 424P0/3 4# Compounds of the general formula in Yfhich X, Y, A, B, n and are as defined in claim.1, or their acid-addition salts with pharmaceutically acceptable mineral or organic acids, and their quaternary ammonium salts produced by reaction v/ith an aliphatic or aromatic alkylating agent, when prepared by a method as claimed in any one of claims 1- 3· 5. A dithiocarbamio acid having the formula in which m, n, R 6. A method of producing a compound as claimed in that comprises reacting a diamine of the formula in which m, n, B and are as defined in Claim with carbon disulphlde. 7· Dithiocarbamio acids according to Claim 5t substantially as described herein ¾ith reference to the Exampleo. HE:mz