Patent GB-791599-A (GB)
Title: Aminobenzoic acid derivatives and the manufacture thereof
IPC: C07D295/088
Filed: 1955-04-20
Abstract: A process for preparing a compound of the formula <FORM:0791599/IV (b)/1> wherein n is an integer from 1 to 6 inclusive, R is a tertiary amino radical, R1 is hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic radical, R2 is an alkyl or aryl radical, R3 is hydrogen, alkyl or aralkyl, R6 is hydrogen or an acyl group and Y is oxygen, sulphur, imino or alkylimino, comprises reacting a hindered 4-acylaminobenzoyl halide of the formula <FORM:0791599/IV (b)/2> wherein R7 is an acyl radical and X is halogen with a compound of the formula HYCnH2nR and, in the case where R6 denotes hydrogen, hydrolysing the compound thus obtained.  The invention also comprises compounds of the first formula above in which R is a tertiary amino radical, Y is oxygen or sulphur, R1 is hydrogen, lower alkyl, cycloalkyl, aralkyl radical, an aryl radical containing not more than 14 carbon atoms or a heterocyclic radical containing not more than 5 carbon atoms, R2 is a lower alkyl radical or an aryl radical containing not more than 14 carbon atoms, R3 is hydrogen, lower alkyl or an aralkyl radical, R6 is hydrogen or an acyl group and when Y is oxygen the total number of carbon atoms in R1 and R2 taken together is at least 3 and wherein lower alkyl contains 1 to 8 carbon atoms, inclusive, and provided that when R1, R3 and R6 are hydrogen and Y is oxygen, R2 is a lower alkyl radical.  Specified alkyl radicals are methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl and octyl. Specified cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl, methylcyclohexyl, dimethylcyclohexyl, ethylcyclohexyl, amylcyclohexyl, hexylcyclohexyl, methylcyclobutyl, methylcyclopentyl, and methylcyclo-octyl.  Aralkyl radicals include benzyl, phenethyl, phenylpropyl and methoxyphenethyl. Aryl radicals specified are phenyl, naphthyl, methoxyphenyl, butoxyphenyl, methoxynaphthyl, chlorophenyl, bromonaphthyl, tolyl, xylyl, trimethylphenyl, ethylphenyl, amylphenyl, methylbutylphenyl, methylnaphthyl, butylnaphthyl, di- and trimethylnaphthyl, dichlorophenyl, dimethoxyphenyl and methoxychlorophenyl.  Suitable aryl radicals are acetyl, propionyl, butyryl, tosyl, benzenesulphonyl and benzoyl.  The hydrolysis to remove R7 (when an aroyl or arylsulphonyl radical) can be effected by treatment with hydrogen bromide and phenol in acetic acid by the method of Specification 676,037.  In examples: (1) 2,6-dimethyl-4-acetamido-benzoyl chloride and b -diethylamino ethylamine are reacted to give N-b -diethylaminoethyl - 2,6 - dimethyl - 4 - acetamidobenzamide; (2) and (3) N-b -diethylaminoethyl-2-methyl - 6 - ethyl - (and 6 - isopropyl) 4 - acetamido-benzamides are prepared similarly.  Lists are given of many similarly prepared compounds containing various combinations of substituent radicals within the scope of the above definition and obtained by (a) reaction of 2,6-dimethyl-4-acetamido-benzoyl chloride with specified tertiary aminoalkylamines; (b) reaction of b -diethylaminoethylamine with other 2,6-dimethyl-4-acylamidobenzoyl halides; (c) reaction of b -diethylaminoethylamine with other substituted 4-acylamidobenzoyl halides; (4) 2,6 - dimethyl - 4 - acetamido - benzoyl chloride and b -diethylamino-ethanol are reacted to form b -diethylaminoethyl 2,6-dimethyl-4-acetamidobenzoate; (5) 2,6-dimethyl-4-acetamidobenzoyl chloride and b -4-morpholinylethanol are reacted to give b -4-morpholinylethyl 2,6-dimethyl-4-acetamidobenzoate.  Similarly obtained are (6) b  - 1 - piperidylethyl 2,6-dimethyl-4-acetamidobenzoate; (7) b -diethylaminoethyl 2-methyl-6-ethyl - 4 - acetamidobenzoate; (8) b -diethylaminoethyl 2-methyl-6-isopropyl-4-acetamidobenzoate. Lists of alternative aminoalcohols which may be reacted with 2,6-dimethyl-4-acetamidobenzoyl chloride, and of other 2,6-dimethyl-4-acylamidobenzoyl halides and 4-acylamidobenzoyl halides which can be reacted with b -diethylaminoethanol to yield products of the first general formula above are given.  Lists are given also of mercaptans of the formula RCnH2nSH which can be reacted with 2,6-dimethyl-4-acetamidobenzoyl chloride to produce the corresponding 2,6-dimethyl-4-acylamidothiolbenzoic acid esters. Lists of the corresponding esters and of esters obtained by reacting b -diethylaminoethyl mercaptan with 2,6-dimethyl-4-acylamidobenzoyl halides and other 4-acylamidobenzoyl halides are also included.  The compounds contain various combinations of radicals selected from those specified above.  In further examples: (9) N-b -diethylaminoethyl - 2,6 - dimethyl - 4 - acetamidobenzamide is refluxed with aqueous alcoholic sodium hydroxide to give N-b -diethylaminoethyl - 2,6 - dimethyl - 4 - aminobenzamide, which is converted to quaternary derivatives and acid addition salts; (10) and (11) N-b -diethylaminoethyl 2-methyl 6-isopropyl (or 6-ethyl)-4-aminobenzamides are obtained similarly.  Lists of other similar hydrolysis products within the scope of the first formula above are given; (12) to (14) b -diethylaminoethyl 2,6-dimethyl - 4 - acetamidobenzoate is hydrolysed to b -diethylaminoethyl 2,6-dimethyl-4-aminobenzoate which is converted to quaternary and acid addition salts (mono- and di-hydrochlorides and citrate). Similarly are prepared (16) b  - 1 - piperidylethyl 2,6 - dimethyl - 4 - amino benzoate; (17) its dihydrochloride; (18) to (20) b -4-morpholinylethyl 2,6 - dimethyl - 4 - aminobenzoate; and the corresponding 2-methyl-6-ethyl- and 2-methyl-6-isopropyl derivatives. Lists of many similar compounds are given.  The 4-acylamidothiolbenzoic acid esters may similarly be hydrolysed to 4-aminothiolbenzoic acid esters, a number of such esters being listed.  Starting materials of the second general formula above, are prepared by subjecting a hindered 4 - oxo - 2 - cyclohexene - 1 - carboxylic acid of the general formula <FORM:0791599/IV (b)/3> to oximation (e.g. with a hydroxylamine salt in pyridine), aromatizing and ocylating the resulting 4 - oximino - 2 - cyclohexene - 1 - carboxylic acid ester (e.g. by heating with an acid chloride together with the corresponding acid or with pyridine) to produce a 4-arylamidobenzoic acid ester of the general formula <FORM:0791599/IV (b)/4> hydrolysing and acylating to produce a corresponding 4-arylamidobenzoic acid and reacting this with an inorganic acid halide to give the 4-acylamido-benzoyl halide.