Patent GB-858426-A (GB)
Title: Production of amido-alkylamides
IPC: C07C233/30
Filed: 1957-10-08
Abstract: The invention comprises compounds of the formula: R1-CO-NH-(CH2)n-Co-NR3R4  wherein R1 is a mono-or poly-lower alkoxy ring-substituted phenyl or styryl group, or a halophenyl group, n is 1 or 2, and R3 and R4 are lower alkyl groups, the lower alkyl and lower alkoxy groups each containing at most 4 carbon atoms ; and their preparation by the following processes (a) reacting an amido-ester of the formula R1-CO-NH-(CH2)n-COOR2, wherein R2 is an alkyl group, with hydrazine and then with nitrous acid to produce the corresponding azide and treating the latter with an amine NHR3R4, or treating the ester directly with this amine, the amido-ester starting material being prepared by reacting the amino-acid ester NH2-(CH2)n-COOR2 either with the acid halide R1-CO-Hal or with the acid R1-COOH in the presence of an N:N1-disubstituted carbodiimide; (b) treating a haloamide of the formula Hal-(CH2)-CONR3R4 (prepared from Hal-(CH2)n-COHal and the amine NHR3R4) with the amide R1-CO-NH2 in presence of an alkali metal hydride ; or (c) reacting the amino-amide NH2 (CH2)-CO-NR3R4 with the aroyl halide R1-CO-Hal.  In examples (1) glycine ethyl ester and 3 : 4 : 5-trimethoxybenzoic acid give the 3 : 4 : 5-trimethoxybenzoic acid amide of glycine ethyl ester, this with hydrazine hydrate gives the hydrazide, and this is treated with nitrous acid and then with diethylamine as in (a) above ; (2) 3 : 4 : 5-trimethoxybenzoic acid and thionyl chloride give 3 : 4 : 5-trimethoxylbenzoyl chloride and this is treated with N : N-diethyl-b -alanine amide as in (c) above ; (3) p-chlorobenzoyl chloride and glycine ethyl ester hydrochloride give p-chlorobenzoylglycine ethyl ester and this is treated with diethylamine as in the alternative procedure of (a) above ; (4) 3 : 4 : 5-trimethoxycinnamic acid and thionyl chloride give 3 : 4 : 5-trimethoxycinramoyl chloride and this is reacted with glycine diethylamide as in (c) ; (5) anisic acid and thionyl chloride give p-anisoyl chloride and this is reacted with glycine diethylamide as in (c) ; (6) veratroyl chloride is prepared similarly and reacted with glycine diethylamide ; (7) 3 : 4 : 5-trimethoxy-benzamide and diethylchloroacetamide are reacted as in (b) above ; (8) the veratric acid amide of glycine hydrazide is prepared as in (1) and is then converted via the azide to the di-n-butylamide ; (9) dimethylamine replaces the diethylamine in the last stage of (1) ; (10) phthaloyl glycine acid chloride is heated with di-isopropylamine in pyridine to give phthaloyl glycine di-isopropylamide, this is heated with hydrazine hydrate in methanol to give glycine di-isopropylamide and this is reacted with 3 : 4 : 5-trimethoxybenzoyl chloride as in (c) ; and (11) 3 : 4 : 5-trimethoxy-benzoic acid is reacted with glycine diethylamide in presence of N : N1-dicyclohexylcarbodiimide to give the same product as in (1).ALSO:Pharmaceutical compositions comprise a compound of the formula R1-CO-NH-(CH2)nCO-NR3R4 wherein R1 is a mono-or polylower alkoxy ring substituted phenyl or styryl group, or a halophenyl group, n is 1 or 2, and R3 and R4 are lower alkyl groups, the lower alkyl and lower alkoxy groups each containing at most 4 carbon atoms, in admixture with suitable diluents.  The compositions may take the form of solutions, tablets or capsules.  An example describes a tablet containing 3:4:5 trimethoxy benzoylglycine diethylamide.