Patent GB-803464-A (GB)
Title: Manufacture of amides
IPC: C07C233/00
Filed: 1955-02-04
Abstract: Amides are made by reacting a carboxylic acid ester, the alcohol component of which is a carbinol having at the carbon atom which is linked to the hydroxy group an electronattracting substituent, i.e. a substituent which is meta-directing in aromatic rings or a halogen atom, with an organic amine the amino group of which has at least one free hydrogen atom.  The reaction may be used for the synthesis of peptides, and acid or basic catalysts, e.g. triethylamine, acetic or sulphuric acids, and solvents such as ethyl acetate, dioxane, dimethyl formamide, acetonitrile, or water may be used.  The esters used as starting materials may be similarly prepared by reaction of a carboxylic acid with a hydrohalic ester of the corresponding alcohol in presence of a tertiary organic base.  In examples: (1) chloracetonitrile is reacted with each of the following acids to give the cyanomethyl esters, which are then reacted with benzylamine to give the benzylamides of these acids: (a) phenylacetic acid, (b) stearic acid, (c) benzoic acid, (d) 3,4,5-trimethoxybenzoic acid, (e) salicylic acid, (f) isonicotinic acid, (g) nicotinic acid, (h) hippuric acid; (2) hippuric acid cyanomethyl ester is reacted with (a) cyclohexylamine, (b) isopropylamine, (c) ethyl glycine, (d) glycine, (e) aniline; (3) benzylamine is reacted with (a) hippuric acid carbethoxymethyl ester (obtained from hippuric acid and bromacetic ethyl ester), (b) hippuric acid dicarbethoxymethyl ester (obtained from hippuric acid and bromomalonic acid diethyl ester), (c) carbobenzoxy-glycine carbamidomethyl ester (obtained from carbobenzoxy-glycine and chloracetamide), (d) hippuric acid acetonyl ester (obtained from hippuric acid and chloracetone), (e) carbobenzoxy-glycine cyanomethyl ester (obtained from carbobenzoxy-glycine and chloracetonitrile), or tosyl- or phthalyl-glycine cyanomethyl ester (obtained similarly); (4) phthalyl-b -alanine cyanomethyl ester is reacted with piperidine to give phthalyl-b -alanine piperidide; (5) glycylglycine hydrochloride is reacted with carbobenzoxyglycine cyanomethyl or carbethoxymethyl ester (the latter having been prepared from carbobenzoxyglycine and ethyl bromacetate; (6) carbobenzoxyglycine cyanomethyl ester is reacted with DL-methionine; (7) carbobenzoxyglycyl-D,L-alanyl-glycine is reacted with chloracetonitrile to give the cyanomethyl ester which is then reacted with glycine methyl ester; (8) benzylamine is reacted with (a) p-nitrobenzoyl-L-glutamic acid dicyanomethyl ester, (b) dicarbobenzoxy-L-cystine dicyanomethyl or dicarbethoxymethyl ester, (c) carbobenzoxy-L-asparagine cyanomethyl or carbethoxymethyl ester; (d) N - tosyl - L - pyrrolidone - 2 - carboxylic acid cyanomethyl ester, (e) 5-benzyloxy-indolyl-3-acetic acid cyanomethyl ester, (f) 5-benzyloxy-indole-2-carboxylic acid carbethoxymethyl ester, all prepared from the acid and chloracetonitrile or ethyl bromacetate; (9) glycine ethyl ester is reacted with the cyanomethyl esters of (a) tosylglutamine, (b) p-nitrobenzyloxycarbonyl-DL-leucine, (c) tosyl-DL-methionine, (d) dicarbobenzoxy - L - tyrosine, (e) carbobenzoxy-L- or -DL-leucine; (10) phenylethylamine or benzylamine is reacted with (a) tosyl-DL-methionine carbethoxymethyl ester, (b) dicarbobenzoxy-L-tyrosine cyanomethyl or carbethoxymethyl ester, (c) carbobenzoxy-DL- or -L-leucine cyanomethyl ester; (11) hippuric acid cyanomethyl ester is reacted with (a) L-isoleucine ethyl ester, (b) L-tyrosine ethyl ester, (c) O-benzoyl-L-tyrosine ethyl ester hydrochloride, (d) DL-leucyl-glycine amide, (e) L-leucyl-glycine ethyl ester; (12) carbobenzoxy-DL-leucine cyanomethyl ester is reacted with glycine amide.