Patent GB-717427-A (GB)
Title: Improvements relating to substituted amides
IPC: C07K1/00
Filed: 1951-11-22
Abstract: Amides of formula RCONR1R11, where RCO is an acyl group and NR1R11 is a radicle derived from an acylatable primary or secondary amine by replacement of hydrogen are made by reacting an amine having at least one reactive hydrogen atom with a mixed anhydride of a carboxylic acid and a diester of phosphorous acid of formula <FORM:0717427/IV (b)/1> where Z and Z1 are non-functional esterifying radicles. Representative of specified esterifying radicles are naphthyl, chloro- and nitrophenyl, ethyl and chlorobutyl.  Anhydrides of mono- or poly-basic carboxylic acids may be used.  Representative of specified amines are ethylamine, allylamine, dimethylamine, chlorethylamine, benzylamine, naphthylamine, m-toluidine, o-chloraniline, 2,4-dibromo-6-nitro-aniline, N-allyl-aniline, piperidine, morpholine, aminopyrimidine and butylenediamine.  With diamines the mono- or di-substituted derivative may be obtained according to the molar amount of anhydride used.  Amides are particularly obtained from naturally occurring amino-acids.  The amino-acid may either be the acid from which the mixed anhydride is formed or the amine to be acylated.  When the amino-acids are used in making the mixed anhydride it is advantageous to block the amino group and other secondary reactive groups by acylation or substitution.  Generally the amino acids are alpha aminoacids of 2-12 C atoms and representative of several specified are alanine, norvaline, isoleucine, phenylalanine, tyrosine, cysteine, methionine, aspartic acid, ornithine, citrulline, tryptophane and hydroxyproline. For peptides it is preferable to react the mixed anhydride with an aminoacid ester rather than with the free acid. The ester group may then be removed by hydrolysis to give the free acid.  By successive reaction of the peptides obtained long-chain polypeptides may be obtained.  Sensitive groups such as aldehyde and keto groups are not destroyed during the reaction.  Reaction is preferably effected in an inert solvent and representative of many specified are xylene, n-octane, chloroform, chlorobenzene, butyl ether, dioxane, dibutyl ketene and ethyl acetate.  Aromatic hydrocarbons are preferred and aliphatic ketones and esters are less satisfactory.  When an inert solvent is used the mixed anhydride may be formed in situ. Temperatures of 40-115 DEG  C. are preferred.  In examples, carbobenzoxyglycine anilide is prepared from mixed anhydrides of carbobenzoxyglycine and phosphorus acid (1), (2) and (3) diethyl, (12) dibutyl, (13) diphenyl and (15) di-o-phenylene diesters; in (4) carbobenzoxyglycine-DL-phenylalanine ethyl ester is made by reacting DL-phenylalanine ethyl ester with a mixed anhydride of carbobenzoxyglycine and phosphorus acid diethyl ester, (5) carbobenzoxy-DL-alanyl-DL-phenylalanine ethyl ester is made from DL-phenylalanine ethyl ester and the mixed anhydride of carbobenzoxy-DL-alanine and phosphorous acid diethyl ester; (6) phthalylglycyl - DL - alanyl - DL - phenylalanine ethyl ester is made from DL-phenylalanine ethyl ester and the mixed anhydride of phthalylglycyl-DL-alanine with phosphorous acid diethyl ester; (7) dicarbobenzoxy-L-lysylglycine ethyl ester is made from glycine ethyl ester and the mixed anhydride of L-dicarbobenzoxylysine with phosphorous acid diethyl ester; (8) butyranilide is made from aniline and the mixed anhydride of butyric acid and phosphorous acid dibutyl ester; (9) acetanilide is made from aniline and the mixed anhydride of acetic acid and phosphorous acid diethyl ester; (10) adipic acid dianilide is made from aniline and the mixed dianhydride of adipic acid and phosphorous acid diethyl ester; (11) the monoanilide of adipic acid is made with the reactants of (10); and in (14) carbobenzoxyglycylglycylglycine ethyl ester is made from glycyl glycine ethyl ester and the mixed anhydride of (1).  Mixed anhydrides may be made by reacting a carboxylic acid or salt thereof with a compound of formula <FORM:0717427/IV (b)/2> where Z and Z1 are as defined and X is a halogen. Conveniently reaction is effected in an anhydrous, inert organic solvent.  Reaction may be effected at room temperature.  The examples show the preparation of all the mixed anhydrides used therein.