Patent GB-715341-A (GB)
Title: Improvements relating to substituted amides
Filed: 1951-11-22
Abstract: Substituted amides having the general formula <FORM:0715341/IV (b)/1> in which R and R1 are organic radicals and R11 is a hydrogen atom or an organic radical, and in which the group-NR1R11 is a radical derived from a substituted or unsubstituted primary or secondary amine having a dissociation constant in water at 25 DEG  C. of not more than 1 X 10-5 and not less than 1 X 10-13 and in which any substituted group which would interact with the amino group has first been converted to a non-functional substituent, are obtained by reacting a carboxylic acid RCOOH in which R is as defined above with a diester-phosphite amide having the general formula <FORM:0715341/IV (b)/2> in which R1 and R11 are as defined above and Z and Z1 are non-functional esterifying radicals.  The radicals Z and Z1 may be aromatic such as phenyl, naphthyl, chlorophenyl and nitrophenyl or aliphatic such as ethyl, propyl, butyl and chlorobutyl. Diesterphosphite amides of the stated formula may be prepared by reacting the substituted or unsubstituted primary or secondary amine with a halophosphite compound having the general formula <FORM:0715341/IV (b)/3> wherein X is a halogen atom and Z and Z1 are as defined above, the reaction being conveniently carried out in an anhydrous, inert, organic solvent, preferably in the presence of a halogen acid acceptor.  Suitable amines are, for example, aromatic amines such as aniline, naphthylamine, o-chloroaniline, N-methylaniline, N-benzylaniline, o-carbethoxyaniline, toluidine, and 2,4-dibromo-6-nitro-aniline; and amines having an a -carbalkoxy group such as N-methyl phenylalanine ethyl ester. The carboxylic acid RCOOH may be any monobasic or polybasic carboxylic acid, e.g. an aliphatic carboxylic acid such as acetic, propionic, butyric, caproic, stearic, and oleic acid; substituted aliphatic acid such as monochloracetic acid, polybasic acid such as succinic and adipic acid; aromatic acid such as benzoic and naphthalic acid, heterocyclic acids such as nicotinic and thiophene carboxylic acid; and alicyclic acid such as naphthenic acid.  When dibasic acids are employed either the monoamide or the diamide may be prepared depending on the number of molecular equivalents of diesterphosphiteamide used.  The method is particularly suitable for preparing amides from derivatives of the naturally occurring aminoacids and the amino acid derivative may be either the amine from which the diesterphosphiteamide is formed or the carboxylic acid which is reacted with the diesterphosphiteamide to form the substituted amide.  In either case the reactive group should be blocked.  Suitable amino acids include alanine, valine, norvaline, leucine, norleucine, isoleucine, isovaline, phenylaniline, tyrosine, serine, cysteine, methionine, aspartic acid, glutamic acid, lysine, ornithine, asparagine, citrulline, histidine, tryptophane, proline, and hydroxyproline.  The process is suitable for preparing long chain polypeptides, thus the dipeptide ester derivative may be prepared by reacting an acylated aminoacid with a diesterphosphiteamide formed from an aminoacid ester and the ester group removed to form the free acid which is then reacted with more diesterphosphiteamide to form the tripeptide ester and so on. The reaction is preferably carried out in an inert solvent such as an aromatic hydrocarbon, e.g. toluene or xylene; an aliphatic hydrocarbon such as normal octane; a chlorinated hydrocarbon such as chloroform, carbon tetrachloride and chlorobenzene; an aliphatic ether such as ethyl ether, cyclic ether such as dioxane, or with less satisfactory results an aliphatic ketone such as dibutyl ketone, or an aliphatic ester such as ethyl acetate. When an inert solvent is employed the diesterphosphiteamide may be formed in situ without the need of isolation.  The reaction may be carried out at room temperature but is preferably effected at the reflux temperature, e.g. 40-110 DEG  C. of the solvent employed. In examples (1) and (17) diethylanilinophosphite is refluxed with carbobenzoxyglycine in toluene and dimethyl formamide respectively to yield carbobenzoxyglycylanilide; (2) diethylanilineophosphite and carbobenzoxy-dl-phenylalanine are reacted as in (1) to yield carbobenzoxy-dl-phenylalanineanilide; (3) as in (2) except that the laevo-rotary form of carbobenzoxyphenylalanine is used, the product being carbobenzoxy-1-phenylalanineanilide; (4) to (7) diethyl-a -carbethoxy-b -phenylethylaminophosphite (obtained by reacting diethylchlorophosphite with dl-phenylalanine ethyl ester in anhydrous ether in the presence of triethylamine) is reacted with carbobenzoxyglycine in anhydrous toluene, wet toluene, ethyl acetate, and chloroform respectively as solvents yield carbobenzoxyglycylphenylalanine ethyl ester; (8) as in (4) except that the refluxing period is reduced; (9) as in (4) except that dibutyl chlorophosphite is used; (10) as in (4) but using diphenyl chlorophosphite; (11) as in (4) but using o-phenylene chlorophosphite; (12) glycine is mixed with diethyl-dl-a -carbethoxy-b -phenylethylaminophosphite and dry hydrogen chloride bubbled through the mixture until it is quite hot, the mixture is then cooled, alcohol added and then evaporated off and the residue taken up in sodium carbonate solution, extracted with ether to remove by-product, the solution made strongly basic with sodium hydroxide and then further extracted with ether, the ether solution dried and the hydrochloride of glycyl-dl-phenylalanine ethyl ester precipitated by bubbling in dry hydrogen chloride; (13) dibutyl-2-chloroanilino phosphite (obtained from dibutyl chlorophosphite and 2-chloroaniline) is refluxed with glacial acetic acid to yield o-chloroacetanilide; (14) diethylanilinophosphite and acetic acid are refluxed to yield acetanilide; (15) diethylanilinophosphite and benzoic acid are refluxed in toluene to yield benzanilide; (16) diethyl-dl-alpha - carbethoxy - beta - phenylethylamino phosphite is refluxed with acetic acid to yield N-acetyl - dl - phenylalanine ethyl ester; (18) diethylanilinophosphite and phthalyl-dl-b -phenylalanine are refluxed in chloroform solution to yield phthalyl-dl-b -phenylalanineanilide.