Patent GB-970952-A (GB)
Title: Histidine peptides and process for producing them
IPC: C07D233/64
Filed: 1962-02-15
Abstract: The invention comprises N(Im)-carbobenzoxy histidine compounds of the formulae:- <FORM:0970952/C1/1> wherein Cbz represents carbobenzoxy (-CO.O.CH2Ph), X represents halogen (e.g. Cl, Br, I), P represents C1-8 alkoxy, substituted or unsubstituted phenyl (C1-8) alkoxy (e.g. -O-CH2Ph, -O-CH2-C6H4-NO2-p) or a radical -NH-Q11-CO-P1, wherein P1 represents C1-8 alkoxy or substituted or unsubstituted phenyl (C1-8) alkoxy, Q and Q11 represent residues derived from an amino acid or a peptide by loss of a terminal amino and a terminal carboxylic group, and R represents an amino protecting group (e.g. -CO.O.CH2Ph, -C(Ph)3, -SO2.C6H4.CH3-p, -CHO, -CO.O.C(CH3)3).  In the above compounds any carboxyl and/or other functional groups in the residues Q and Q11 may be blocked by suitable protecting groups.  Thus, the alcoholic radical in the tyrosine residue may be protected as benzyloxy (-O.CH2Ph); the thiol radical in the cysteine residue as benzylthio (-S.CH2Ph), the amino radical in the lysine and ornithine residues as carbobenzoxyamino (-NHCO.O.CH2Ph); tritylamino (-NH.C(Ph)3), tosylamino (-NHSO2.C6H4.CH3-p), formylamino (-NHCHO) or tert-butyloxy carbonylamino (-NHCO.O.C(CH3)3); the guanidyl in the arginine residue as nitroguanidyl <FORM:0970952/C1/2> or tosylguanidyl <FORM:0970952/C1/3> and the carboxyl radical in the glutamic acid and aspartic acid residues as methoxycarbonyl (-CO.O.CH3), tert.-butoxycarbonyl (-CO.O.C(CH3)3) or benzyloxycarbonyl (-CO.O.CH2Ph). Compounds of the formula:- <FORM:0970952/C1/4> are prepared by treating compounds of the formula:- <FORM:0970952/C1/5> with a hydrogen halide in an anhydrous inert organic solvent such as dioxan, glacial acetic acid, diethyl phosphite, methanol or ethanol at a temperature between 0 and 40 DEG C.  The dihydrohalide thus produced is converted to the base of the formula:- <FORM:0970952/C1/6> by treatment with an alkali such as sodium bicarbonate, ammonia water or tertiary amines in the presence of a water-immiscible organic solvent such as dichloromethane, chloroform, ethyl acetate, dioxane, tetrahydrofuran or dimethylformamide. The base thus produced is converted to a peptide of the formula:- <FORM:0970952/C1/7> by treatment with an amino acid or peptide of the formula HOOC-Q-NH-R or a derivative thereof in which any functional group in Q may be protected and/or the free carboxyl group is replaced by a reactive functional derivative of a carboxyl group such as carboxylic halide, carboxylic azide, carboxylic anhydride, carboxylic thioester, -CO.O.C6H4.NO2-p or -CO.O.CH2CN, preferably in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or tetraethyl pyrophosphite. The N(Im)-carbobenzoxy group in the peptide product may be subsequently removed by hydrogenolysis or by alkaline hydrolysis to give a product of the formula:- <FORM:0970952/C1/8> The peptide product may also be employed as a histidine-introducing agent when the amino-protecting group R is susceptible to the an acid reagent.  Thus, treatment with hydrogen halide in an inert organic solvent yields a compound of the formula:- <FORM:0970952/C1/9> which on treatment with alkali in the presence of a water-immiscible organic solvent yields a base of the formula:- <FORM:0970952/C1/100> This base may then be treated with an amino acid or peptide of the formula HOOC-Q1-NH-R1 or a derivative thereof in which the free carboxyl group is replaced by a reactive functional derivative of a carboxyl group, both Q1 and R1 being analogous to Q and R respectively, to yield as a product a peptide of the formula:- <FORM:0970952/C1/111> The N(Im)-carbobenzoxy group may be removed from this peptide product by hydrogenolysis or by alkaline hydrolysis, yielding a product of the formula:- <FORM:0970952/C1/122> The examples describe the preparation of N (a ), N (Im) - dicarbobenzoxy - L - histidine methyl ester hydrochloride, N(a ), N(Im)-dicarbobenzoxy-L-histidine, N(a ), N(Im)-dicarbobenzoxy-L-histidyl-L-phenylolanine methyl ester, formylglycyl-o-benzyl-L-serine methyl ester, formylglycyl-o-benzyl-L-serine, carbobenzoxy-L-prolyl-L-phenylalanine methyl ester, carbobenzoxy-L-prolyl-L-phenylalanine, N(a ), N (Im)-dicarbobenzoxy-L-histidyl-L-phenylalanine benzyl ester and N(a ), N(Im)-dicarbobenzoxy-L-histidyl-L-leucine methyl ester as starting materials, and as preferred products N(Im)-carbobenzoxy-L-histidine methyl ester dihydrobromide, N(Im)-carbobenzoxy-L-leucine methyl ester dihydrobromide, N(Im)-carbobenzoxy-L-histidyl- L-phenylalanine methyl ester dihydrobromide, N(Im)-carbobenzoxy-L-histidyl-L-phenylalanine benzyl ester dihydrobromide (which, for purposes of purification, is converted to N(Im)-carbobenzoxy-L-histidyl-L-phenylalanine benzyl ester monohydrochloride), carbobenzoxyglycyl-N(Im)-carbobenzoxy-L-histidine methyl ester, carbobenzoxy-glycyl-N(Im)-carbobenzoxy-L-histidyl-L-leucine methyl ester, carbobenzoxy-N(Im)-carbobenzoxy-L-histidyl-L-phenylalanine methyl ester, formyl-g -methyl-L-glutamyl-N(Im) - carbobenzoxy - L - histidyl-L-phenylalanine benzyl ester, N(a ), N(Im)-dicarbobenzoxy-L-histidyl-N(Im) - carbobenzoxy-L-histidyl-L-phenylalanine, carbobenzoxy-o-benzyl-L-seryl-N(Im)-carbobenzoxy - L - histidyl-L-leucine methyl ester, formylglycyl-o-benzyl-L-seryl-N(Im)-carbobenzoxy-L-histidy-L - leucine methyl ester, carbobenzoxy-L-prolyl - L - phenylalamyl - N(Im)-carbobenzoxy-L-histidyl-L-leucine methyl ester, glycyl-N(Im)-carbobenzoxy-L-histidyl-L-phenylalanine methyl ester dihydrobromide, carbobenzoxyglycyl - L - histidyl - L - phenylalanine, formyl-g -methyl-L-glutamyl - L - histidyl-L-phenylalanine, carbobenzoxy-g  - tert. - butyl-L-glutamyl-N(Im)-carbobenzoxy-L-histidyl-L-phenylalanine methyl ester and carbobenzoxy-g -tert.-butyl-L-glutamyl-L-histidyl - L - phenylalanine. Carbobenzoxy-g -tert.-butyl-L-glutamyl-L-histidyl-L-phenylalanine may be coupled with G-tosyl-L-arginyl-L-tryptophyl-glycine methyl ester in the presence of N, N1-dicyclohexylcarbodiimide to yield carbobenzoxy-g -tert.-butyl-L-glutamyl-L-histidyl-L-phenylalanyl-G -tosyl - L - arginyl-L-tryptophyl-glycine methyl ester, which on elimination of protecting group yields L-glutamyl-L-histidyl -L- phenylalanyl -L- tryptophyl-glycine. Carbobenzoxy-g -tert.-butyl -L- glutamyl-L-histidyl-L-phenylalanyl-G-tosyl-L - arginyl-L-tryptophyl-glycine methyl ester may also be catalytically reduced using a palladium catalyst to yield g -tert.-butyl-L-glutamyl-L - histidyl-L-phenylalanyl-G-tosyl-L-arginyl-L-tryptophyl-glycine methyl ester coupled with carbobenzoxy-L-methionine in the presence of N,N1-dicyclohexylcarbodiimide to yield after elimination of protecting radicals, L-methionyl-L - glutamyl-L-histidyl-L-phenylalanyl-L-arginyl - L - tryptophyl-glycine.