Patent GB-946405-A (GB)
Title: Process for the manufacture of n-acyl-peptides
IPC: C07K1/08
Filed: 1960-05-16
Abstract: N-Acyl-peptides are prepared by reacting a reactive ester of an N-acylamino-acid or of an N-acylpeptide with a free amino acid or a free peptide in a C2-6 aliphatic acid in the liquid state. Specified reactive ester residues are derived from phenol, thiophenol, para-introphenol, para-nitrothiophenol and cyanomethyl alcohol.  The free amino acid or peptide reactant excludes cysteine, histidine or aminoacids containing a carbamide group. The C2-6 aliphatic acids used as the catalytic solvent are preferably liquid at room temperature, are capable of being distilled at temperatures below 100 DEG C. under reduced pressure, are exemplified by acetic, propionic and methoxyacetic acids, and exclude the free amino acids and free peptides used as reactants. When a free aminoacid is used that contains a plurality of amino groups, e.g. lycine or arginine, reaction at only one nitrogen atom can be achieved by using the aminoacid in the form of a hydrohalide thereof.  After the formation of the N-acyl-peptides any unreacted free aminoacid or peptide may be precipitated with ethyl acetate and extracted with water, while the N-acylpeptide may be extracted from the ethyl acetate with aqueous bicarbonate solution and precipitated therefrom by acidification.  In examples (1) carbobenzoxy-L-leucine-thiophenyl ester and glycine yield carbobenzoxy-L-leucyl-glycine; (2) carbobenzoxy-glycine-thiophenyl ester and L-phenylalamine yield carbobenzoxy-glycyl-L-phenylalamine; (3) N-trifluoracetyl-L-phenylalamine-thiophenyl ester and glycine yield N-trifluoracetyl-L-phenylalanyl-glycine and with further treatment with aqueous ammonia L-phenylalanyl-glycine; (4) and (5) carbobenzoxy-glycine-thiophenyl ester and DL-valine yield carbobenzoxy-glycyl-DL-valine; (6) carbobenzoxy-L-alamine, thiophenyl ester and L-valine yield carbobenzoxy-L-alanyl-L-valine; (7) carbobenzoxy-glycine-thiophenyl ester and L-alamine yield carbobenzoxy-glycyl-L-alamine; (8) carbobenzoxy-glycine-thiophenyl ester and glycine yield carbobenzoxy-glycyl-glycine; (9) carbobenzoxy-glycine-thiophenyl ester and glycyl-L-leucine yield carbobenzoxy-glycyl-glycyl-L-leucine; (10) carbobenzoxy-glycine-thiophenyl ester and L-leucine yield carbobenzoxy-glycyl-L-leucine; (11) N-trifluoroacetyl-L-alamine-thiophenyl ester and glycine yield N-trifluoracetyl-L-alanyl-glycine and with further treatment with aqueous ammonia L-alanyl-glycine; (12) N-trifluoracetyl-L-alaminethiophenyl ester and L-alanine yield N-trifluoracetyl-L-alanyl-L-alanine; (13) carbobenzoxy-glycine-thiophenyl ester and L-proline yield carbobenzoxy-glycyl-L-proline; (14) carbobenzoxy-glycine-thiophenyl ester and L-methionine yield carbobenzoxy-glycine-L-methionine; (15) carbobenzoxy-glycine-thiophenyl ester and O-benzyl-L-serine yield carbobenzoxy-glycine-DL-O-benzylserine; (16) carbobenzoxy-L-alaminethiophenyl ester and glycine yield carbobenzoxy-L-alanyl-glycine; (17) carbobenzoxy-glycine-para-nitrothiophenyl ester and L-tryptophane yield carbobenzoxy-glycyl-L-tryptophane; (18) carbobenzoxy-L-aspartic acid-b -methyl-a -para-nitro-phenyl ester and glycine yield carbobenzoxy-L-asparagyl-a -glycine-b -methyl ester; (19) carbobenzoxy-glycine-thiophenyl ester and glycyl-glycine yield carbobenzoxy-diglycyl-glycine; (20) carbobenzoxy-glycyl-L-leucine-thiophenyl ester and glycine yield carbobenzoxy-glycyl-L-leucyl-glycine and by further heating with anhydrous trifluoracetic acid glycyl-L-leucyl-glycine; (21) carbobenzoxy-L-leucine-thiophenyl ester and L-alanine yield carbobenzoxy-L-leucyl-L-alanine; (22) carbobenzoxy-L-alanyl-glycine-thiophenyl ester and glycine yield carbobenzoxy-L-alanyl-glycyl-glycine, also prepared from carbobenzoxy-L-alanine-thiophenyl ester and glycyl-glycine; (23) carbobenzoxy-L-alanine-thiophenyl ester and diglycyl-L-leucine yield carbobenzoxy-L-alanyl-glycyl-glycyl-L-leucine; (24) phthalyl-glycine-thiophenyl ester and L-leucine yield phthalyl-glycyl-L-leucine; (25) phthalyl-glycine-thiophenyl ester and glycine yield phthalyl-glycyl-glycine; (26) phthalyl-glycine-thiophenyl ester and L-tyrosine yield phthalyl-glycl-L-tyrosine; (27) phthalyl-glycine-thiophenyl ester and L-alanine yield phthalyl-glycyl-L-alanine; (28) phthalyl-glycine-thiophenyl ester and L-valine yield phthalyl-glycyl-L-valine; (29) phthalyl-glycine-thiophenyl ester and L-phenylalanine yield phthalyl-glycyl-L-phenylalanine; (30) phthalyl-glycine-thiophenyl ester and L-tryptophane yield phthalyl-glycyl-L-tryptophane; (31) phthalyl-glycine-thiophenyl ester and L-proline yield phthalyl-glycyl-L-proline; (32) phthalyl-L-phenylalanine-thiophenyl ester and glycine yield phthalyl-L-phenylalanyl-glycine; (33) N-trifluoracetyl-L-phenylalanine-thiophenyl ester and L-alanine yield N-trifluor-acetyl-L-phenylalanyl-L-alanine; (34) N-trifluor-acetyl-L-phenylalanine-thiophenyl ester and L-valine yield N-trifluoracetyl-L-phenylalanyl-L-valine; (35) N-trifluoracetyl-L-phenylalanine-thiophenyl ester and L-leucine yield N-trifluoracetyl-L-phenylalanyl-L-leucine; (36) N-trifluoracetyl-L-phenylalanine-thiophenyl ester and L-phenylalanine yield N-trifluoracetyl-L-phenylalanyl-L-phenylalanine; (37) N-trifluoracetyl-L-phenyl-alanine-thiophenyl ester and L-methionine yield N-trifluoracetyl-L-phenylalanyl-L-methionine; (38) N-trifluoracetyl-glycine-cyanomethyl ester and L-leucine yield N-trifluoracetyl-glycyl-L-leucine; (39) carbobenzoxy-glycine-phenyl ester and DL-valine yield carbobenzoxy-glycyl-DL-valine, carbobenzoxy-glycyl-L-valine is prepared similarly; (40) carbobenzoxy-glycyl-L-alanine-thiophenyl ester and L-phenylalanyl-glycine yield carbobenzoxy-glycyl-L-alanyl-L-phenylalanyl-glycine; (41) carbobenzoxy-glycine-thiophenyl ester and L-lysine monohydrochloride yield e -carbobenzoxy-glycyl-L-lycine, which is isolated via the copper complex; (42) phthalyl-glycine-para-nitrothiophenyl ester and L-alanine yield phthalyl-glycyl-L-alanine; and (43) carbobenzoxy-L-alanyl-glycyl-glycine-thiophenyl ester and L-alanyl-glycyl-glycine yield carbobenzoxy - L - alanyl-glycyl-glycyl - L -alanyl-glycyl-glycine. Specification 803,464 is referred to.