Patent GB-1104271-A (GB)
Title: Process for removing amino-protecting groups in the manufacture of amino-acids and peptides
IPC: C07K1/12
Filed: 1965-08-31
Abstract: In processes for the production of aminoacids and peptides in which a free amino group is protected by conversion into an N-arylsulphenyl group, the free amino group is later re-formed by treating the N-arylsulphenyl derivative in a weakly acid medium with (1) an organic or inorganic compound containing di- or tetra-valent sulphur or (2) hydrocyanic or hydrazoic acid or a salt thereof or (3) a salt of hydriodic acid. Other amino-protecting groups which may be present, e.g. a tert.-butyloxycarbonyl or a tert.-butyl ester group, are not affected by the treatment. Examples are given in which (1) the arylsulphenyl group is a nitrophenyl-, a 2,4-dinitrophenyl- or a pentachlorophenyl-sulphenyl group, (2) the reagent used for eliminating the arylsulphenyl group is hydrocyanic acid, sodium thiosulphate, sulphurous acid, sodium azide, ammonium thiocyanate, sodium bisulphide, thiophenol, thioglycollic acid, dithioglycol, thiourea, thioacetamide, potassium iodide, m-thiocresol, toluene-3,4-dithiol, N-phenylthiourea, thiobenzamide or xanthogen amide and (3) the products obtained are L-valyl-L-phenylalanine methyl ester and its hydrochloride, N1 - tert. - butyloxycarbonyl - L-lysine methyl ester acetate, formate and propionate, N11 - tert. - butyloxycarbonyl - L - lysyl - N1 - tert - butyloxycarbonyl - L - lysine methyl ester monochloracetate, glycine, L-proline, L-valine, glycine ethyl ester, glycyl-L-phenylalanine methyl ester, N1 - tert. - butyloxycarbonyl - L - lysine and its methyl ester, N1 - tert. - butyloxycarbonyl - L - lysyl - L - prolyl - L - valylglycine ethyl ester, N1 - tert. - butyloxycarbonyl - L - lysyl - L - valyl - L - tyrosyl - L - proline tert. - butyl ester, S - trityl - L - cysteine and N - benzyloxycarbonyl - L - phenylalanyl - N1 - tert. - butyloxycarbonyl - L - lysylglycine hydrazide.  The synthesis of the last-named compound on a solid substratum is described, the process comprising (a) treating the substrate with tert.-butyloxycarbonyl-glycine, (b) further treating with N-o-nitro-phenylsulphenyl - N1 - tert. - butyloxycarbonyl-L-lysine and dicyclohexylcarbodiimide, (c) eliminating the o-nitrophenylsulphenyl group by means of thioacetamide, (d) treating the product with benzyloxycarbonyl-L-phenylalanine and dicyclohexylcarbodiimide to form N-benzyloxycarbonyl - L - phenylalanyl - N1 - tert. -butyloxycarbonyl - L - lysylglycine on the substrate and (e) treating the last-named product with hydrazine hydrate.  Other specified sulphur compounds which may be used for the elimination of an arylsulphenyl group include hydrogen sulphide, thiocarbamic acid derivatives and thioacetic acid.  The preparation of certain starting materials is described as follows.  N - o - nitrophenylsulphenyl - N1 - tert. - butyloxycarbonyl - L - lysine methyl ester is prepared from o - nitrophenylsulphenyl chloride and N1 - tert. - butyloxycarbonyl - L - lysine by way of the dicyclohexyl ammonium salt, the free acid liberated from which is reacted with diazomethane.  N - o - Nitrophenylsulphenyl - N1 - tert. - butyloxycarbony - L - lysyl - N11 - tert. - butyloxycarbonyl - L - lysine methyl ester is prepared from N - o - nitrophenylsulphenyl - N1 - tert. - butyloxycarbonyl - L - lysine and N1 - tert. - butyloxycarbonyl - L - lysine methyl ester by reaction with dicyclohexylcarbodiimide.  N - o - nitrophenylsulphenylglycyl - L - phenylalanine methyl ester is obtained similarly from o - nitrophenylsulphenyl glycine, L-phenylalanine methyl ester hydrochloride and dicyclohexylcarbodiimide.  N - o - Nitrophenylsulphenyl - N1 - tert. - butyloxycarbony - L - lysyl - L - prolyl - L - valylglycine ethyl ester is prepared from N-o-nitrophenylsulphenyl - N1 - tert. - butyloxycarbonyl-L-lysine and L-prolyl-L-valylglycine ethyl ester by reaction with dicyclohexylcarbodiimide.  N - o - Nitrophenylsulphenyl - N1 - tert. - butyloxycarbony - L - lysyl - L - valyl - L - tyrosyl - L - proline tert.-butyl ester is obtained similarly from N - o - nitrophenylsulphenyl - N1 - tert. - butyloxycarbony L - lysine, L - valyl - L - tyrosyl-L-proline tert.-butyl ester and dicyclohexylcarbodiimide.  N - Pentachlorophenylsulphenyl - N1 - tert.-butyloxycarbonyl - L - lysine methyl ester is prepared from pentachlorophenylsulphenyl chloride and N1 - tert. - butyloxycarbonyl - L - lysine methyl ester.  N - 2,4 - Dinitrophenylsulphenyl - N1 - tert. -butyloxycarbonyl - L - lysine methyl ester is prepared from 2,4-dinitrophenylsulphenyl chloride and N1 - tert. - butyloxycarbonyl - L - lysine methyl ester.