GB826925A - Improvements in or relating to -a-and -y-glutamyl peptides - Google Patents

Abstract

The invention comprises (1) the preparation of a - glutamyl - peptides HOOC-CHR1-NH-CO-CH(NH2) -CH2-CH2-COOH by reacting an N-tritylated glutamic monoester (a or g ) with an amino-ester NH2-CHR1-COOR, in the presence of dicyclohexyl-carbodiimide (cf. Specification 820,789), hydrolysing the two ester groups with alkali and removing the trityl group with hot aqueous acetic acid; (2) the preparation of g -glutamyl peptides HOOC-CH(NH2) -CH2-CH2-CO-NH-CHR1-COOH by reacting an N-tritylated a -benzyl glutamate with a benzyl ester NH2-CHR1-COOCH2C6H5, removing the benzyl group by hydrogenolysis and detritylating; (3) the N-trityl derivatives of the a - and g -glutamyl-peptides and their diesters. In the formul R1 is hydrogen or an alkyl or aralkyl group (which may be substituted) of not more than 8 carbon atoms. The starting materials are made by di-esterifying glutamic acid, tritylating the ester, and either monohydrolysing to remove the g -ester group, or if the a -esterifying group is benzyl removing this by hydrogenolysis. Such an a -benzyl g -alkyl N-tritylglutamate can be obtained by alkaline alcoholysis of the dibenzyl ester as in Specification 813,927. In process (1) above hydrolysis of the two ester groups proceeds via an N-substituted tritylamino-glutarimide so that the a -peptide is obtained irrespective of whether the a - or g -monoester is used as starting material. In all these steps racemization is negligible so that DL-, D- and L-products can be obtained. In the examples the following are prepared: (1) N-trityl-g -glutamyl-glycine diethyl ester, N-trityl-a -glutamyl-glycine and a -glutamyl-glycine; (2) N - trityl - a - glutamyl - glycine methyl ethyl ester and a -glutamyl-glycine; (3) N-trityl-g -glutamyl-glycine dibenzyl ester, N-trityl a - and g -glutamyl-glycine and a - and g -glutamyl glycine; (4) N-trityl-a -glutamyl-leucine dimethyl ester, N - trityl - a - glutamyl - leucine and a - glutamyl - leucine; (5) N - trityl - g - glutamyl-leucine dibenzyl ester, N-trityl-g -glutamyl-leucine and g -glutamyl-leucine; (6) N-trityl - a - glutamyl - tyrosine methyl ethyl ester, N - trityl - a - glutamyl - tyrosine and a - glutamyl - tyrosine; (7) N - trityl g - glutamyl-tyrosine dibenzyl ester and g -glutamyl-tyrosine. Details are also given of the preparation of glycine benzyl ester, leucine methyl ester, tyrosine ethyl ester (from their hydrochlorides), and the a -methyl, a -ethyl and a -benzyl esters of N-trityl glutamic acid; the a -methyl and a -ethyl esters form salts with D-(-)-threo-1-p-nitrophenyl - 2 - aminopropane - 1 : 3 - diol (see Specification 826,926). In general the esterifying groups can be methyl, ethyl, propyl, butyl isobutyl, benzyl, phenyl or cyclohexyl. Specification 791,319 also is referred to.