IE37409L - 3-heterocyclic thiomethylcephalosporins - Google Patents

Abstract

1358027 3 - Heterocyclic α - amino - phydroxybenzyl cephalosporins SMITHKLINE CORP 30 March 1973 [14 June 1972 15 Sept 1972] 15308/73 Heading C2A Novel α-amino-p-hydroxybenzyl cephalosporins having the Formula (I) and salts thereof, wherein R is 5-methyl-1,3,4- thiadiazol-2-yl or 1-methyl-5-tetrazolyl are prepared by (1) N-acylating a 7-aminocephalosporin compound of Formula (II) or a carboxyl-protected ester or alkali metal salt thereof, wherein X is -S-R and R is either as defined above or is a group -OCOCH 3 , with α-amino-p-hydroxyphenylacetic acid or an N-acylating active derivative thereof, the -OH and -NH 2 groups being protected if necessary, and (2) when R is the group -OCOCH 3 , reacting the product with a heterocyclic thiol: HS-R or an alkali metal salt thereof, in which R is as defined above in connection with Formula (I), followed by (3) removal of any protecting group or groups. The sequence of reactions (1) and (2) may be reversed, i.e. 7-aminocephalosporanic acid or its salt or ester being reacted at the 3- position with the said heterocyclic thiol followed by N-acylation of the product with α- amino-p-hydroxyphenylacetic acid or its active derivative, with subsequent removal of any protecting groups. Protective groups used are conventional amino-, hydroxy- and carboxyl-protecting groups which are removable by, e.g. hydrolysis or hydrogenolysis. The N-acylation is usually performed with the acid itself in the presence of a condensing agent, or with a typically activated derivative of the acid. The 3-position replacement may be effected by reacting the amino-protected cephalosporin or its alkali metal salt with the thiol or its salt, at a pH near neutrality in acetone or aqueous acetone at elevated temperature. The product may be recovered by slight acidification of the reaction mixture followed by extraction with an immiscible solvent. Since the compound (I) has both acidic and basic groups, its salts may be base- or acidaddition salts; alternatively the compound may be in zwitterionic form. The compounds (I) and their salts have broad spectrum anti-bacterial activity and may be made up into various pharmaceutical compositions (e.g. for oral or parenteral administration) with the aid of an appropriate carrier, diluent or excipient. [GB1358027A]