PROCESS FOR THE PREPARATION OF PENAM DERIVATIVES

摘要

A process for the preparation of a penam derivative of formula (I): IMAGE (I) wherein RA is hydrogen or a group of formula (Ia): IMAGE (Ia) wherein X is -CO2R1, or SO3R1; R is C1-6alkyl, aryl, or heterocyclyl; R1 is hydrogen, or a pharmaceutically acceptable salt-forming ion or ester-forming radical, and R2 represents hydrogen or a pharmaceutically acceptable salt-forming ion or in vivo hydrolyzable ester-forming radical; which process comprises reacting a compound of formula (II): IMAGE (II) wherein RB is hydrogen, a removable amino blocking group, or a group of formula (IIa): IMAGE (IIa) wherein Y is -CO2Rx or -SO3Rx; R is as defined with respect to formula (I) above; Rx represents an ester-forming radical, RY represents hydrogen, a salt-forming radical or a carboxyl-blocking group, and R3 represents an alkyl, benzyl, or aryl group; with methanol in the presence of copper ions; and thereafter if necessary carrying out one or more of the following steps: (i) removal of any blocking group; (ii) converting the product to a pharmaceutically acceptable salt or ester thereof.