Methods in the preparation of D-phenylglycine-containing cefotaxime double esters

Alkylation of cefotaxime sodium with 1-iodoethyl 2-N(Boc)-D- phenylglycine (3a and 3b) led to double esters 4a, 4b where the carboxyl group of D-phenylglycine was linked to the 4-carboxyl group of cefotaxime via an ethyledine moiety, and their Δ² isomeric analogues 5a and 5b. The Δ³→Δ² isomeric transformation from 4a and 4b to 5a and 5b during the synthesis was successfully eliminated by the addition of TBA+HSO₄^- to the reaction media. Hydrolysis of the mixture of 4a and 4b followed by medium pressure liquid chromatographic separation afforded the D-phenylglycine- containing double ester prodrugs of cefotaxime (1a and 1b). Compounds 1a and 1b were stable in acidic phosphate buffer solution, but were degraded fairly rapidly in a pH 7.39 phosphate buffer solution. The t 1/4 of 1a and 1b in mucosal suspension prepared from rat intestine were 11 minutes and 1 minute respectively. These two compounds failed to demonstrate satisfactory stability for formulation as oral prodrugs of cefotaxime.