Study on the Δ3 - Δ2 Isomerization During Preparation of Cefuroxime Double Ester Prodrugs

Abstract

Δ3->Δ2 Isomerization during preparation of cephalosporin ester prodrugs has been frequently reported. Methods to eliminate the isomerization must be established. In the course of preparing cefuroxime double ester prodrugs, quarternary ammonium salts with different counter ions were used as catalysts for alkylations and their effects on the isomerization were compared. The structures ofΔ3 andΔ2 isomeric esters 1a and 1b were identified with 1H-1H COSY 2D NMR and DEPT 135 NMR.The degree of isomerization during alkylation was monitored with HPLC. It was demonstrated that tetrabutyl ammonium hydrogen sulfate (TBA+HS04-) was a better catalyst than TBA+I-in regard to preventing any isomerization. The desired cefuroxime double ester 1a was obtained as a sole product in this reaction when the molar ratio of TBA+ HSO4- to cefuroxime sodium was beyond 0.35. We have successfully eliminated theΔ3->Δ2 isomerization commonly reported for preparation of cephalosporin esters.