Studies on Orally Active Cephalosporin Esters. III. Effect of the 3-Substituent on the Chemical Stability of Pivaloyloxymethyl Esters in Phosnhate Buffer Solution

Abstract

The effect of substituents at the C-3 position on the degradation kinetics of the pivaloyloxymethyl (POM) ester of A3cephalosporin in phosphate buffer solution (pH 6—8) was investigated. In the degradation, the isomerization process to the A2ester was the rate-determining step. In this study, the logarithm of the isomerization rate to the A2ester (log k]2) correlated with the carbon-13 nuclear magnetic resonance chemical shift difference value at C-3 and C-4 of the A3ester (Δδ (4-3)). The energy level of the lowest unoccupied molecular orbital (LUMO) of the A3 esters also correlated with logk12. The electronic properties at the C-2 position had no effect on the isomerization reaction. On the other hand, the logarithm of the isomerization rate back to the A3ester (logk21) correlated with the van der Waals volume (MV) of the 3-substituent. These results show that the substituent at the C-3 position influences mainly the electronic structure of the conjugated π-bond system (C3 = C4-C4 = O) and consequently affects the feasibility of isomerization to the A2ester, i.e., the stability to degradation. © 1989, The Pharmaceutical Society of Japan. All rights reserved.