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

Abstract

The effect of substituents at the C-3 position on the degradation kinetics of the pivaloyloxymethyl (POM) ester of Δ³ cephalosporin in phosphate buffer solution (pH6-8) was investigated. In the degradation, the isomerization process to the Δ² ester was the rate-determining step. In this study, the logarithm of the isomerization rate to the Δ² ester (log k₁₂) correlated with the carbon-13 unclear magnetic resonance chemical shift difference value at C-3 and C-4 of the Δ³ ester (Δδ(4-3)). The energy level of the lowest unoccupied molecular orbital (LUMO) of the Δ³ esters also correlated with log k₁₂. 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 Δ³ ester (log k₂₁) 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 Δ² ester, i.e., the stability to degradation.