The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

Abstract

The degradation of cefaclor (l), an oral cephalosporin antibiotic, was studied at 37O in a neutral aqueous medium by HPLC and 'H-NMR. Under these conditions, 1 underwent intramolecular aminolysis by the 7-sidechain NH, group on the 8-lactam moiety to give a piperazine-2,s-dione. The most prominent peak in the HPLC profile of a degradation solution from 1 was isolated by prep. HPLC. Mechanistically, the formation of this degradation product cis-11 from 1 involves the contraction from a six-membered cephem ring to a live-membered ring, which presumably takes place via a common episulfonium ion intermediate 9 (see Scheme). Loss of the C1-atom from 3-chloro-3-cephem is a general reaction subsequent to b-lactam ring opening.

Isolation and Structure Elucidation of the Major Degradation Products of Cefaclor Formed Under Aqueous Acidic Conditions

“…The degradation pathways of cefaclor under neutral and basic pH conditions are complex, essentially unexplored, and remain to be elucidated. The recent study by Vilanova et al 24 describing a major pathway of cefaclor degradation under neutral conditions provides an excellent start to exploring these degradation pathways. The major solid-state degradation pathways described by Dorman et al 21 lead to multiple degradation products, many of which are not formed under aqueous conditions.…”

“…In a more recent study of the neutral aqueous degradation of cefaclor, Vilanova et al 24 provided structural evidence for this intramolecular cyclization pathway. Under acidic conditions, however, the nitrogen would be protonated, significantly reducing nucleophilicity.…”

Cover Picture: (Electroanalysis 12/2014)

“…19 We found that the ring‐opened products showed the expected diagnostic shift in absorbance due to piperazinedione formation,19a and, in contrast to intact cefaclor, no longer showed any spectral change upon treatment with NDM‐1, as would be expected for products that lack a β‐lactam bond. We did not further purify each component from the resulting mixture, due to the well‐documented instability of the degradation products of cefaclor and related cephems,19c, d and we used the mixture for inactivation tests.…”

Detection of the iron complexes with hydrolysis products of cephalexin and cefradine upon high‐performance liquid chromatography/electrospray ionization mass spectrometry analysis

“…Electrospray ionization mass spectrometry, usually coupled with high‐performance liquid chromatography (HPLC/ESI‐MS), has been successfully applied to their analysis . However, there is little nuclear magnetic resonance (NMR) data reported concerning the products of their hydrolysis and, to the best of our knowledge, there is no ESI‐MS data reported concerning the products. It is reasonable to expect that the products of cephalosporin hydrolysis are unstable and undergo further transformation (e.g.…”