HPLC AND H-1-NMR STUDIES OF ALKALINE-HYDROLYSIS OF SOME 7-(OXYIMINOACYL)CEPHALOSPORINS

Alkaline hydrolysis (pH 10.5) of the three 7-(oxyiminoacyl)cephalospor ins 1a-c (cefuroxime, ceftazidime, and ceftriaxone) was studied at 37- degrees using HPLC and H-1-NMR techniques. The 7-epicephalosporin 2, t he 3-methylidene compound 3, and the 6-epimer 4 of the 3-methylidene c ompound 3 were identified for each cephalosporin as the major degradat ion products under the conditions used: ceftazidime (1b) yielded also the DELTA2-isomer 5b (Scheme 1). A kinetic scheme was developed to acc ount for the production of these compounds, and the different kinetic constants involved in the process were calculated. The experimental re sults show that the presence of a pyridinio group at position C-C(3) f avours the appearance of the DELTA2-isomer, which was detected mainly in cephalosporins bearing an ester function at C(4). The presence of a n oxyimino group at C-CONH-C(7) facilitates epimerization at C(7) (--> 2), whereas that of an electron-withdrawing group at C-C(3) results i n a increased formation constant for the 3-methylidene compound 3. The 3-methylidene compounds 3a-c produced by the three cephalosporins on cleavage of the beta-lactam ring all underwent epimerization at C(6) t o yield the corresponding 6-epimer 4.