SYNTHESIS OF 7-[ALPHA-(2-AMINO-[2-C-14]THIAZOL-4-YL)-ALPHA-(Z)-METHOXYIMINOACETAMIDO]-3-(1-METHYLPYRROLIDINIO)METHYL-3-CEPHEM-4-CARBOXYLATE HYDROCHLORIDE ([C-14]CEFEPIME HYDROCHLORIDE)

The title compound 9 was prepared by the route outlined in Scheme I. [C-14]Thiourea (1) was condensed with ethyl 4-bromo-3-oxo-2-methoxyiminoacetate (2), providing ethyl 2-(2-amino-4-[2-C-14)thiazolyl)-2-methoxyiminoacetate (3), as the pure Z-isomer. Saponification gave the amino acid 4; this was reacted with 1-hydroxybenzotriazole to give the activated ester 5. Condensation in situ with 7-amino-3-(1-methylpyrrolidinio) methyl-3-cephem-4-carboxylate (6) yielded the product as the pure sulfate salt (7). Treatment of 7 with base provided the zwitterion 8, isolated as the stable N-methyl-2-pyrrolidinone adduct. An aqueous solution of the adduct was converted to the crystalline title compound, [C-14]Cefepime hydrochloride hydrate (9), with hydrochloric acid/acetone. Radiochemical purity was 99.0% and specific activity, 34.2 muCi/mg. Overall yield from (C-14)thiourea was 18%.