Synthesis of 7-[α-(2-amino-[2-14C]thiazol-4-yl)-α-(Z)-methoxyiminoacetamido]-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate hydrochloride ([14C]cefepime hydrochloride)

Abstract The title compound 9 was prepared by the route outlined in Scheme I. [ 14 C]Thiourea ( 1 ) was condensed with ethyl 4‐bromo‐3‐oxo‐2‐methoxyiminoacetate ( 2 ), providing ethyl 2‐(2‐amino‐4‐[2‐ 14 C]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, [ 14 C]Cefepime hydrochloride hydrate ( 9 ), with hydrochloric acid/acetone. Radiochemical purity was 99.0% and specific activity, 34.2 μCi/mg. Overall yield from [ 14 C]thiourea was 18%.