Synthesis of [1-~(15)N,2-~(13)C]-Iabeled difloxacin

摘要

The synthesis of [1-~(15)N,2-~(13)C]-difloxacin, an arylfluoroquinolone antibacterial agent, is reported. As a crucial initial step, the starting materials ethyl 2,4,5-tri-fluorobenzoylacetate, [formyl-~(13)C]-triethyl orthoformate, and [~(15)N]-4-fluoroaniline were reacted to ethyl [~(15)N,3-~(13)C]-3-(4-fluoroanilino)-2-(2,4,5-trifluorobenzoyl)acrylate. After cyclization and ester cleavage, the resulting intermediate was reacted with 1-methylpiperazine to [ 1-~(15)N,2-~(13)C]-1 -(4-fluorophenyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, i.e., [1-~(15)N,2-~(13)C]-difloxacin. The overall yield was 62% based on the non-labeled and 43% based on the labeled starting materials (both used in 1.4 molar excess). The product was identified by ~(1)H-, ~(13)C-, and ~(15)N-NMR spectroscopy and by cochromatography (TLC, HPLC) with an authentic reference; its purity (HPLC) was above 98%. Prior to synthesis of [1-~(15)N,2-~(13)C]-difloxacin, non-labeled difloxacin was synthesized in order to optimize procedures and to identify and characterize all intermediates.