A New Generation Of Antimicrobial Drug Intermediates 2 - Methoxy - 7 - Fluoro - 8 - Bromine - [1, 5) The Synthesis Of Nalidixic

8-Bromo-7-fluoro-2-methoxy-1,5-naphthyridine is the key intermediate for the synthesis of novel naphthyridine antibiotics. In the first step,2-chloro-6-methoxypyridine was successfully converted to8-bromo-7-fluoro-2-methoxy-1,5-naphthyridine via nitration, Stille coupling, electrophilic fluorination, enamine synthesis, reduction/cyclization reaction and bromination. The optimal condition for each step was screened by examining the reagents, reaction temperature and reaction time. The target compound was obtained in63.8%overall yield for the six steps. All of the involved intermediates were identified by1H NMR and LC-MS. The final product was fully characterized by1H NMR,13C NMR,19F NMR, IR, LC-MS and microelemental analysis.In the Stille coupling reaction, the solvent was screened and the problem of coordination action between acetonitrile and catalyst was solved successfully. The use of one-pot protocol for accomplishing the reduction/cyclization provided several advantages, such as no interfering with the double bond in the hydrogenation reaction and improving the yield from76.9%in two steps to96.1%.This synthetic route has been scaled up to one hundred-gram reaction. Thus, the developed route represents an appealing protocol for preparation of the target1,5-naphthyridine molecule.