合成路线1

The chiral pyrrolidinone derivative (I) was fluorinated to (II) by means of N-fluoro benzenesulfonimide in the presence of LDA at -78 C. The trans-fluoroderivative (II) was then epimerized to the cis-isomer (III) upon enolization with LDA in cold THF, followed by reprotonation with 2,6-di-tert-butylphenol. After conversion of (III) to the corresponding thiolactam (IV) using Lawesson’s reagent, desulfurization of (IV) in the presence of Raney-Ni yielded pyrrolidine (V). The 1-phenylethyl group of (V) was then removed by dealkylation with benzyl chloroformate, yielding carbamate (VI). Ester hydrolysis of (VI) and subsequent carbonyldiimidazole-mediated condensation with ammonia gave rise to amide (VII). Hofmann rearrangement of amide (VII) in the presence of lead tetraacetate and tert-butanol generated the tert-butyl carbamate (VIII). The N-benzyloxycarbonyl protecting group of (VIII) was then removed by hydrogenolysis over Pd/C to give amine (IX), which was condensed with the difluoroquinolone (X) to provide adduct (XI). The N-Boc group of (XI) was finally cleaved by treatment with aqueous HCl.