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抯 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.

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抯 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.

The intermediate fluoropyrrolidine (XIV) was obtained as follows: Alkylation of ethyl acetoacetate (I) with 1,2-dibromoethane (II) led to the cyclopropane derivative (III). Bromination of (III) provided bromo ketone (IV), which was condensed with (S)-1-phenylethylamine (V), yielding amino ketone (VI). Acylation of amine (VI) with (diethylfosfonyl)fluoroacetyl chloride (VII) gave amide (VIII). Intramolecular Wadsworth-Emmons condensation of keto phosphonate (VIII) in the presence of potassium tert-butoxide produced the pyrrolinone (IX). Catalytic hydrogenation of the pyrroline double bond of (IX), followed by separation of the resultant diastereomeric mixture, furnished pyrrolidinone (X). After saponification of the ethyl ester group of (X), the resulting acid (XI) was subjected to Curtius rearrangement in the presence of DPPA and t-BuOH, giving rise to carbamate (XII). Lactam (XII) reduction by means of borane in THF afforded pyrrolidine (XIII). The N-phenylethyl group of (XIII) was then removed by hydrogenation over Pd/C to furnish the required intermediate pyrrolidine (XIV) (See scheme no. 27170201a, intermediate (IX)).

The quinolone intermediate (X) has been obtained as follows: Acid chloride (I), prepared from 3-methyl-2,4,5-trifluorobenzoic acid (II) and SOCl2, was condensed with ethyl 3-(dimethylamino)acrylate (III) to produce the enamino keto ester (IV). Displacement of the dimethylamino group of (IV) with the cyclopropylamine (V) gave rise to (VI), which was further cyclized to the quinolone (VII) under basic conditions. Acid hydrolysis of ethyl ester (VII) provided carboxylic acid (VIII). Electrophilic nitration of the quinoline ring of (VIII) by means of nitronium fluoroborate yielded the nitro derivative (IX), which was finally reduced to the target aminoquinolone (X) by catalytic hydrogenation (See scheme no. 27170201a, intermediate (X)).