Reaction of 2,3,5,6-tetrafluoropyridine (I) with benzylamine (II) in refluxing acetonitrile gives 2-(benzyl-amino)-3,5,6-trifluoropyridine (III), which is debenzylated with H2 over Pd/C in methanol to yield 3,5,6-trifluoropyridine-2-amine (IV). Reaction of amine (IV) with 4-methoxybenzylamine (V) in N-methylpyrrolidone at 140 C affords 3,5-difluoro-6-(4-methoxybenzylamino)pyridine-2-amine (VI), which is cyclized with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) ?obtained by condensation of 2-(3-chloro-2,4,5-trifluorobenzoyl)acetic acid ethyl ester (VIII) with triethyl orthoformate (IX) by means of acetic anhydride ?in hot DMF in the presence of K2CO3 to provide the N-protected aminoquinolone derivative (X). Reaction of quinolone (X) with HCl in refluxing acetic acid gives 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI), which is finally condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in refluxing acetonitrile.
Reaction of 2,3,5,6-tetrafluoropyridine (I) with ammonia in formamide gives the 2-aminopyridine derivative (IV), which is condensed with tert-butylamine (XIII) in N-methylpyrrolidone to yield 6-(tert-butylamino)-3,5-di- fluoropyridine-2-amine (XIV). Condensation of amine (XIV) with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) gives the adduct (XV), which is cyclized by means of K2CO3 in DMF to afford the quinolone derivative (XVI). Treatment of quinolone (XVI) with HCl in AcOH produces simultaneous ester hydrolysis and tert-butyl group removal, providing 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI). Finally, this compound is condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in DMF.