合成路线1

Coupling of 6-fluoro-4-nitro-2-benzofuran-1(3H)-one (I) with 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (II) in the presence of Et3N in2-Me-THF affords the (Z)-alkene (III), which by reaction with MeOH in the presence of HCl affords the methyl ester (IV). Condensation of ketone (IV) with 4-fluorobenzaldehyde (V) in the presence of L-proline in DMSO at 45 °C gives the (E)-propene derivative (VI), which then cyclizes by hydrogenation over Pd/C in MeOH to yield the 3,4-dihydroquinolin-1(2H)-ol derivative (VII). Reduction of the hydroxylamine derivative (VII) by means of Fe in the presence of HCl in refluxing MeOH provides the tetrahydroquinolone derivative (VIII), which can also be obtained by reductive cyclization of the nitro derivative (VI) with Fe in the presence of HCl in refluxing MeOH . Alternatively, compound (VIII) can be obtained by reductive cyclocondensation of intermediate (IV) with 4-fluorobenzaldehyde (V) by means of either TiCl3 in THF/MeOH at 30-50 °C, Fe in the presence of HCl in MeOH/THF at 60 °C, SnCl2 in the presence of HCl in MeOH/THF at 45 ° or by hydrogenation over Pd/C in MeOH/AcOH. Chiral resolution of the methyl ester (VIII) by supercritical fluid chromatography (SFC) or simulated moving bed (SMB) unit in MeOH provides the desired (2S,3S)-isomer (IX), which finally reacts with NH2NH2·H2O in EtOH or acetonitrile or MeOH. Alternatively, cyclocondensation of the methyl ester (VIII) with NH2NH2·H2O in MeOH gives the racemate (X) , which is finally resolved through the SFC unit .