合成路线1

Nitration of 2,3,4-trifluorobenzoic acid (I) using HNO3 and H2SO4 gives 2,3,4-trifluoro-5-nitrobenzoic acid (II), which by displacement with NH4OH in H2O at 0 °C yields 4-amino-2,3-difluoro-5-nitrobenzoic acid (III). Fisher esterification of acid (III) with Me3SiCHN2 in THF/MeOH at 0 °C affords 4-amino-2,3-difluoro-5-nitrobezoic acid methyl ester (IV), which is condensed with 2-fluoroaniline (V) in xylene at 140 °C to provide methyl 4-amino-3-fluoro-2-(2-fluorophenylamino)-5-nitrobenzoic acid methyl ester (VI). Reduction and cyclization of intermediate (VI) using formic acid and Pd(OH)2/C in EtOH at 95 °C generates methyl 4-fluoro-5-(2-fluorophenylamino)-benzimidazole-6-carboxylate (VII), which by bromination with NBS and p-TsOH in DMF produces the bromo derivative (VIII). N-Methylation of compound (VIII) with methyl iodide by means of K2CO3 in DMF at 75 °C gives compound (IX), which is hydrolyzed with NaOH in THF/H2O to yield the free carboxylic acid (X). Condensation of carboxylic acid (X) with O-[2-(vinyloxy)ethyl]hydroxylamine (XI) using HOBt, Et3N and EDC in DMF affords amide (XII), which is finally treated with HCl in EtOH (1).
Intermediate O-[2-(vinyloxy)ethyl]hydroxylamine (XI) is prepared by Mitsnoubu reaction of 2-(vinyloxy)ethanol (XIII) with N-hydroxy - phthalimide (XIV) using PPh3 and DEAD in THF at 0 °C to give 2-[2-(vinyloxy)ethoxy]-1H-isoindole-1,3(2H)-dione (XV), which is finally treated with MeNHNH2 in CH2Cl2 .