合成路线1

Synthesis of intermediate (XI): Treatment of 2,4-difluorophenol (I) with triethylamine and ethyl chloroformate (II) in dichloromethane yields O-ethoxycarbonyl-2,4-difluorophenol (III), which is then nitrated by means of HNO3/H2SO4 and hydrolyzed with Na2CO3 or NaHCO3 in MeOH/H2O to provide (IV). The nitro group of (IV) is then hydrogenated over Pd/C in EtOAc to afford 5-amino-2,4-difluorophenol (V), which is N-protected by reaction with pivaloyl chloride (VI) in pyridine to furnish pivaloylamino derivative (VII). Treatment of (VII) with 3,4-dihydro-2H pyran (VIII) and camphorsulfonic acid (CSA) in dichloromethane gives O-protected derivative (IX), which is converted into ethyl benzoate (X) by first reaction in THF with hexamethylphosphoric triamide (HMPA) and n-BuLi in hexane, followed by treatment with ethyl chloroformate (II). Finally, methylation of (X) by means of iodomethane (MeI) and LDA in THF/hexane yields intermediate (XI). Alternatively, intermediate (XI) can be also obtained by following this pathway: lithiation of derivative (IX) with LDA followed by treatment with TMSCl in THF affords trimethylsilylated compound (XII), which is converted into ethyl benzoate (XIII) by reaction with BuLi and ethyl chloroformate (II). Finally, TMS removal of (XIII) is achieved by treatment with tetrabutyl ammonium fluoride (TBAF) in THF to furnish derivative (X), which is methylated as described above.