合成路线1

Reaction of picolinic acid (I) with hot thionyl chloride in DMF gives 4-chloropyridine-2-carbonyl chloride (II), which is treated with methanol to give ester (III). Subsequent displacement of the methyl ester function with methylamine provides amide (IV). Alternatively, acid chloride (II) is directly converted into amide (IV) by reaction with a cold solution of methylamine. In a different synthetic procedure, amide (IV) can be obtained from 4-chloropyridine (V) via the Menisci reaction using N-methylformamide and hydrogen peroxide in the presence of FeSO4 and H2SO4. Coupling of the amide (IV) with potassium 4-aminophenolate (VI) -obtained by treatment of 4-aminophenol (VII) with potassium tert-butoxide- in hot DMF yields the pyridyloxyaniline (VIII). Aniline (VIII) is finally condensed with either 4-chloro-3-(trifluoromethyl)phenyl isocyanate (IX) in CH2Cl2 or 4-chloro-3-(trifluoromethyl)aniline (X) by means of CDI in CH2Cl2.

合成路线2

合成路线3

Chlorination of picolinic acid (I) with SOCl2 in the presence of DMF at 72 °C gives 4-chloropyridine-2-carbonyl chloride hydrochloride (II), which is then esterified with MeOH to afford the corresponding methyl ester (III). Aminolysis of ester (III) with methylamine in MeOH gives 4-chloro-N-methylpyridine-2-carboxamide (IV) , which can also be prepared by direct amidation of acid chloride (II) with methylamine in THF/MeOH or by Minisci reaction of 4-chloropyridine (V) with N-methylformamide (VI) in the presence of H2SO4, H2O2 and FeSO4·7H2O . Condensation of chloropicolinamide (IV) with 4-amino-3-fluorophenol (VII) –prepared by reduction of 3-fluoro-4-nitrophenol (VIII) by means of H2 and Pd/C in EtOAc– in the presence of t-BuOK in DMAc at 100 °C provides the 4-phenoxypyridine derivative (IX), which is finally coupled with 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (X) in toluene .