合成路线1

Reaction of 2-acetyl-4-methylpyridine (XVI) with (trimethylsilyl)trifluoromethane (XVII) in the presence of NaOAc in DMSO produces the silylated tertiary alcohol (XVIII), which is further desilylated to alcohol (XIX) by treatment with k2CO3 in MeOH. Treatment of alcohol (XIX) with MsCl and NaH in THF, followed by substitution of the resultant mesylate (XX) with Me3Al in cyclohexane/hexane provides 4-methyl-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine (XXI). Metalation of pyridine (XXI) with LDA (prepared from n-hexyllithium and didiisopropylamine in hexane) in THF, followed by condensation with Weinreb amide (XXII) at –15 °C, and subsequent quenching with H2SO4 in toluene leads to ketone (XXIII). Cyclization of crude ketone (XXIII) with thiourea (XXIV) in the presence of NBS in toluene/EtOH gives the hydrobromide salt 2-aminothiazole (XXV), which is finally converted to the free base intermediate (X) using pyridine in THF . Alternatively, intermediate (XXI) can be obtained by lithiation of 2,4-lutidine (XXVI) with BuLi in methyltetrahydrofuran at –30 °C, followed by condensation with diethyl carbonate (XXVII) in the same solvent, and subsequent dialkylation with MeI to produce the 2-pyridylisobutyrate (XXVIII). Finally, ethyl ester (XXVIII) is hydrolyzed with NaOH in EtOH at 78 °C, and the obtained sodium carboxylate (XXIX) subsequently fluorinated by using SF4 and HF .