合成路线1

Iodination of 3-(trifluoromethyl)-2-pyridinol (I) with NIS in acetonitrile/DMF at 80 °C gives 5-iodo-3-(trifluoromethyl)-2-pyridinol (II), which is treated with POCl3 in DMF at 110 °C under microwave to yield 2-chloro-5-iodo-3-(trifluoromethyl)pyridine (III). Condensation of iodide (III) with 4-methoxybenzylamine (IV) in the presence of Pd2dba3, xantphos and t-BuONa in refluxing toluene or using Pd(OAc)2, BINAP, Et3N and Cs2CO3 in toluene under microwave provides secondary amine (V), which is reacted with Zn(CN)2 in the presence of Pd2dba3 and dppf in DMF at 130 °C to obtain nitrile (VI). N-Deprotection of compound (VI) by means of TFA in CH2Cl2 affords 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile (VII), which is condensed with thiophosgene (VIII) in CHCl3/H2O to yield 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (IX). Finally, isothiocyanate (IX) is submitted to cyclocondensation with nitrile (X) in DMF at 80 °C under microwave, followed by treatment with HCl in refluxing MeOH .
Synthesis of intermediate (X): Condensation of 2,4-difluorobenzoyl chloride (XI) with methylamine (XII) in THF produces 2,4-difluoro-N-methylbenzamide (XIII), which is condensed with 4-methoxybenzylamine (IV) in acetonitrile (1, 3, 4) or DMSO at 190 °C under microwave (2) to give the secondary amine (XIV). N-Deprotection of compound (XIV) by means of TFA in CH2Cl2 provides 4-amino-2-fluoro-N-methylbenzamide (XV), which is finally condensed with cyclobutanone (XVI) and NaCN in AcOH at 80 °C . Alternatively, amino nitrile (X) is obtained by direct condensation of fluoride (XIII) with 1-aminocyclobutanecarbonitrile (XVII) (prepared by Strecker reaction of cyclobutanone (XVI) with NaCN, NH4Cl and NH3 in the presence of MgSO4) .