Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C(F)(F)F)=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].Cl.Cl.[CH3:22][N:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH:24]1[CH2:25][NH:26][CH2:27]2.C(N(C(C)C)C(C)C)C>CC#N>[CH3:22][N:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH:24]1[CH2:25][N:26]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:16]([F:17])([F:18])[F:19])[CH2:27]2A solution of 296 mg (0.85 mMol) N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (WO 2005/051366; Step 14.2) in 5 ml of CH3CN is added at 5° C. within 30 min to a solution of 213 mg (1.00 mMol) 9-methyl-3,9-diaza-bicyclo[3.3.1]nonane dihydrochloride (synthesized according to Barnes, Roderick A. et al.: J. Am. Chem. Soc. 1953, 75, 975) and 0.7 ml (4 mMol) ethyldiisopropylamine in 10 ml CH3CN. After 1.5 h at 5-10° C., the solvent is evaporated off under reduced pressure. The residue is dissolved in EtOAc and washed with NaHCO3. The aq. phase is re-extracted with EtOAc and the combined organics are washed with water, brine and dried over Na2SO4. The solvent is evaporated off under reduced pressure and the residue is dissolved in a mixture of 10 ml MeOH and 2 ml of a 2 M NaOH solution and stirred at 50° C. for 3 h. The MeOH is evaporated off under reduced pressure, the mixture is diluted with water and extracted 3 times with EtOAc. The combined organics are washed with water and brine and dried (Na2SO4). The solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (SiO2; CH2Cl2/EtOH/NH3 95:4.5:0.5) to afford the title compound as a crystalline solid.
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