[Mg].II.Br[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13].[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH4+].[Cl-]>C(OCC)C>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([CH2:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[F:13])([OH:27])[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1To a suspension of magnesium strip (763 mg) in diethyl ether (7 mL) was added iodine (one crystal) followed by 0.4 mL of 2-(bromomethyl)-1,4-difluorobenzene under nitrogen. The reaction was initiated with a heat gun and 2-(bromomethyl)-1,4-difluorobenzene (5.0 g, 24.25 mmol) in diethyl ether (7 mL) was added slowly. After addition was completed the reaction mixture was refluxed for 100 minutes, cooled to room temperature. To this is reaction mixture a solution of 1-benzylpiperidin-4-one (4.57 g, 24.24 mmol) in diethyl ether (12 mL) was added dropwise with vigorous stirring. After addition was completed the mixture was left at room temperature over night. Saturated aqueous NH4Cl solution (excess) was added and stirred at room temperature until hydrolysis was completed and the mixture was extracted with diethyl ether. The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane, 0.2% NH4OH) to give intermediate 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol (2.74 g) containg large quantities of unknown impurities. To a suspension of NaH (55%, 1.12 g, 26.0 mmol) in toluene (10 mL) was added slowly a solution of 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol in toluene (15 mL). After addition was completed the reaction mixture was stirred at 110° C. (in a pre heated oil bath), after 5 minutes, DMF (9 mL) was added and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.2% NH4OH) to give sub title compound (190 mg). 1H-NMR (CDCl3, 400 MHz): δ 7.39-7.26 (m, 5H); 6.88-6.76 (m, 2H); 6.67 (dd, J=4.2, 8.7 Hz, 1H); 3.59 (s, 2H); 2.99 (s, 2H); 2.68-2.47 (m, 4H); 2.03-1.94 (m, 2H); 1.86-1.76 (m, 2H).
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