[H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2F)([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)C=O.O>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1To a stirring suspension of magnesium strip (763 mg) in diethyl ether (7 mL) was added a crystal of iodine followed by 0.4 mL of 2-(bromomethyl)-1,4-difluorobenzene under nitrogen. The reaction was initiated with a high intensity heat gun, then 2-(bromomethyl)-1,4-difluorobenzene (5.0 g, 24.25 mmol) in diethyl ether (7 mL) was added at such a rate that a gentle reflux was maintained. After addition was complete the reaction mixture was kept on stirring at reflux for 100 min, cooled to room temperature. To this reaction mixture a solution of 1-benzylpiperidin-4-one (4.57 g, 24.25 mmol) in diethyl ether (12 mL) was added dropwise with vigorous stirring. After addition was complete a white cake was formed which was left overnight at room temperature. The cake was hydrolized by treatment with aqueous ammonium chloride (NH4Cl) solution, extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane, 0.1% ammonium hydroxide, NH4OH) to give intermediate compound 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol (2.74 g) containing large amount of impurities. To a suspension of sodium hydride (NaH) (55%, 1.12 g, 26.0 mmol) in toluene (10 mL) was slowly added a solution of 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol in toluene (15 mL). After addition was complete, the reaction mixture was kept on stirring at 110° C. (in a preheated oil bath), after 5 minutes dimethylformamide (9 mL) was added and stirring was continued at reflux for 2 h. The reaction mixture was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate. The organic layer was dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.1% ammonium hydroxide, NH4OH) to give the subtitled compound (190 mg).
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