An oven dried flask was charged with (R)-tert-butyl 3-((R)-hydroxy(phenyl)-methyl)piperidine-1-carboxylate (162 mg, 0.557 mmol) and 60% NaH in mineral oil (112 mg, 5 equiv.). The flask was purged with N2 gas, cooled to 0° C. and anhydrous THF (6 mL) was added slowly. After 5 min, the reaction mixture was allowed to warn to rt slowly. A solution of 3-methoxypropyl methanesulfonate (468 mg, 4 equiv.) in anhydrous THF (5 mL) was added. The mixture was heated at reflux for 4 h. LC-MS indicated the reaction was complete. The reaction mixture was cooled to 0° C. and water was added dropwise. After separation, the aqueous layer was extracted with ether (3×). The combined organic layers were washed with 5% aq HCl, satd aq NaHCO3 and brine, and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 4-g silica gel cartridge eluted with a 0-35% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-((R)-(3-methoxypropoxy)(phenyl)-methyl)piperidine-1-carboxylate (196 mg, 97% yield) as a clear oil. LC-MS (3 min) tR=2.19 min, m/z 386 (M+Na).
