Water → (R)-tert-butyl 3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

An oven dried flask was charged with (R)-tert-butyl 3-((R)-hydroxy(phenyl)methyl)-piperidine-1-carboxylate (3.18 g, 10.9 mmol) and 60% NaH in mineral oil (2.19 g, 54.8, 5 equiv). The flask was purged with N2 gas, cooled to 0° C. and anhydrous THF (100 mL) was added slowly. The mixture was allowed to warm to rt slowly. A solution of 3-ethoxypropyl methanesulfonate (6.0 g, 32.9 mmol, 3 equiv) in anhydrous THF (50 mL) was added. The mixture was heated at reflux for 4 h. LC-MS indicated the reaction completed. The reaction mixture was cooled to 0° C. slowly and water was added dropwise to quench the reaction. After separation, the aqueous layer was extracted with ether three times. The combined organic layers were washed with 5% aq HCl, satd aq NaHCO3, brine, and dried over Na2SO4. After concentration, the crude product was purified by flash chromatography on a 120-g silica gel cartridge eluted with a 0-30% EtOAc in hexanes gradient) to afford (R)-tert-butyl 3-((R)-(3-ethoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate (3.70 g, 90%) as a clear oil. Chiral HPLC indicated 95.5% purity. LC-MS (3 min) tR=2.38 min, m/z 400 (M+Na). 1H NMR (CDCl3) δ 7.26 (m, 5H), 4.39 (d, 1H), 3.89 (t, 2H), 3.53-3.40 (m, 4H), 3.38-3.23 (m, 2H), 2.75-2.60 (m, 2H), 1.85-1.47 (m, 4H), 1.45 (s, 9H), 1.40-1.22 (m, 2H), 1.15 (t, 3H), 1.10-0.96 (m, 1H).

Provenance & Evidence