To a suspension of NaH (3.5 g, 88.4 mmol) in THF (100 mL) at 0-5° C. was added dropwise a solution of (R)-tert-butyl 3-((2,3-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (9.6 g, 29.5 mmol) in THF (50 mL), the reaction mixture was stirred for 1 h at rt. A solution of ethyl bromoacetate (14.7 g, 88.4 mmol) in THF (50 mL) was added dropwise to the above mixture, and then refluxed for 3-5 h. The reaction mixture was poured into saturated aqueous NH4Cl, then extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica gel chromatography to afford (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (9.5 g, 79%). 1H NMR (CDCl3, 400 MHz) δ 7.22 (m, 1H), 7.08 (m, 2H), 4.62 (d, 2H), 4.33 (d, 2H), 4.18 (q, 3H), 3.95 (m, 4H), 3.82 (d, 2H), 2.77 (m, 4H), 1.88 (m, 3H), 1.44 (s, 9H), 1.26 (t, 3H).
