Ethyl bromoacetate → (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate

Participants

Reaction Steps

To a stirred suspension of NaH (0.608 g, 15.2 mmol) in THF (100 mL) at 0-5° C. was added dropwise a solution of (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(hydroxy)methyl)-piperidine-1-carboxylate (4.35 g, 12.68 mmol) in THF (30 mL). The reaction mixture was stirred for an additional 1 h at rt. A solution of ethyl bromoacetate (2.52 g, 15.2 mmol) in THF (30 mL) was added dropwise and the mixture was refluxed for 5 h. Tlc showed the starting material had disappeared. The reaction mixture was poured into satd aq NH4Cl, extracted with EtOAc (3×100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (4.368 g, 80%). 1H NMR (400 MHz, CDCl3): 0.861 (m, 2H), 1.25 (m, 6H), 1.38&1.43 (s, 9H), 1.59-2.10 (m, 3H), 2.75 (m, 1H), 3.80 (s, 1H), 3.96 (m, 2H), 4.18 (m, 2H), 4.62 (m, 1H), 7.12 (m, 1H), 7.33 (m, 2H); MS (E/Z): 430 (M+1)

Provenance & Evidence