Ethyl 1-Cbz-3-ethylpiperidine-3-carboxylate synthesis

Yield:1338930-81-6 7.28 g

Reaction Conditions:

with triethylamine in tetrahydrofuran at 0 - 20;Inert atmosphere;

Steps:

3.1. 1-Benzyl 3-ethyl 3-ethylpiperidine-1,3-dicarboxylate (10b)

The 3-ethyl 3-ethylpiperidin carboxylate 9b was synthesized as reported in the literature.¹⁹ To a solution of ethyl nipecotate 8 (7.00 g; 44.6 mmol) in THF (10 mL), was added dropwise sodium hexamethyl disilazane (NaHMDS) in THF (1.05 M, 50 ml) at -20 °C to -10 °C, and the resulting solution was stirred for 1 h. EtI (6.95 g; 44.6 mmol) was then added to the solution while keeping the temperature at -10 °C to -20 °C, and the resulting mixture was allowed to warm to room temperature without the cold bath. The reaction mixture was next quenched by H₂O and separated, and the organic layer was dried over Na₂SO₄ and concentrated to afford the intermediate 9b (8.20 g), which was used in the next reaction without purification. To a solution of 9b and triethylamine (TEA) (6.75 g) in THF was slowly added carbobenzyloxy chloride (CbzCl) (6.4 ml) at 0 °C, and the resulting mixture was allowed to warm to room temperature with the ice-bath. The reaction mixture was then filtered through Celite, washed with satd NH₄Cl aq and brine, dried over Na₂SO₄, and the filtrate was concentrated. The residue was purified by SiO₂ column chromatography (Hexane/EtOAc = 10/1 to 5/1) to give 7.28 g (51%) of 10b as a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 0.82 (3H, bs), 1.18 (3H, br s), 1.40-1.70 (5H, m), 2.04-2.10 (1H, m), 3.10-3.25 (2H, m), 3.60-3.65 (1H, m), 4.00-4.18 (3H, m), 5.12 (2H, s), 7.27-7.40 (5H, m). LRMS (ESI⁺): m/z 414.2.

References:

Nishio, Yukihiro;Kimura, Hidenori;Sawada, Naoyuki;Sugaru, Eiji;Horiguchi, Masakuni;Ono, Michiko;Furuta, Yudai;Sakai, Mutsuko;Masui, Yumi;Otani, Misato;Hashizuka, Takahiko;Honda, Yayoi;Deguchi, Jiro;Nakagawa, Tsutomu;Nakahira, Hiroyuki [Bioorganic and Medicinal Chemistry,2011,vol. 19,# 18,p. 5490 - 5499] Location in patent:experimental part