Hydrochloric Acid → HCID 131730435, compound

Participants

Reaction Steps

1-(Methoxycarbonyl)-2-phenylpiperidine-4-carboxylic acid (5.133 g, 19.50 mmol) (reference compound 34) was dissolved in methyl THF (90 mL) and di(1H-imidazol-1-yl)methanone (4.74 g, 29.24 mmol) was added. The suspension was stirred at room temperature under nitrogen overnight (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (5.97 g, 35.09 mmol) was suspended in methyl THF (90 mL) and magnesium chloride (3.34 g, 35.09 mmol) was added. The suspension was stirred at room temperature under nitrogen overnight (flask 2). Then, the slightly yellow suspension in flask 1 was added to the white suspension in flask 2. The resulting white suspension was stirred under nitrogen at room temperature for 6 h 30 min. In the meantime, potassium 3-ethoxy-3-oxopropanoate (5.97 g, 35.09 mmol) was suspended in methyl THF (90 mL) and magnesium chloride (3.34 g, 35.09 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 2 h and then added to the reaction mixture. The resulting white suspension was stirred at room temperature under nitrogen for 3 days. The mixture was acidified to pH 1 with 1 M HCl and MTBE was added. The phases were separated and the organic phase washed with water, satd NaHCO3 and water. The solvents were evaporated to yield a yellow oil. The diastereoisomers were separated by column chromatography on silica (Biotage, gradient 0%=>50% EtOAc in heptane; Biotage® KP-SIL 340 g column) to yield trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-phenylpiperidine-1-carboxylate (1.14 g, 19%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-phenylpiperidine-1-carboxylate (3.77 g, 62%). Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22-1.31 (m, 3H), 1.84-2.11 (m, 3H), 2.26-2.35 (m, 1H), 2.82-2.92 (m, 1H), 3.28-3.48 (m, 3H), 3.63 (s, 3H), 4.12-4.21 (m, 3H), 4.96-5.04 (m, 1H), 7.17-7.35 (m, 5H). MS m/z 334 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.13-1.25 (m, 3H), 1.44-1.95 (m, 3H), 2.45-2.66 (m, 2H), 2.78-2.88 (m, 1H), 3.39 (s, 2H), 3.68 (s, 3H), 3.98-4.34 (m, 3H), 5.55 (s, br., 1H), 7.10-7.23 (m, 3H), 7.26-7.34 (m, 2H). MS m/z 334 (M+H)+.

Provenance & Evidence