Hydrochloric Acid → HCID 131730385, compound

Participants

Reaction Steps

2-(4-Chlorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.49 g, 11.72 mmol) (reference compound 11) was dissolved in methyl THF (120 mL), then di(1H-imidazol-1-yl)methanone (2.85 g, 17.58 mmol) was added. The mixture was stirred at room temperature under nitrogen for 3 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (3.59 g, 21.10 mmol) was suspended in methyl THF (120 mL), then magnesium chloride (2.009 g, 21.10 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 3 h using a large magnetic stirring bar (flask 2). The contents of flask 1 was transferred to flask 2. The resulting white suspension was stirred under nitrogen at room temperature overnight. The mixture was acidified to pH 1 with 3.8 M HCl, then MTBE (50 mL) and water (50 mL) was added. The phases were separated and the organic layer was washed with water, satd NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated giving a slightly yellow oil. The residue was purified by automated column chromatography on Biotage (340 g) with a gradient of 20-60% EtOAc in n-heptane (8 CV) to yield trans-methyl 2-(4-chlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (205 mg, 5%) and cis-methyl 2-(4-chlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.27 g, 53%). Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.21-1.32 (m, 3H), 1.82-2.15 (m, 3H), 2.22-2.31 (m, 1H), 2.81-2.92 (m, 1H), 3.26-3.49 (m, 3H), 3.63 (s, 3H), 4.06-4.22 (m, 3H), 4.91-4.99 (m, 1H), 7.11-7.18 (m, 2H), 7.24-7.31 (m, 2H). MS m/z 366 (M−H)−. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.16-1.33 (m, 3H), 1.47-2.02 (m, 3H), 2.43-2.70 (m, 2H), 2.75-2.91 (m, 1H), 3.42-3.48 (m, 2H), 3.74 (s, 3H), 4.00-4.39 (m, 3H), 5.45-5.71 (s, br., 1H), 7.14 (d, 2H), 7.29-7.35 (m, 2H). MS m/z 368 (M+H)+.

Provenance & Evidence