Hydrochloric Acid → HCID 131730407, compound

Participants

Reaction Steps

2-(4-Chloro-3-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.430 g, 4.53 mmol) (reference compound 22) was dissolved in methyl THF (20 mL) and di(1H-imidazol-1-yl)methanone (1.102 g, 6.79 mmol) added. The reaction was stirred at room temperature for 6 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (1.388 g, 8.15 mmol) was suspended in methyl THF (20.00 mL) and magnesium chloride (0.776 g, 8.15 mmol) added. The suspension was stirred at 50° C. for 6 h (flask 2). The white suspension from flask 2 was added to flask 1. A white suspension was formed. The suspension was stirred at room temperature for 18 h. The suspension was acidified to pH 1 with 3 M HCl. MTBE (100 mL) and water (150 mL) were added, shaken and the phases separated. The organic phase was washed with water (150 mL), satd NaHCO3 (150 mL) and brine (150 mL), dried with Na2SO4, filtered and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient of 20% EtOAc in heptane over 2 CV followed by 20-60% of EtOAc in heptane over 10 CV was used as mobile phase. Cis-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.153 g, 66.0%) and trans-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.107 g, 6.12%) were isolated as colorless oils. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.19-1.30 (m, 3H), 1.73-1.97 (m, 2H), 2.00-2.16 (m, 1H), 2.20-2.27 (m, 1H), 2.81-2.89 (m, 1H), 3.24-3.48 (m, 3H), 3.60-3.65 (m, 3H), 4.04-4.20 (m, 3H), 4.84-4.98 (m, 1H), 6.86-7.01 (m, 2H), 7.28-7.34 (m, 1H). MS m/z 386 (M+H)+. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.19-1.29 (m, 3H), 1.38-2.98 (m, 6H), 3.39-3.49 (m, 2H), 3.63-3.82 (m, 3H), 4.00-4.37 (m, 3H), 5.56 (s, br., 1H), 6.86-7.02 (m, 2H), 7.33-7.39 (m, 1H). MS m/z 386 (M+H)+

Provenance & Evidence