Hydrochloric Acid → HCID 131730500, compound

Participants

Reaction Steps

1-(Methoxycarbonyl)-2-(3,4,5-trifluorobenzyl)piperidine-4-carboxylic acid (3.42 g, 10.32 mmol) (reference compound 60) was dissolved in methyl THF (60 mL) and di(1H-imidazol-1-yl)methanone (2.51 g, 15.49 mmol) added. The suspension was stirred at room temperature under nitrogen for 6 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (3.16 g, 18.58 mmol) was suspended in methyl THF (60.0 mL) and magnesium chloride (1.769 g, 18.58 mmol) added. The suspension was stirred under nitrogen for 6 h (flask 2). The white suspension in flask 2 was then added to the brown suspension in flask 1. The resulting suspension was stirred at room temperature for 18 h. The mixture was acidified to pH 1 with 3 M HCl. MTBE (250 mL) and water (250 mL) were added, shaken and the phases separated. The organic phase was washed with water (250 mL), satd NaHCO3 (250 mL) and brine (250 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 20% EtOAc in heptane over 2 CV followed by 20% to 60% of EtOAc in heptane over 8 CV was used as mobile phase. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorobenzyl)-piperidine-1-carboxylate (0.309 g, 7.46%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (1.967 g, 47.5%) were isolated. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.19-1.30 (m, 3H), 1.62-1.96 (m, 4H), 2.61-2.68 (m, 1H), 2.68-2.76 (m, 1H), 2.80-2.87 (m, 1H), 2.96-3.04 (m, 1H), 3.46 (s, 2H), 3.65 (s, 3H), 3.83-3.94 (m, 1H), 4.09-4.20 (m, 3H), 6.76-6.84 (m, 2H). MS m/z 402 (M+H)+. Trans-isomer: MS m/z 402 (M+H)+

Provenance & Evidence