Hydrochloric Acid → HCID 131730471, compound

Participants

Reaction Steps

1-(Methoxycarbonyl)-2-(2-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (4.718 g, 13.66 mmol) (reference compound 49) was dissolved in methyl THF (100 mL) and di(1H-imidazol-1-yl)methanone (3.32 g, 20.49 mmol) added. The suspension was stirred at room temperature under nitrogen overnight (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (4.19 g, 24.59 mmol) was suspended in methyl THF (100 mL) and magnesium chloride (2.342 g, 24.59 mmol) added. The suspension was stirred at 50° C. under nitrogen overnight using an oversized stirring bar (flask 2). The yellow suspension in flask 1 was now added to the white suspension in flask 2. The resulting white suspension was stirred under nitrogen at room temperature for 3 days. The mixture was acidified to pH 1 with 3.8 M HCl and MTBE and water added. The phases were separated and the organic phase washed with water and satd NaHCO3. Evaporated the solvents to yield a yellow oil. The diastereomers were separated in 2 runs on Biotage (20%=>50% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-(trifluoromethyl)-benzyl)piperidine-1-carboxylate (0.67 g, 12%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.11 g, 37%) were isolated as yellow oils. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.22 (t, 3H), 1.65-1.99 (m, 4H), 2.65-2.73 (m, 1H), 2.85-2.91 (m, 1H), 2.95-3.02 (m, 1H), 3.15 (ddd, 1H), 3.35 (s, 3H), 3.46 (s, 2H), 4.01 (dd, 1H), 4.12-4.19 (m, 2H), 4.23-4.33 (m, 1H), 7.20 (d, 1H), 7.27 (t, 1H), 7.41 (t, 1H), 7.60 (d, 1H). MS m/z 416 (M+H)+. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.13-1.27 (m, 3H), 1.41-1.97 (m, 5H), 2.79-3.67 (m, 8H), 4.01-4.33 (m, 3H), 4.64 (br. d, 1H), 7.07-7.50 (m, 3H), 7.53-7.62 (m, 1H). MS m/z 416 (M+H)+

Provenance & Evidence