Hydrochloric Acid → HCID 131730503, compound

Participants

Reaction Steps

2-(3,5-Di-tert-butylbenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.723 g, 9.56 mmol) (reference compound 61) was dissolved in methyl THF (70 mL) and di(1H-imidazol-1-yl)methanone (2.325 g, 14.34 mmol) added. The suspension was stirred at room temperature under nitrogen overnight (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (2.93 g, 17.20 mmol) was suspended in methyl THF (70.0 mL) and magnesium chloride (1.638 g, 17.20 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 2 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, satd NaHCO3 and water. Evaporated the solvents to yield a yellow oil. The diastereomers were separated in 2 runs on Biotage (0%=>40% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Trans-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.734 g, 17%) and cis-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.027 g, 46%) were isolated as colorless oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.19-1.35 (m, 21H), 1.63-1.99 (m, 4H), 2.62-3.05 (m, 4H), 3.46 (s, 2H), 3.57-3.64 (m, 3H), 3.88-3.97 (m, 1H), 4.07-4.26 (m, 3H), 6.97-7.01 (m, 2H), 7.24-7.28 (m, 1H). MS m/z 460 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.11-1.39 (m, 21H), 1.40-2.02 (m, 4H), 2.52-3.14 (m, 4H), 3.33-3.55 (m, 3H), 3.64 (s, br., 2H), 3.98-4.35 (m, 3H), 4.37-4.80 (m, 1H), 6.91-7.12 (m, 2H), 7.24-7.30 (m, 1H). MS m/z 460 (M+H)+

Provenance & Evidence