Hydrochloric Acid → cis-Methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

Participants

Reaction Steps

2-(Cyclohexyloxymethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.425 g, 8.1 mmol) (reference compound 38) was dissolved in methyl THF (60 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (1.970 g, 12.15 mmol) was added. The suspension was stirred at room temperature for 3 h (flask 1). In a separate flask was potassium 3-ethoxy-3-oxopropanoate (2.482 g, 14.58 mmol) suspended in methyl THF (30 mL) and magnesium chloride (1.388 g, 14.58 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 22 h using an oversized stirring bar (flask 2). The contents of flask 1 was added to flask 2 and the resulting white suspension was stirred at room temperature for 20 h. In a separate flask was potassium 3-ethoxy-3-oxopropanoate (1.241 g, 7.29 mmol) suspended in methyl THF (30 mL) and magnesium chloride (0.694 g, 7.29 mmol) was added. The suspension was stirred at 50° C. for 5 h and then added to the reaction mixture. The mixture was stirred at room temperature for 15 h. 0.1 M HCl and DCM were added and the phases separated. The aqueous phase was extracted with DCM, the combined organic layers filtered through a phase separator and evaporated. The residue was purified via Biotage (5:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). Trans-methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (210 mg, 7%) and cis-methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.13 g, 38%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.14-2.14 (m, 17H), 2.70-2.79 (m, 1H), 3.11-3.30 (m, 2H), 3.34-3.62 (m, 4H), 3.69 (s, 3H), 3.82-3.91 (m, 1H), 4.07-4.24 (m, 3H). MS m/z 370 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.16-2.19 (m, 17H), 2.80-3.10 (m, 2H), 3.16-3.32 (m, 1H), 3.44-3.64 (m, 4H), 3.66-3.74 (m, 3H), 3.97-4.27 (m, 3H), 4.33-4.57 (m, 1H). MS m/z 370 (M+H)+

Provenance & Evidence