Hydrochloric Acid → HCID 131730421, compound

Participants

Reaction Steps

2-(4-Chloro-3,5-difluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.6 g, 4.79 mmol) (reference compound 28) was dissolved in methyl THF (30 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (1.166 g, 7.19 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 (1.469 g, 8.63 mmol) suspended in methyl THF (15 mL) and magnesium chloride (0.822 g, 8.63 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 7 h using an oversized stirring bar (flask 2). To flask 2 the contents of flask 1 was added and the resulting white suspension was stirred at room temperature for 20 h. In a separate flask was potassium 3-ethoxy-3-oxopropanoate (0.734 g, 4.32 mmol) suspended in methyl THF (15 mL) and magnesium chloride (0.411 g, 4.32 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 by column chromatography on silica (2:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). Cis-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.448 g, 74.8%) and trans-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.178 g, 9.19%) were isolated as colorless oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.23-1.32 (m, 3H), 1.74-2.19 (m, 3H), 2.20-2.30 (m, 1H), 2.82-2.92 (m, 1H), 3.23-3.34 (m, 1H), 3.46 (s, 2H), 3.63-3.69 (m, 3H), 4.04-4.23 (m, 3H), 4.84-4.95 (m, 1H), 6.81-6.90 (m, 2H). MS m/z 404 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.33 (m, 3H), 1.48-1.92 (m, 2H), 1.92-2.04 (m, 1H), 2.36-2.51 (m, 1H), 2.54-2.70 (m, 1H), 2.82 (dt, 1H), 3.47 (d, 2H), 3.73 (s, 3H), 4.08-4.45 (m, 3H), 5.56 (s, br., 1H), 6.86 (d, 2H). MS m/z 404 (M+H)+

Provenance & Evidence