Ammonium Chloride → HCID 131730446, compound

Participants

Reaction Steps

2-(Difluoromethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.2 g, 9.27 mmol) (reference compound 39) was dissolved in methyl THF (60 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (2.256 g, 13.91 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 (2.84 g, 16.69 mmol) suspended in methyl THF (60 mL) and magnesium chloride (1.590 g, 16.69 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 potassium 3-ethoxy-3-oxopropanoate (0.71 g, 4.17 mmol) was suspended in methyl THF (30 mL) under nitrogen atmosphere and magnesium chloride (0.41 g, 4.31 mmol) was added. The suspension was stirred vigorously at 50° C. for 6 h. The suspension was added to the reaction mixture and stirring was continued at room temperature for 17 h. Satd NH4Cl and DCM were added and the phases were separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient of 5:1 to 1:1 of EtOAc in heptane over 15 CV was used as mobile phase. Trans-methyl 2-(difluoromethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (203 mg, 7%) and cis-methyl 2-(difluoromethyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (1.38 g, 48%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.29 (t, 3H), 1.47-2.09 (m, 4H), 2.70-2.83 (m, 1H), 3.05-3.18 (m, 1H), 3.51 (d, 2H), 3.73 (s, 3H), 3.91-4.02 (m, 1H), 4.20 (q, 2H), 4.11-4.30 (m, 1H), 5.91 (dt, 1H). MS m/z 308 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.28 (t, 3H), 1.39-2.32 (m, 4H), 2.88-3.23 (m, 2H), 3.51 (s, 2H), 3.73 (s, 3H), 4.20 (q, 2H), 4.11-4.70 (m, 2H), 5.88 (t, 1H). MS m/z 308 (M+H)+

Provenance & Evidence