Hydrochloric Acid → HCID 131730449, compound

Participants

Reaction Steps

2-((4,4-Difluorocyclohexyl)methyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.82 g, 15.09 mmol) (reference compound 40) was dissolved in methyl THF (150 mL), then di(1H-imidazol-1-yl)methanone (3.67 g, 22.64 mmol) was added. The mixture was stirred at room temperature under nitrogen for 3 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (4.62 g, 27.17 mmol) was suspended in methyl THF (150 mL), then magnesium chloride (2.59 g, 27.17 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 3 h using a large magnetic stirring bar (flask 2). The contents of flask 1 was transferred into flask 2. The resulting yellow suspension was stirred under nitrogen at room temperature overnight. The mixture was acidified to pH 1 with 3.8 M HCl, then MTBE (100 mL) and water (100 mL) was added. The phases were separated and the organic layer was washed with water, satd NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated leaving a colourless oil. The residue was purified by automated flash chromatography on Biotage (340 g) with a gradient of 20-50% (8 CV). The column was conditioned at 20% (1 CV). Trans-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (300 mg, 5%) and cis-methyl 2-((4,4-difluoro-cyclohexyl)methyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.66 g, 45%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.15-2.11 (m, 18H), 2.66-2.76 (m, 1H), 2.98-3.09 (m, 1H), 3.50 (s, 2H), 3.70 (s, 3H), 3.83-3.93 (m, 1H), 4.11-4.24 (m, 3H). MS m/z 390 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.15-2.13 (m, 18H), 2.77-2.94 (m, 2H), 3.49 (s, 2H), 3.70 (s, 3H), 3.97-4.33 (m, 3H), 4.34-4.65 (m, 1H).

Provenance & Evidence