Hydrochloric Acid → HCID 131730483, compound

Participants

Reaction Steps

To a mixture of 2-(2,5-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.4 g, 23.62 mmol) (reference compound 54) in anhydrous methyl-THF (150 mL) was added di(1H-imidazol-1-yl)methanone (5.74 g, 35.43 mmol) at room temperature under nitrogen. The suspension was stirred at room temperature for 4 h (flask 1). To a mixture of potassium 3-ethoxy-3-oxopropanoate (7.24 g, 42.52 mmol) in anhydrous methyl-THF (150 mL) was added magnesium chloride (4.05 g, 42.52 mmol) at room temperature under nitrogen. The mixture was heated at 50° C. for 4 h, and then allowed to cool to room temperature (flask 2). The suspension in flask 1 was added to the suspension in flask 2. The reaction mixture was stirred at room temperature for 48 h. The mixture was acidified to pH 1 with 4 M HCl and then water and MTBE was added. The organic phase was separated, washed with water, satd NaHCO3, dried and evaporated. The diastereomers were separated by flash chromatography on silica gel using iso-hexane/EtOAc (100:15 and 100:50) as eluent. Trans-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.6 g, 18%) and cis-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (6.2 g, 69%) were isolated as oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.32 (m, 3H), 1.64-2.00 (m, 4H), 2.67-3.15 (m, 4H), 3.48 (s, 2H), 3.58 (s, 3H), 3.87-3.99 (m, 1H), 4.07-4.32 (m, 3H), 6.82-7.01 (m, 3H). Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22-1.32 (m, 3H), 1.45-2.01 (m, 4H), 2.52-3.12 (m, 4H), 3.41-3.74 (m, 5H), 4.04-4.34 (m, 3H), 4.48-4.74 (m, 1H), 6.82-7.06 (m, 3H). MS m/z 384 (M+H)+

Provenance & Evidence