Hydrochloric Acid → HCID 131730382, compound

Participants

Reaction Steps

2-(4-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (8.4 g, 29.86 mmol) (reference compound 10) was dissolved in methyl THF (120 mL) and di(1H-imidazol-1-yl)methanone (7.26 g, 44.80 mmol) added. The suspension was stirred at room temperature under nitrogen for 2 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (9.15 g, 53.75 mmol) was suspended in methyl THF (120 mL) and magnesium chloride (5.12 g, 53.75 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3 h using an oversized stirring bar (flask 2). The beige suspension in flask 1 was now added to the white suspension in flask 2. The resulting beige suspension was stirred under nitrogen at room temperature for 23 h. The mixture was acidified to pH 1 with 3 M HCl (50 mL) and MTBE (200 mL) and water (70 mL) were added. The phases were separated and the organic phase extracted with water (30 mL), satd NaHCO3 (30 mL) and water (30 mL), dried over anhydrous Na2SO4 and evaporated. The diastereoisomers were separated on Biotage (20%=>55% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column) to yield trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenyl)piperidine-1-carboxylate (1.26 g, 12%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenyl)piperidine-1-carboxylate (6.58 g, 62%) as colorless oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.27 (t, 3H), 1.83-2.14 (m, 3H), 2.27 (ddd, 1H), 2.80-2.93 (m, 1H), 3.26-3.50 (m, 3H), 3.64 (s, 3H), 4.10-4.22 (m, 3H), 4.93-5.01 (m, 1H), 6.95-7.05 (m, 2H), 7.14-7.22 (m, 2H). MS m/z 352 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.18-1.33 (m, 3H), 1.50-1.89 (m, 2H), 1.90-2.02 (m, 1H), 2.47-2.59 (m, 1H), 2.59-2.72 (m, 1H), 2.79-2.91 (m, 1H), 3.47 (s, 2H), 3.76 (s, 3H), 4.08-4.30 (m, 3H), 5.50-5.69 (s, br., 1H), 6.98-7.10 (m, 2H), 7.10-7.23 (m, 2H). MS m/z 350 (M−H)−

Provenance & Evidence