反应详情

2-(2,6-Difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.72 g, 15.07 mmol) (reference compound 55) was dissolved in methyl THF (108 mL) and di(1H-imidazol-1-yl)methanone (3.66 g, 22.60 mmol) was added. The suspension was stirred at room temperature for 3 h 45 min under nitrogen (flask 1). In a separate flask was to a suspension of potassium 3-ethoxy-3-oxopropanoate (4.62 g, 27.12 mmol) in methyl THF (108 mL) magnesium chloride (2.58 g, 27.12 mmol) added. The suspension was stirred with a large stirring bar for 3.5 h at 50° C. under nitrogen (flask 2). The suspension in flask 1 was added to the suspension in flask 2 and the reaction mixture was then stirred at room temperature overnight. The reaction mixture was acidified to pH 1 with 2 M HCl. MTBE and water were added and the phases were separated. The organic phase was washed with water, satd NaHCO3 and water before it was dried and concentrated. The residue was purified in 2 runs by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient from 15% to 50% of EtOAc in heptane over 8 CV (3 CV initial waste+5 CV collected) was used as mobile phase. Trans-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.405 g, 7%) and cis-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.404 g, 41%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.33 (m, 3H), 1.68-2.05 (m, 4H), 2.65-2.89 (m, 2H), 2.93-3.16 (m, 2H), 3.49 (s, 5H), 3.96 (dd, 1H), 4.14-4.22 (m, 2H), 4.27-4.40 (m, 1H), 6.77-6.89 (m, 2H), 7.09-7.20 (m, 1H). MS m/z 384 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22-1.34 (m, 3H), 1.41-2.01 (m, 4H), 2.75-3.20 (m, 4H), 3.37-3.70 (m, 5H), 4.02-4.32 (m, 3H), 4.55-4.85 (m, 1H), 6.81-6.92 (m, 2H), 7.11-7.23 (m, 1H). MS m/z 384 (M+H)+

1. additionadded
2. stirringThe suspension was stirred with a large stirring bar for 3.5 h at 50° C. under nitrogen (flask 2)
3. additionThe suspension in flask 1 was added to the suspension in flask 2
4. stirringthe reaction mixture was then stirred at room temperature overnight
5. customthe phases were separated
6. washThe organic phase was washed with water
7. customwas dried
8. concentrationconcentrated
9. customThe residue was purified in 2 runs by automated flash chromatography on a Biotage® KP-SIL 340 g column
10. customA gradient from 15% to 50% of EtOAc in heptane over 8 CV (3 CV initial waste+5 CV collected)