反应详情

2-(3,4-Difluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (5.655 g, 18.90 mmol) (reference compound 9) was dissolved in THF (60 mL) and di(1H-imidazol-1-yl)methanone (4.60 g, 28.34 mmol) added. The suspension was stirred at room temperature under nitrogen for 5 h (flask 1). In a separate flask 3-ethoxy-3-oxopropanoic acid, potassium salt (6.47 g, 37.79 mmol) and magnesium chloride (3.60 g, 37.79 mmol) were suspended in THF (60 mL) and stirred with an oversized stirring bar at 50° C. under nitrogen for 5 h. The white suspension in flask 2 was then added to flask 1. The thick white suspension was stirred at room temperature for 18 h. The reaction mixture was acidified by addition of 3 M HCl to pH 1. The solvent was evaporated in vacuo. EtOAc (250 mL) and water were added, shaken and the phases separated. The organic phase was washed with water (200 mL), satd NaHCO3 (200 mL), brine (200 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient from 10% EtOAc in heptane over 2 CV followed by 10% to 40% of EtOAc in heptane over 9 CV was used as mobile phase. Cis-methyl 2-(3,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (5.23 g, 74.9%) and trans-methyl 2-(3,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.502 g, 7.19%) were obtained. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.23-1.30 (m, 3H), 1.74-2.18 (m, 3H), 2.22-2.30 (m, 1H), 2.82-2.91 (m, 1H), 3.24-3.37 (m, 1H), 3.44 (d, 2H), 3.65 (s, 3H), 4.05-4.22 (m, 1H), 4.18 (q, 2H), 4.85-4.98 (m, 1H), 6.90-6.97 (m, 1H), 6.98-7.05 (m, 1H), 7.05-7.14 (m, 1H). MS m/z 370 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.23-1.32 (m, 3H), 1.51-2.02 (m, 3H), 2.42-2.53 (m, 1H), 2.59-2.71 (m, 1H), 2.77-2.88 (m, 1H), 3.47 (d, 2H), 3.76 (s, 3H), 4.19 (q, 2H), 4.14-4.33 (m, 1H), 5.47-5.66 (m, 1H), 6.90-6.97 (m, 1H), 6.99-7.07 (m, 1H), 7.11-7.20 (m, 1H). MS m/z 370 (M+H)+

1. stirringstirred with an oversized stirring bar at 50° C. under nitrogen for 5 h
2. additionThe white suspension in flask 2 was then added to flask 1
3. stirringThe thick white suspension was stirred at room temperature for 18 h
4. customThe solvent was evaporated in vacuo
5. additionEtOAc (250 mL) and water were added
6. stirringshaken
7. customthe phases separated
8. washThe organic phase was washed with water (200 mL), satd NaHCO3 (200 mL), brine (200 mL)
9. customdried with a phase separator
10. customevaporated in vacuo
11. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column