反应详情

温度

50 °C

Magnesium chloride (4.55 g, 47.75 mmol) and potassium 3-ethoxy-3-oxopropanoate (8 g, 47.00 mmol) were dissolved in methyl THF (100 mL) under nitrogen and the resulting suspension was stirred at 50° C. with an oversized stirring bar for 6 h 30 min, then cooled to room temperature (flask 1). To a suspension of 2-(2,4-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.48 g, 23.88 mmol) (reference compound 57) in methyl THF (100 mL) was added di(1H-imidazol-1-yl)methanone (5.81 g, 35.81 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 1 h 20 min (flask 2). The contents of flask 2 is transferred into flask 1 by transfer needle. Wash with methyl THF (30 mL). The resulting suspension was stirred at room temperature for 16 h. 3.8 M HCl was added (ca. 200 mL) and the resulting biphasic mixture stirred vigorously for 30 min. Water and MTBE were added and the phases separated. The organic phase was washed with water, satd NaHCO3 and water, then dried over MgSO4 and evaporated. The residue was purified via Biotage (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes, then 20%=>60% over 7 CV). Trans-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.18 g, 13%) and cis-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (4.17 g, 45%) were isolated as yellow oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.32 (m, 3H), 1.59-1.99 (m, 4H), 2.66-3.12 (m, 4H), 3.48 (s, 2H), 3.55 (s, 3H), 3.89-3.98 (m, 1H), 4.07-4.29 (m, 3H), 6.71-6.83 (m, 2H), 7.05-7.17 (m, 1H). MS m/z 384 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.19-1.35 (m, 3H), 1.42-2.02 (m, 4H), 2.65-3.11 (m, 4H), 3.38-3.75 (m, 5H), 4.02-4.34 (m, 3H), 4.45-4.70 (m, 1H), 6.73-6.89 (m, 2H), 7.03-7.34 (m, 1H). MS m/z 384 (M+H)+

1. temperaturecooled to room temperature (flask 1)
2. stirringThe resulting mixture was stirred at room temperature for 1 h 20 min (flask 2)
3. customThe contents of flask 2 is transferred into flask
4. washWash with methyl THF (30 mL)
5. stirringThe resulting suspension was stirred at room temperature for 16 h
6. addition3.8 M HCl was added (ca. 200 mL)
7. stirringthe resulting biphasic mixture stirred vigorously for 30 min
8. additionWater and MTBE were added
9. customthe phases separated
10. washThe organic phase was washed with water
11. dry with materialdried over MgSO4
12. customevaporated
13. customThe residue was purified via Biotage (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes