反应详情

温度

50 °C

Magnesium chloride (7.39 g, 77.58 mmol) and potassium 3-ethoxy-3-oxopropanoate (13.20 g, 77.58 mmol) were suspended in methyl THF (100 mL) under nitrogen and the resulting suspension heated to 50° C. while stirring with an oversized stirring bar for 4 h, then cooled to room temperature (flask 1). In a separate flask was added to cis-1-(methoxycarbonyl)-2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylic acid (14.1 g, 40.83 mmol) (reference compound 46) in methyl THF (100 mL) di(1H-imidazol-1-yl)methanone (10 g, 61.67 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 4 h 30 min (flask 2). Then, the contents of flask 2 is transferred into flask 1 by transfer needle, washed with methyl THF (40 mL). The resulting suspension was stirred at room temperature for 19 h 30 min. Additional magnesium chloride (3.7 g, 38.86 mmol) and potassium 3-ethoxy-3-oxopropanoate (6.6 g, 38.78 mmol) in methyl THF (50 mL) were sonicated at 50° C. for 2 h 30 min, then added to the reaction mixture. Stirred at room temperature for 21 h. The reaction mixture was partitioned between 2 M HCl (ca. 150 mL) and MTBE. The phases were separated. The organic phase was washed with brine and satd NaHCO3, then dried over MgSO4 and evaporated. Crude cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (14.9 g, 88%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.21-1.30 (m, 3H), 1.63-2.04 (m, 4H), 2.67-2.86 (m, 2H), 2.93-3.09 (m, 2H), 3.46 (s, 2H), 3.60 (s, 3H), 3.85-3.98 (m, 1H), 4.11-4.26 (m, 3H), 7.30 (d, 2H), 7.53 (d, 2H). MS m/z 416 (M+H)+

1. temperaturecooled to room temperature (flask 1)
2. stirringThe resulting mixture was stirred at room temperature for 4 h 30 min (flask 2)
3. customThen, the contents of flask 2 is transferred into flask
4. wash1 by transfer needle, washed with methyl THF (40 mL)
5. stirringThe resulting suspension was stirred at room temperature for 19 h 30 min
6. additionadded to the reaction mixture
7. stirringStirred at room temperature for 21 h
8. customThe reaction mixture was partitioned between 2 M HCl (ca. 150 mL) and MTBE
9. customThe phases were separated
10. washThe organic phase was washed with brine
11. dry with materialdried over MgSO4
12. customevaporated