反应详情

温度

-10 °C

Charge a 5 L, 3-neck round bottom flask equipped with a magnetic stirrer, thermal couple, addition funnel and N2 inlet with diisopropylamine (176 mL, 1265 mmoles) and 2-methyltetrahydrofuran (500 mL). Cool the solution to ˜−10° C. (salt/ice bath) with stirring and add a solution of n-BuLi (2.5 M in hexanes, 504 mL, 1259 mmoles) drop wise while maintaining a temperature at or below 0° C. Rinse the addition funnel with 2-methyltetrahydrofuran (25 mL). Stir the solution for about 15 min, at ˜−5° C. Add a solution of N-benzyl-2-pyrrolidinone (100.8 g, 575 2 mmoles), ethyl isovalerate (90 g, 690 mmoles) in 2-Me-THF (500 mL) drop wise at a rate to maintain a temperature at or below 5° C. to provide a yellow slurry. Stir the reaction mixture about 1 hour at −5° C., add heptane (1 L) drop wise, and stir for an additional 1 hr. at −5° C. Collect the solid by filtration through a medium fritted funnel, wash with a 1:1 solution of 2-methyltetrahydrofuran/heptane (250 mL) followed by heptane (250 mL) and air dry until the solid becomes powder-like. Place the yellow solid into a 5 L, 3-neck round bottom flask equipped with a magnetic stirrer and add MTBE (1 L) and 10% citric acid (1 L). Stir the mixture for about 1 hour at room temperature to provide a homogeneous mixture. Separate the layers and wash the organic layer with H2O (2×500 mL), followed by brine (500 mL). Dry over Na2SO4, filter and concentrate to give the crude intermediate (128 g) as an orange oil. A Kuegelrohr distillation removes the major impurity from the crude material to yield the desired intermediate as a dark orange oil (117.4 g, 452.7 mmoles, 78.7% yield). 1H NMR (300 MHz, CDCl3) δ 7.38-7.16 (m, 5H), 4.55-4.35 (m, 2H), 3.62 (dd, 1H, J=5.86, 9.37 Hz), 3.38-3.14 (m, 2H), 2.92-2.8 (m, 1H), 2.64-2.42 (m, 2H), 2.28-2.11 (m, 1H), 2.08-1.93 (m, 1H), 0.96 (d, 3H, J=7.03 Hz) 0.93 (d, 3H, J=7.04 Hz). GC/MS=260 (M+1).

1. additionCharge a 5 L, 3-neck round bottom flask
2. customequipped with a magnetic stirrer
3. temperaturewhile maintaining a temperature at or below 0° C
4. washRinse the addition funnel with 2-methyltetrahydrofuran (25 mL)
5. stirringStir the solution for about 15 min
6. customat ˜−5° C
7. temperatureto maintain a temperature at or below 5° C.
8. customto provide a yellow slurry
9. stirringStir the reaction mixture about 1 hour at −5° C.
10. stirringstir for an additional 1 hr
11. customat −5° C
12. customCollect the solid
13. filtrationby filtration through a medium fritted funnel
14. washwash with a 1:1 solution of 2-methyltetrahydrofuran/heptane (250 mL)
15. customdry until the solid
16. customequipped with a magnetic stirrer
17. additionadd MTBE (1 L) and 10% citric acid (1 L)
18. stirringStir the mixture for about 1 hour at room temperature
19. customto provide a homogeneous mixture
20. customSeparate the layers
21. washwash the organic layer with H2O (2×500 mL)
22. dry with materialDry over Na2SO4
23. filtrationfilter
24. concentrationconcentrate
25. customto give the crude intermediate (128 g) as an orange oil
26. distillationA Kuegelrohr distillation
27. customremoves the major impurity from the crude material