反应详情

温度

-78 °C

To a cooled (−78° C.) solution of diisopropylamine (4.9 mL, 0.032 mol) in dry THF (15 mL), n-BuLi (0.030 mol) was added dropwise under argon atmosphere, stirred the reaction mixture for 30 min at −78° C., then for one hour at −20° C. The resulting LDA solution was transferred to a solution of (S)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.7 g, 0.010 mol) in THF (15 mL), via cannula and then stirred for 30 minutes at −78° C., then at 0° C. for one hour. The reaction mixture was once again cooled to −78° C., and methyl iodide (0.54 mL, 0.010 mol) was added over 10 min and then warmed to RT over 2 h. After completion of the reaction, the reaction mixture was quenched with 1N HCl (20 mL) and extracted with DCM. The organic layer was concentrated under reduced pressure using a rotary evaporator to give a crude gum, which was purified through column chromatography (10-20% ethyl acetate:hexane, basic alumina, diameter of column—2.5 cm, Height of alumina—approx. 7 inch) to give the desired (rac)-4,4-difluoro-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.1 g) as a white solid.

1. additionwas added dropwise under argon atmosphere
2. waitfor one hour at −20° C
3. stirringstirred for 30 minutes at −78° C.
4. waitat 0° C. for one hour
5. temperatureThe reaction mixture was once again cooled to −78° C.
6. temperaturewarmed to RT over 2 h
7. customAfter completion of the reaction
8. customthe reaction mixture was quenched with 1N HCl (20 mL)
9. extractionextracted with DCM
10. concentrationThe organic layer was concentrated under reduced pressure
11. customa rotary evaporator
12. customto give a crude gum, which
13. customwas purified through column chromatography (10-20% ethyl acetate:hexane, basic alumina, diameter of column—2.5 cm, Height of alumina—approx. 7 inch)