反应详情

温度

-78 °C

N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 7b (300 mg, 0.59 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (1.2 mL, 1.18 mmol) was added dropwise. After the mixture was stirred for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (133 mg, 1.18 mmol) was added, and the mixture was stirred for another 1 hour, then warm up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 9 (130 mg, yield 47.3%) as a yellow solid.

1. stirringthe mixture was stirred for another 1 hour
2. temperaturewarm up to room temperature
3. stirringstirred for 12 hours
4. concentrationThe reaction mixture was concentrated
5. additionadded with 10 mL of water
6. extractionextracted with dichloromethane (25 mL×3)
7. washThe combined organic extracts were washed with saturated brine (30 mL×2)
8. dry with materialdried over anhydrous sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated under reduced pressure
11. customthe resulting residue was purified by silica gel column chromatography with elution system