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 (100 mg, 0.20 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (400 μL, 0.40 mmol), and the mixture was stirred for 45 minutes, added with (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (100 mg, 0.85 mmol). After stirring for another 1 hour, the reaction mixture was warmed up to room temperature and stirred for 12 hours. The reaction mixture was added with water (1 mL) and methanol (1 mL), extracted with dichloromethane (100 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, then 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-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamide 7 (60 mg, yield 65.2%) as a yellow solid.

1. stirringAfter stirring for another 1 hour
2. temperaturethe reaction mixture was warmed up to room temperature
3. stirringstirred for 12 hours
4. extractionextracted with dichloromethane (100 mL×3)
5. washThe combined organic extracts were washed with saturated brine (30 mL×2)
6. dry with materialdried over anhydrous sodium sulfate
7. filtrationfiltered
8. concentrationthe filtrate was concentrated under reduced pressure
9. customthe resulting residue was purified by silica gel column chromatography with elution system