反应详情

A solution of ethyl 3-[((3S,4S)-3-(tert-butoxycarbonyl)amino-4methylpyrrolidin-1-yl)-2,5-difluoro-3-methylphenyl]-3-oxopropionate (2.58 g, 5.86 mmol) and N,N-dimethylformamide dimethylformamide dimethylacetal (3.99 mL, 30.0 mmol) in benzene (40 mL) was refluxed for 4 hours. The temperature of the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (20 mL), and cyclopropylamine (693 μL, 10.0 mmol) was added dropwise to the solution under cooling with ice, followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in 1,4-dioxane (30 mL), and 55% oily sodium hydride (436 mg, 10.0 mmol) was added to the solution at room temperature, followed by stirring for 2 hours. Subsequently, the resultant mixture was poured to an ice-cooling saturated aqueous ammonium chloride solution. The resultant mixture was extracted with ethyl acetate (200 mL×2), washed by saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (chloroform:methanol=25:1), to thereby yield the title compound (957 mg, 33.4%).

1. concentrationThe reaction mixture was concentrated under reduced pressure
2. dissolutionThe obtained residue was dissolved in dichloromethane (20 mL)
3. temperatureunder cooling with ice
4. concentrationThe reaction mixture was concentrated under reduced pressure
5. dissolutionThe obtained residue was dissolved in 1,4-dioxane (30 mL)
6. stirringby stirring for 2 hours
7. extractionThe resultant mixture was extracted with ethyl acetate (200 mL×2)
8. washwashed by saturated brine (100 mL)
9. dry with materialdried over anhydrous sodium sulfate
10. filtrationAfter filtration
11. concentrationthe filtrate was concentrated under reduced pressure
12. customThe obtained residue was purified through silica gel column chromatography (chloroform:methanol=25:1)