反应详情

Acryloyl chloride (100 μL, 0.986 mmol) and triethylamine (689 μL, 4.93 mmol) were added to a solution of hydroxy-pyrrolidine-2,5-dione (commercially available, 227 mg, 1.973 mmol) in methylene chloride (anhydrous, 2 mL), and the mixture was stirred at room temperature for 30 minutes. 5-aminomethyl-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (150 mg, 0.355 mmol) obtained in Step A was added to this solution, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was evaporated under reduced pressure, and the resultant residue was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-(acryloylamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid as a white solid. This product was confirmed for the structure by LC/MS. LC/MS (positive mode) m/z 477 (M+1). This compound was dissolved in methylene chloride (anhydrous, 10 mL) under argon flow. N,N-diisopropylethylamine (250 μL, 1.42 mmol), O-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-hydroxylamine (135 mg, 0.71 mmol), 1-hydroxy-1H-benzotriazole (71 mg, 0.533 mmol), and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (102 mg, 0.533 mmol) were added sequentially to the solution. The mixture was stirred at room temperature for 20 hours.

1. stirringthe mixture was stirred for 1 hour
2. customAfter completion of the reaction
3. customthe reaction mixture was evaporated under reduced pressure
4. extractionthe resultant residue was extracted with ethyl acetate
5. washThe organic layer was washed sequentially with water and saturated brine
6. dry with materialdried over anhydrous sodium sulfate
7. concentrationconcentrated under reduced pressure