反应详情

温度

120 °C

To a solution of ethyl 2-(2-(((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)amino)-ethoxy)-3-bromo-6-methyl-5-((methylsulfonyl)oxy)benzoate (116f, 0.54 g, 0.86 mmol) in methanol (2 mL) was added sodium hydroxide solution (50% in water, 0.73 g, 9.2 mmol). The reaction mixture was heated at 120° C. in the microwave for 1 hour then diluted with water and acidified with concentrated hydrochloric acid to pH ˜4. The resulting precipitate was collected by vacuum filtration then taken up in N,N-dimethylacetamide (5 mL). N,N-diisopropylethyl amine (0.38 mL, 2.2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.39 g, 1.0 mmol) were added and the reaction was stirred at room temperature overnight. The crude reaction was diluted with water (10 mL) and extracted with dichloromethane (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was dissolved in N,N-dimethylacetamide (5 mL) and cesium carbonate (0.51 g, 1.6 mmol) and 2-iodopropane (0.12 mL, 1.2 mmol) were added. The mixture was heated at 75° C. for 1 hour, cooled to room temperature then diluted with water (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (30% EtOAc/Heptane) to give 4-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-bromo-7-isopropoxy-6-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (116 g, 242 mg, 48% yield) as a clear sticky solid.

1. filtrationThe resulting precipitate was collected by vacuum filtration
2. customThe crude reaction
3. extractionextracted with dichloromethane (2×15 mL)
4. washThe combined organic layers were washed with brine (15 mL)
5. dry with materialdried over magnesium sulfate
6. concentrationconcentrated under vacuum
7. dissolutionThe residue was dissolved in N,N-dimethylacetamide (5 mL)
8. temperatureThe mixture was heated at 75° C. for 1 hour
9. temperaturecooled to room temperature
10. extractionextracted with ethyl acetate (2×15 mL)
11. washThe combined organic layers were washed with brine (15 mL)
12. dry with materialdried over magnesium sulfate
13. concentrationconcentrated under vacuum
14. custompurified by column chromatography (30% EtOAc/Heptane)