Hydrochloric Acid → 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

Participants

Reaction Conditions

Reaction Steps

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.

Provenance & Evidence