Reaction Steps
To a solution of 7-bromo-2,3-difluoro-9H-xanthen-9-one (3.1 g, 9.97 mmol) and 2,2,2-trifluoroethanol (1.445 mL, 19.93 mmol) in DMF (33 mL) at 0° C. was added sodium hydride (0.598 g, 14.95 mmol) slowly in portions. After addition, the mixture was stirred at RT for overnight. Then, H2O (100 mL) was added slowly and the mixture was extracted with EtOAc (1×100 mL). The organic layer was collected, dried over MgSO4, and concentrated. The residue was then washed with hexane (1×100 mL) to give 2.76 g of 7-bromo-2-fluoro-3-(2,2,2-trifluoroethoxy)-9H-xanthen-9-one as a light yellow solid. MS (ESI, positive ion) m/z: 390.9, 392.9 (M+1). Step 2: To a solution of 7-bromo-2-fluoro-3-(2,2,2-trifluoroethoxy)-9H-xanthen-9-one (2.00 g, 5.11 mmol) in THF (25 mL) at 0° C. was added methylmagnesium bromide 3.0 M in diethyl ether (3.41 mL, 10.23 mmol) slowly. After addition, the mixture was stirred at RT for overnight. Then, the mixture was cooled to 0° C. and saturated ammonium chloride (50 mL) was added slowly. The mixture was then stirred at RT for 15 min. Then, the organic layer was collected and the aqueous layer was extracted with EtOAc (1×50 mL). The combined organic extracts were dried over MgSO4, concentrated, and dried in vacuo to give 7-bromo-2-fluoro-9-methylene-3-(2,2,2-trifluoroethoxy)-9H-xanthene as a brown solid. MS (ESI, positive ion) m/z: 388.9, 390.9 (M+1). Step 3: To a solution of iodine (0.254 mL, 4.93 mmol) in THF (25 mL) at −20° C. was added silver cyanate (0.616 mL, 16.45 mmol). After addition, the mixture was stirred at −20° C. for 1 h. Then, a solution of 7-bromo-2-fluoro-9-methylene-3-(2,2,2-trifluoroethoxy)-9H-xanthene (1.600 g, 4.11 mmol) in THF (1.5 mL) was added and the mixture was stirred at 0° C. for 2 h. Then, the mixture was filtered through celite with the aid of THF (15 mL). Then, ammonia (6.17 mL, 12.33 mmol) (2 M in i-PrOH) was added dropwise to the filtrate. The resulting mixture was stirred at RT for overnight. Then, saturated Na2O3S2 (5 mL) was added followed by saturated NaHCO3 (5 mL). The mixture was stirred at room temperature for 5 min. The organic layer was collected, dried over MgSO4, and concentrated. The residue was then mixed with silica gel and the solid mixture was purified by silica gel column chromatography using ISCO instrument (solid loading, 0%-20% MeOH/DCM) to give 7′-bromo-2′-fluoro-3′-(2,2,2-trifluoroethoxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a light yellow solid. MS (ESI, positive ion) m/z: 446.9, 448.9 (M+1). Step 4: To a solution of 7′-bromo-2′-fluoro-3′-(2,2,2-trifluoroethoxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (0.250 g, 0.559 mmol) in 1,2-Dimethoxyethane (2.5 mL) at RT was added sodium carbonate monohydrate crystals (0.070 mL, 1.677 mmol), 5-pyrimidinylboronic acid (0.104 g, 0.839 mmol), tetrakis(triphenylphosphine)palladium (0.052 g, 0.045 mmol), and H2O (0.5 mL). The resulting mixture was then heated to 90° C. for 5 h. Then, the mixture was cooled to RT and EtOAc (5 mL) was added. The mixture was stirred at RT for 1 min. The organic layer was collected, dried over MgSO4, and concentrated. The residue was then dissolved in DMSO (2 mL) and the solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give a desired product in a solution of MeCN 0.1% TFA/H2O 0.1% TFA. Then, solution mixture was neutralized by saturated NaHCO3 and MeCN was removed in vacuo. Then saturated NaHCO3 (2 mL) was added and the mixture was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over MgSO4, concentrated, and dried in vacuo to give the product depicted above as a colorless solid. MS (ESI, positive ion) m/z: 447 (M+1).
