反应详情

A solution of 5,6-difluoro-4-oxo-N-({3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methyl)-3,4-dihydroquinazoline-2-carboxamide obtained in Step 1 of Example 44 (150 mg, 0.219 mmol) and 4-(2-hydroxyethyl)benzoic acid (40 mg, 0.241 mmol) in DMA (4 mL) was added dropwise to a suspension of 60% sodium hydride (oil dispersion, 0.031 mg, 0.767 mmol) in DMA (2 mL) at room temperature, and the mixture was stirred at room temperature for 20 min, and then stirred at 80° C. under heating for 3 hr. After the reaction mixture was allowed to cool to room temperature, water (50 mL) was added thereto, and the mixture was washed with ethyl acetate (50 mL×2) The aqueous layer was neutralized with 0.1N hydrochloric acid, and the objective compound was extracted with ethyl acetate (80 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in dichloromethane (2 mL) were added trifluoroacetic acid (0.47 mL) and triethylsilane (0.037 mL, 0.235 mmol) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mm×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/100/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and crystallized from ethanol-diethyl ether to give the title compound as a yellow powder (36 mg, 28% in two steps).

1. stirringstirred at 80° C.
2. temperatureunder heating for 3 hr
3. temperatureto cool to room temperature
4. washthe mixture was washed with ethyl acetate (50 mL×2) The aqueous layer
5. extractionthe objective compound was extracted with ethyl acetate (80 mL)
6. washThe organic layer was washed with saturated brine
7. dry with materialdried over sodium sulfate
8. concentrationconcentrated under reduced pressure
9. stirringthe mixture was stirred for 1 hr
10. concentrationThe reaction mixture was concentrated under reduced pressure
11. customthe residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mm×50 mm), mobile phase
12. distillationdistilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid)
13. distillationgradient: distilled water/acetonitrile=90/100/100, time
14. custom10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and crystallized from ethanol-diethyl ether