反应详情

Diphenyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphine oxide (10.9 g), 2-[(4R,6S)-6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (4.5 g), and tetrahydrofuran (90.0 mL) were added to a reactor under nitrogen atmosphere. The reaction mixture was cooled to −40˜−30° C. A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 20.0 mL) was slowly added to the reaction mixture, while maintaining the temperature of −40˜−30° C. The temperature of the reaction mixture was raised to 0˜5° C. for 30 minutes. The reaction mixture was stirred at the same temperature for 2˜3 hours. The reaction was monitored with thin layer chromatography (ethyl acetate/n-hexane=1:3). An ammonium chloride solution (50.0 mL) was added to the reaction mixture. The separated organic layer was washed with 8% sodium bicarbonate solution (50.0 mL) and then concentrated under reduced pressure. Isopropanol (45.0 mL) was added to the resulting residue. The reaction mixture was stirred at 0˜5° C. for 1˜2 hours and then filtered under reduced pressure. The resulting white solid was dried under vacuum to obtain E-(6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide (7.8 g, yield 75%).

1. temperatureThe reaction mixture was cooled to −40˜−30° C
2. temperaturewhile maintaining the temperature of −40˜−30° C
3. temperatureThe temperature of the reaction mixture was raised to 0˜5° C. for 30 minutes
4. washThe separated organic layer was washed with 8% sodium bicarbonate solution (50.0 mL)
5. concentrationconcentrated under reduced pressure
6. additionIsopropanol (45.0 mL) was added to the resulting residue
7. stirringThe reaction mixture was stirred at 0˜5° C. for 1˜2 hours
8. filtrationfiltered under reduced pressure
9. customThe resulting white solid was dried under vacuum