反应详情

Under a nitrogen atmosphere, to a solution (18.5 g) of 28% sodium methoxide in methanol was added tetrahydrofuran (284 ml), N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide 45 (28.4 g) obtained in Step 1 was added, and the mixture was stirred at room temperature for 1 hr. Acetic acid (12.5 ml) was added, and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. A 9:1 mixed solvent (426 mL) of 1-butanol and water was added to the obtained solid, and the mixture was stirred with heating under reflux for 3 hrs. The mixture was allowed to return to room temperature and stirred overnight, and the crystals were collected by filtration and dried. A 9:1 mixed solvent (426 mL) of 1-butanol and water was added again to the obtained crystals, and the mixture was stirred with heating under reflux for 3 hrs. The mixture was allowed to return to room temperature and stirred overnight. The crystals were collected by filtration and washed with a 9:1 mixed solvent of methanol and water and dried to give N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide 46 (26.35 g, yield 93%) as white crystals.

1. additionwas added
2. stirringthe mixture was stirred at room temperature for 1 hr
3. concentrationconcentrated under reduced pressure
4. additionA 9:1 mixed solvent (426 mL) of 1-butanol and water was added to the obtained solid
5. stirringthe mixture was stirred
6. temperaturewith heating
7. temperatureunder reflux for 3 hrs
8. customto return to room temperature
9. stirringstirred overnight
10. filtrationthe crystals were collected by filtration
11. customdried
12. additionA 9:1 mixed solvent (426 mL) of 1-butanol and water was added again to the obtained crystals
13. stirringthe mixture was stirred
14. temperaturewith heating
15. temperatureunder reflux for 3 hrs
16. customto return to room temperature
17. stirringstirred overnight
18. filtrationThe crystals were collected by filtration
19. washwashed with a 9:1 mixed solvent of methanol and water
20. customdried