反应详情

To a 2 L flask (1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine hydrochloride (248.0 g, 733 mmol), water (1240 ml), THF (124 ml) and activated carbon (24.12 g) was added and stirred for about 10 min. The resulting mixture was filtered through celite rinsing with a mixture of water (100 mL) and THF (24 mL). Potassium carbonate (668 g, 4836 mmol) and THF (1736 ml) were added and a solution of 3,3,3-trifluoropropane-1-sulfonyl chloride (315 g, 1524 mmol, Matrix) in THF (620 ml) was added over about 1 hr. After cooling to ambient temperature the layers were separated and the aqueous layer extracted with THF (500 mL). The combined organic layers were washed with aqueous ammonium chloride (3×100 mL) and concentrated to approximately 1 L. Water (1770 mL) was added slowly at about 50° C. and the slurry cooled to about 23° C. The solids were collected by filtration, washed with 35% THF in water (750 mL) and dried in a vacuum oven. The crude material was dissolved in MeOH (4.5 L) and treated with activated carbon (28.3 g). After filtering through celite and rinsing with MeOH (500 mL), the solution was concentrated under reduced pressure to approximately 1 L and water (800 mL) was added slowly at about 50° C. then cooled to 35° C. when additional water (360 mL) was added. The product was collected by filtration, washed with 1:1 MeOH:water (2×350 mL) and dried in a vacuum oven to afford N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (215.3 g, 71%) as a white crystalline solid (m.p. 225° C.). 1H NMR (400 MHz, DMSO) δ 11.99 (bs, 1H), 8.30 (s, 1H), 7.40 (bs, 1H), 7.38 (s, 1H), 7.27-7.07 (m, 1H), 6.62 (d, J=3.4 Hz, 1H), 3.75 (dt, J=10.1, 7.8 Hz, 1H), 3.70-3.55 (m, 1H), 3.15-3.02 (m, 2H), 2.61-2.40 (m, 2H), 2.40-2.29 (m, 1H), 2.23 (dd, J=13.3, 6.9 Hz, 1H), 2.16-2.03 (m, 1H), 1.94-1.77 (m, 1H), 1.20-0.99 (m, 1H), 0.17 (d, J=7.0 Hz, 3H).

1. filtrationThe resulting mixture was filtered
2. washthrough celite rinsing with a mixture of water (100 mL) and THF (24 mL)
3. customwere separated
4. extractionthe aqueous layer extracted with THF (500 mL)
5. washThe combined organic layers were washed with aqueous ammonium chloride (3×100 mL)
6. concentrationconcentrated to approximately 1 L
7. additionWater (1770 mL) was added slowly at about 50° C.
8. temperaturethe slurry cooled to about 23° C
9. filtrationThe solids were collected by filtration
10. washwashed with 35% THF in water (750 mL)
11. customdried in a vacuum oven
12. dissolutionThe crude material was dissolved in MeOH (4.5 L)
13. additiontreated with activated carbon (28.3 g)
14. filtrationAfter filtering through celite
15. washrinsing with MeOH (500 mL)
16. concentrationthe solution was concentrated under reduced pressure to approximately 1 L and water (800 mL)
17. additionwas added slowly at about 50° C.
18. temperaturethen cooled to 35° C. when additional water (360 mL)
19. additionwas added
20. filtrationThe product was collected by filtration
21. washwashed with 1:1 MeOH
22. dry with materialwater (2×350 mL) and dried in a vacuum oven