反应详情

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0 °C

A slurry of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (61 g, 170 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (41 g, 175 mmol) in CH3CN (1300 mL) was heated to reflux for 1.5 hours. During this time, the slurry transformed from thin and yellowish to thick and brilliant white. The mixture was then cooled to 0° C. and stirred at this temperature for 15 min. The mixture was then filtered and washed with cold CH3CN (650 mL). The resulting solid was dried for 20 hours at 38° C. under house vacuum. The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3(sat) (1300 mL). The mixture was stirred until no more solid remained. Then, the aqueous and organic layers were separated and the aqueous layer was washed with EtOAc (390 mL). The combined organic layers were dried over MgSO4, filtered, washed with EtOAc (130 mL) and concentrated to a minimal volume on rotavap. The resulting mixture was re-crystallized out of EtOAc and hexane to give the desired product as a white solid (56.2 g, 72%) 1H NMR (MeOD, 400 MHz): 0.40-0.45 (2H, m), 0.60-0.65 (2H, m), 1.3-1.4 (1H, m), 2.05 (2H, s), 3.25-3.40 (2H, m), 3.85-3.40 (4H, m), 5.40-5.50 (2H, m), 7.50-7.55 (2H, d), 7.65-7.70 (2H, d). ES+522.

1. temperatureto reflux for 1.5 hours
2. filtrationThe mixture was then filtered
3. washwashed with cold CH3CN (650 mL)
4. customThe resulting solid was dried for 20 hours at 38° C. under house vacuum
5. additionThe white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3(sat) (1300 mL)
6. stirringThe mixture was stirred until no more solid
7. customThen, the aqueous and organic layers were separated
8. washthe aqueous layer was washed with EtOAc (390 mL)
9. dry with materialThe combined organic layers were dried over MgSO4
10. filtrationfiltered
11. washwashed with EtOAc (130 mL)
12. concentrationconcentrated to a minimal volume on rotavap
13. customThe resulting mixture was re-crystallized out of EtOAc and hexane