反应详情

温度

85 °C

To a mixture of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylthio)pyrimidin-4-amine (150 g, 0.58 mol), 3-cyclopropyl-3-fluoroazetidine hydrochloride (132.2 g, 0.87 mol) was added diisopropylethylamine (208 g, 1.61 mol) and isopropanol (1.125 L) and then heated to reflux for 23 hours. The reaction was cooled to slightly hazy solution to 85° C. and filtered and the homogeneous solution concentrated to a minimal volume. EtOAc was added (1 L) and concentrated to minimal volume. EtOAc (1 L) and H2O (1 L) were added and the layers separated (organic started to crystallize product during the extraction). The aqueous layer was further extracted with EtOAc (500 ml). Concentrated the 1st organic to dryness to give a white solid. Hexane (750 ml) was added to the 2nd organic extract and the slurry was stirred at ambient temperature, then cooled to 0° C. for 30 min. Filtered and washed with copious Heptane. The filter cake was dried under vacuum. The filter cake and the white solid from the 1st extraction were combined to afford 155.1 g of the desired product. (155.1 g, 77%). 1H NMR (DMSO, 400 MHz) 0.44 (2H, m), 0.60 (2H, m), 1.38-1.43 (1H, m), 2.18 (3H, s), 2.42 (3H, s), 3.89-3.97 (4H, m), 5.92 (1H, br s), 6.04 (1H, br s), 9.23 (1H, s), 11.86 (1H, s). ES+ 335

1. temperatureheated
2. temperatureto reflux for 23 hours
3. filtrationfiltered
4. concentrationthe homogeneous solution concentrated to a minimal volume
5. additionEtOAc was added (1 L)
6. concentrationconcentrated to minimal volume
7. additionEtOAc (1 L) and H2O (1 L) were added
8. customthe layers separated (
9. customto crystallize product
10. extractionduring the extraction)
11. extractionThe aqueous layer was further extracted with EtOAc (500 ml)
12. concentrationConcentrated the 1st organic to dryness
13. customto give a white solid
14. extractionorganic extract
15. temperaturecooled to 0° C. for 30 min
16. filtrationFiltered
17. washwashed with copious Heptane
18. customThe filter cake was dried under vacuum
19. extractionThe filter cake and the white solid from the 1st extraction