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) and 3-cyclopropyl-3-fluoroazetidine hydrochloride (132.2 g, 0.87 mol) was added diisopropylethylamine (208 g, 1.61 mol) and isopropanol (1.125 L). The mixture was heated to reflux for 23 hours. The reaction was then cooled to 85° C. (a slightly hazy solution) and filtered. The homogeneous solution was concentrated to a minimal volume. EtOAc was then added (1 L) and the solution was concentrated to a minimal volume. EtOAc (1 L) and H2O (1 L) were then added and the layers were separated. Crystallized product began to crystallize out of the organic layer during the extraction. The aqueous layer was further extracted with EtOAc (500 ml). The 1st organic layer was concentrated to dryness to give a white solid. Hexane (750 ml) was added to the second organic extract and the slurry was stirred at ambient temperature, and then cooled to 0° C. for 30 min. The slurry was 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. temperatureThe mixture was heated
2. temperatureto reflux for 23 hours
3. filtrationfiltered
4. concentrationThe homogeneous solution was concentrated to a minimal volume
5. additionEtOAc was then added (1 L)
6. concentrationthe solution was concentrated to a minimal volume
7. additionEtOAc (1 L) and H2O (1 L) were then added
8. customthe layers were separated
9. customto crystallize out of the organic layer during the extraction
10. extractionThe aqueous layer was further extracted with EtOAc (500 ml)
11. concentrationThe 1st organic layer was concentrated to dryness
12. customto give a white solid
13. extractionorganic extract
14. temperaturecooled to 0° C. for 30 min
15. filtrationThe slurry was filtered
16. washwashed with copious Heptane
17. customThe filter cake was dried under vacuum
18. extractionThe filter cake and the white solid from the 1st extraction