反应详情

温度

100 °C

To a 5 mL microwave reaction tube was added 4-(1-(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ethyl)morpholine (0.523 g, 1.55 mmol), 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Example 3, 0.322 g, 1.28 mmol), Am-Phos (Aldrich, 0.0531 g, 0.075 mmol) and potassium acetate (Aldrich, 0.379 g, 3.87 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 15 min. The reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The layers were separated and saturated NH4Cl (30 mL) was added to the aqueous phase. The aqueous phase was extracted with EtOAc (2×40 mL). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50 g, eluent: EtOAc in hexanes 20% to 70% then IPA/CHCl3 0% to 12.5%) to afford 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine (0.30 g, 55% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.27-8.37 (m, 3H) 5.86 (d, J=10.37 Hz, 1H) 4.15-4.24 (m, 1H) 3.78-3.88 (m, 1H) 3.64-3.75 (m, 4H) 3.53 (q, J=6.72 Hz, 1H) 2.89 (s, 3H) 2.50-2.60 (m, 2H) 2.38-2.48 (m, 2H) 2.01-2.22 (m, 3H) 1.69-1.91 (m, 3H) 1.43 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion): 427.1 (M+H)+.

1. customThe mixture was degassed
2. customby bubbling argon through for 5 min
3. customThe reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL)
4. customThe layers were separated
5. additionsaturated NH4Cl (30 mL) was added to the aqueous phase
6. extractionThe aqueous phase was extracted with EtOAc (2×40 mL)
7. washThe combined organic phases were washed with saturated aqueous sodium chloride (100 mL)
8. dry with materialThe organic phase was dried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customThe crude product was purified by silica gel column chromatography (50 g, eluent