反应详情

温度

70 °C

Sodium hydride, NaH (60% in mineral oil, 23 mg, 0.69 mmol) was added to a suspension of 9H-purin-6-ylamine (93 mg, 0.69 mmol) in DMF (1 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 15 min then 2-chloromethyl-6-fluoro-1-phenyl-1H-benzoimidazole (148 mg, 0.57 mmol) in DMF (1 mL) added. After 30 min stirring at RT, the temperature was increased to 70° C. and stirring continued for 3 h. The volatiles were removed under reduced pressure and the resulting residue partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2N NH3/MeOH in DCM) to afford still impure 9-(6-fluoro-1-phenyl-1H-benzoimidazol-2-ylmethyl)-9H-purin-6-ylamine. Impure 9-(6-fluoro-1-phenyl-1H-benzoimidazol-2-ylmethyl)-9H-purin-6-ylamine was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 20-98%, 0.1% HCO2H in acetonitrile/water) to afford pure 376 as a white solid (45 mg, 22%). LCMS (Method K): RT 3.18 min [M+H]+ 360.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.06 (1H, s), 8.04 (1H, s), 7.68-7.55 (6H, m), 7.21 (2H, br s), 7.15-7.08 (1H, m), 6.97 (1H, dd, J=8.98, 2.55 Hz), 5.58 (2H, s)

1. stirringAfter 30 min stirring at RT
2. stirringstirring
3. waitcontinued for 3 h
4. customThe volatiles were removed under reduced pressure
5. customthe resulting residue partitioned between DCM and water
6. extractionThe aqueous phase was extracted with DCM (×3)
7. dry with materialthe combined organic fractions dried (Na2SO4)
8. concentrationconcentrated in vacuo
9. customThe resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2N NH3/MeOH in DCM)