反应详情

温度

120 °C

A mixture of 7-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-7-azaspiro[3.5]nonan-2-ol (75 mg, 0.18 mmol), 2-ethylbenzimidazole (29 mg, 0.20 mmol), Pd2(dba)3 (4.1 mg, 2.5 mol %), Xphos (8.5 mg, 10 mol %) and Cs2CO3 (87 mg, 0.27 mmol) in dioxane (2.0 mL) was purged with argon gas then heated at 120° C., for 18 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 20-98%) to give 465 (42 mg, 44%) as an off white solid. LCMS: (Method I): RT 2.47 min; [M+H]+ 531.3. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1H), 7.76-7.72 (m, 1 H), 7.28-7.22 (m, 2 H), 4.37-4.27 (m, 5 H), 3.86 (t, J=4.7 Hz, 4 H), 3.78 (s, 3 H), 3.34 (q, J=7.5 Hz, 2 H), 3.17-3.02 (m, 2 H), 2.99-2.81 (m, 2 H), 2.71-2.39 (m, 4 H), 2.31-2.24 (m, 2 H), 1.74-1.64 (m, 6 H), 1.44 (t, J=7.5 Hz, 3 H)

1. customwas purged with argon gas
2. washwashed with MeOH
3. washthe desired product eluted with 2 M NH3 in MeOH
4. customThe resulting residue was purified by flash chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM)