反应详情

温度

80 °C

To a suspension of (6-bromo-4-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)amino) quinoline-3-yl)(cyclopropyl)methanone (60 mg, 0.13 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (54 mg, 0.20 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). The reaction mixture was degassed with nitrogen and heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with a satd. aq. NaHCO3 (20 mL) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired fractions were combined and concentrated and the residue was dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.5 mL, 1.9 mmol). The mixture was concentrated to obtain the desired product (42.9 mg, 55%) as an off-white solid. 1H NMR (500 MHz, MeOD) δ 9.35 (br s, 1H), 8.47 (br s, 1H), 8.27 (dd, J=8.8, 1.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.60 (br s, 1H), 7.53 (d, J=11.1 Hz, 1H), 4.51 (br s, 1H), 3.74-3.66 (m, 2H), 3.18-3.07 (m, 4H), 2.85 (br s, 1H), 2.44 (br s, 2H), 2.24-1.96 (m, 5H), 1.83-1.71 (m, 2H), 1.36-1.18 (m, 6H). ESI MS m/z 522 [C30H33ClFN3O2+H]+; HPLC 98.9% (AUC), tR=10.35 min.

1. customThe reaction mixture was degassed with nitrogen
2. temperatureThe reaction mixture was cooled to room temperature
3. additiondiluted with a satd
4. extractionaq. NaHCO3 (20 mL) and extracted with ethyl acetate
5. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
6. concentrationconcentrated
7. custompurified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA)
8. concentrationconcentrated
9. dissolutionthe residue was dissolved in methanol (4 mL)
10. concentrationThe mixture was concentrated