反应详情

温度

80 °C

To a suspension of (6-bromo-4-((6-((2-(dimethylamino)ethyl)amino)pyridin-3-yl)amino)quinolin-3-yl)(cyclopropyl)methanone (91 mg, 0.20 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (87 mg, 0.30 mmol) and Pd(dppf)Cl2 (14.6 mg, 0.02 mmol) in dioxane (6 mL) was added Cs2CO3 (1.0 M in H2O, 0.6 mL, 0.6 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 CHCl3/isopropanol (3:1). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with a mixture of CHCl3/isopropanol (3:1). The desired fractions were concentrated and dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.5 mL, 1.9 mmol). The resulting solution was concentrated to give the desired product (95.6 mg, 74%) as an off-white solid. NMR (500 MHz, MeOD) δ 9.38 (s, 1H), 8.33-8.23 (m, 2H), 8.19 (d, J=2.5 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.77 (dd, J=9.2, 2.6 Hz, 1H), 7.45 (s, 2H), 7.06 (d, J=9.2 Hz, 1H), 3.88 (t, J=6.1 Hz, 2H), 3.45 (t, J=6.1 Hz, 2H), 2.98 (s, 6H), 2.88-2.79 (m, 1H), 1.24-1.18 (m, 4H). ESI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC 98.4% (AUC), tR=10.24 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 CHCl3/isopropanol (3:1)
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
8. additionwith a mixture of CHCl3/isopropanol (3:1)
9. concentrationThe desired fractions were concentrated
10. dissolutiondissolved in methanol (4 mL)
11. concentrationThe resulting solution was concentrated