反应详情

温度

80 °C

To a suspension of 1-(6-bromo-4-((trans-4-(2-(dimethylamino)ethyl)cyclohexyl)amino)quinolin-3-yl)ethanone (63 mg, 0.15 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.22 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 a mixture of CHCl3/isopropanol (3:1). The desired fractions were concentrated and dissolved in methanol and resultant residue was dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.5 mL, 1.9 mmol) was added. The resulting solution was concentrated to give the desired product (55.9 mg, 67%) as an off-white solid NMR (500 MHz, MeOD) δ 9.10 (s, 1H), 8.50 (s, 1H), 8.27 (dd, J=8.7, 1.7 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.52 (dd, J=11.4, 2.3 Hz, 1H), 4.54-4.50 (m, 1H), 3.25-3.17 (m, 2H), 2.90 (s, 6H), 2.73 (s, 3H), 2.42 (d, J=12.2 Hz, 2H), 2.04 (d, J=12.9 Hz, 2H), 1.80-1.68 (m, 4H), 1.59 (br s, 1H), 1.39-1.27 (m, 2H). ESI MS m/z 484 [C27H31ClFN3O2+H]+; HPLC>99% (AUC), tR=10.01 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
8. additionwith a mixture of CHCl3/isopropanol (3:1)
9. concentrationThe desired fractions were concentrated
10. dissolutiondissolved in methanol
11. dissolutionresultant residue was dissolved in methanol (4 mL)
12. concentrationThe resulting solution was concentrated