反应详情

温度

100 °C

To a vial charged with 6-bromo-4-(((3R,4R)-3-ethyl-1-(2-hydroxy-2-methylpropanoyl)-piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.044 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.88 mg, 0.088 mmol), and PdCl2(dppf)-CH2Cl2 Adduct (3.61 mg, 4.42 μmol) were added 1,4-dioxane (295 μl) and a 2M solution of potassium phosphate (66.3 μl, 0.133 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 2 hrs. The reaction was diluted with methanol (10 ml), filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm). The collected fractions were combined and dried via centrifugal evaporation, yielding 4-(((3R,4R)-3-ethyl-1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)amino)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (14.6 mg, 0.030 mmol, 68.6% yield) as a white solid. 1H NMR (500 MHz, 1:1 Chloroform-d/Methanol-d4) δ 8.10 (s, 1H), 7.83 (s, 1H), 7.75-7.72 (m, 2H), 6.92 (d, J=1.5 Hz, 1H), 4.65-4.50 (m, 2H), 4.32 (s, 2H), 4.15 (br. s., 1H), 2.97 (d, J=12.4 Hz, 1H), 2.36 (d, J=11.4 Hz, 1H), 1.79 (br. s., 1H), 1.70-1.61 (m, 2H), 1.57 (d, J=6.4 Hz, 6H), 1.49 (s, 6H), 1.41-1.25 (m, 1H), 1.01 (t, J=7.4 Hz, 3H). HPLC (Method F) Rt: 1.966 min. LCMS (Method K) m/z 482.29 ([M+H]+).

1. customThe suspension was purged with nitrogen for 5 minutes
2. customThe vial was sealed
3. additionThe reaction was diluted with methanol (10 ml)
4. filtrationfiltered
5. concentrationconcentrated under reduced pressure
6. customThe crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm)
7. customdried via centrifugal evaporation