反应详情

温度

110 °C

A 5 mL pressure tube was charged with 6-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)pyridazin-3(2H)-one 109g (20.0 mg, 0.089 mmol), 2-tert-butyl-5-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 109f (43.9 mg mg, 0.11 mmol), 1.27 M of potassium phosphate in water (0.15 mL, 0.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.1 mg, 0.0044 mmol), S-Phos (4.4 mg, 0.011 mmol), and 1,4-dioxane (1.4 mL). The mixture was purged with nitrogen, sealed, and heated at 110° C. overnight. The reaction mixture was cooled to room temperature, and filtered through Celite®. The filter cake was washed with methylene chloride/methanol (˜9:1). The filtrate was concentrated. The residue was purified on silica eluted with a gradient of 0 to 3.5% methanol in methylene chloride. The material obtained was further purified by reverse phase HPLC: C-18 column, eluted with a gradient of 0 to 80% acetonitrile in water over 20 min with 0.05% trifluoroacetic acid to afford 2-tert-butyl-5-(2-methyl-3-(5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one (109) (13 mg, 31%). M+1476.2. 1H NMR (400 MHz, DMSO) δ 12.92 (s, 1H), 9.17 (s, 1H), 7.72 (s, 1H), 7.48 (d, J=2.2, 1H), 7.44 (dd, J=5.3, 3.9, 1H), 7.32 (dd, J=6.5, 2.7, 2H), 6.08 (d, J=2.3, 1H), 4.91 (s, 2H), 3.67 (s, 3H), 2.07 (s, 3H).

1. customThe mixture was purged with nitrogen
2. customsealed
3. temperatureThe reaction mixture was cooled to room temperature
4. filtrationfiltered through Celite®
5. washThe filter cake was washed with methylene chloride/methanol (˜9:1)
6. concentrationThe filtrate was concentrated
7. customThe residue was purified on silica
8. washeluted with a gradient of 0 to 3.5% methanol in methylene chloride
9. customThe material obtained
10. customwas further purified by reverse phase HPLC
11. washC-18 column, eluted with a gradient of 0 to 80% acetonitrile in water over 20 min with 0.05% trifluoroacetic acid