反应详情

温度

100 °C

A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (241 mg, 0.49 mmol), 6-chloro-4-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (100 mg, 0.29 mmol), potassium phosphate (152 mg, 0.72 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.7 mg, 0.03 mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (8.24 mg, 0.01 mmol) was added and the resulting solution heated at 100° C. in for 2 h. The resulting mixture was cooled, poured into a saturated solution of ammonium chloride and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and treated with a lithium hydroxide solution (0.5 mL, 2.0 M), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride (2×50 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 14% methanol in dichloromethane) and recrystallized from dichloromethane and isopropyl acetate to give 6-tert-Butyl-2-(3-{5-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one (47 mg, 26%) as a light yellow solid: mp 245-247° C.; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.18 Hz, 4H) 1.38 (s, 10H) 2.13-2.42 (m, 2H) 3.09 (br. s., 5H) 3.77 (s, 3H) 4.16-4.72 (m, 3H) 7.20-8.10 (m, 9H) 8.28-8.64 (m, 2H) 9.23 (s, 1H).

1. additionwas added
2. temperatureThe resulting mixture was cooled
3. extractionextracted with methylene chloride (2×100 mL)
4. customThe layers were separated
5. dry with materialthe organic phase dried over magnesium sulfate
6. filtrationThe mixture was filtered
7. concentrationconcentrated in vacuo
8. dissolutionThe residue was dissolved in dioxane (10 mL)
9. additiontreated with a lithium hydroxide solution (0.5 mL, 2.0 M)
10. additionThe resulting mixture was poured into a saturated ammonium chloride solution
11. extractionextracted with methylene chloride (2×50 mL)
12. customThe layers were separated
13. dry with materialthe organic phase dried over magnesium sulfate
14. filtrationThe mixture was filtered
15. concentrationconcentrated in vacuo
16. customThe residue was purified by flash chromatography (silica gel, 24 g, 1% to 14% methanol in dichloromethane)
17. customrecrystallized from dichloromethane and isopropyl acetate