反应详情

温度

60 °C

To 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (153 mg, 220 μmol, Eq: 1.00) in THF (2.0 ml) was added an aqueous solution of 1N NaOH (2.0 mL, 2.00 mmol, Eq: 9.08). The resulting solution heated at 60° C. for 2 h. The mixture was cooled to room temperature. The solution was diluted with saturated NaHCO3 and DCM. The layers were separated. The aqueous layer was extracted three times with DCM. The combined organics were dried over MgSO4. The solution was filtered. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a cream solid. The solid was triturated with Et2O. The solid was filtered, then dissolved in 2 ml DCM. A solution of 1.0 M HCl in Et2O (2 ml) was added. A solid formed. The solid was filtered and dried under vacuum to give 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one HCl (57.5 mg, 38%). LC/MS-ESI observed [M+H]+ 653. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.80 Hz, 6H) 1.37 (s, 9H) 3.08 (d, J=11.33 Hz, 2H) 3.46 (d, J=10.20 Hz, 2H) 3.76 (s, 5H) 4.39 (d, J=6.04 Hz, 2H) 7.41-7.59 (m, 5H) 7.73 (d, J=13.97 Hz, 1H) 7.86 (s, 1H) 8.06 (d, J=2.27 Hz, 1H) 8.42 (s, 1H) 8.50 (d, J=2.27 Hz, 1H) 9.31 (s, 1H)

1. temperatureThe mixture was cooled to room temperature
2. customThe layers were separated
3. extractionThe aqueous layer was extracted three times with DCM
4. dry with materialThe combined organics were dried over MgSO4
5. filtrationThe solution was filtered
6. concentrationConcentrated in vacuo
7. customThe crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient)
8. customto give a cream solid
9. customThe solid was triturated with Et2O
10. filtrationThe solid was filtered
11. dissolutiondissolved in 2 ml DCM
12. additionA solution of 1.0 M HCl in Et2O (2 ml) was added
13. customA solid formed
14. filtrationThe solid was filtered
15. customdried under vacuum