反应详情

温度

-78 °C

A dry 25 ml round bottom flask under nitrogen was charged with 2.5 M nBuLi in Hexanes (0.420 ml, 1.06 mmol); which was diluted with THF (1 ml). This was cooled to −78° C. and 4-methylthiazole (100 mg, 1.01 mmol) dissolved in 2 ml of THF was added slowly via syringe. This was stirred at −78° C. for 2 hours, slowly warmed up to −10° C. and stirred at this temperature for 0.5 hour. Reaction cooled back to −78° C. and 0.5M zinc(II) chloride in THF (3.03 ml, 1.51 mmol) added via syringe. Reaction stirred at −78° C. for 0.5 hour then at room temperature for 1 hour. At this time, 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (115 mg, 0.250 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) added and reaction stirred under nitrogen at 65° C. for 48 hours. Reaction stopped, cooled to room temperature, diluted with aq. EDTA/NaHCO3 solution. This was extracted with ethyl acetate. Organic portion was dried with Na2SO4, filtered, and concentrated to give light brown residue. This was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of Aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, concentrated to afford pure N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiazol-2-yl)phthalazin-1-amine as a yellow solid. MS m/z=519 [M+H]+. Calc'd for C28H22N8OS: 518.59.

1. additionwas added slowly via syringe
2. temperatureslowly warmed up to −10° C.
3. stirringstirred at this temperature for 0.5 hour
4. customReaction
5. temperaturecooled back to −78° C.
6. customReaction
7. stirringstirred at −78° C. for 0.5 hour
8. waitat room temperature for 1 hour
9. customreaction
10. stirringstirred under nitrogen at 65° C. for 48 hours
11. customReaction
12. temperaturecooled to room temperature
13. extractionThis was extracted with ethyl acetate
14. dry with materialOrganic portion was dried with Na2SO4
15. filtrationfiltered
16. concentrationconcentrated
17. customto give light brown residue
18. customThis was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA)
19. additionbasified by addition of Aq. NaHCO3
20. extractionextracted with ethyl acetate
21. dry with materialThe organic portion was dried with Na2SO4
22. filtrationfiltered
23. concentrationconcentrated