反应详情

温度

100 °C

4-(5-(azetidine-1-carbonyl)pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one (56 mg, 175 μmol, Eq: 1.00), potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (83.1 mg, 175 μmol, Eq: 1), x-phos (13.0 mg, 27.3 μmol, Eq: 0.156) and potassium phosphate tribasic (81.8 mg, 385 μmol, Eq: 2.2) were dissolved in a 10% aq. methanol solution (10 ml). The reaction was degassed. Finally bis(dibenzylideneacetone)palladium (9.06 mg, 15.8 μmol, Eq: 0.09) was added and the reaction mixture was stirred at 100° C. for 100 min. The reaction mixture was filtered and the filtercake was washed with methanol. The combined filtrate and washes were concentrated and extracted with ethyl acetate and water. The organic phase was separated, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate. Hexane was added until precipitate was formed. The precipitate was filtered off to give crude product as a yellow solid. This crude product was purified by silica gel chromatography to give a yellow solid which was dissolved in dioxane. 1 M sodium hydroxide solution (263 μl, 263 μmol, Eq: 1.5) was added and the resulting reaction mixture was stirred over night at room temperature. The reaction mixture was treated again with 1 M sodium hydroxide solution (10 eq.) and heated to 40° C. for 4 hr. The reaction was diluted with dichlormethane and water and extracted with dichloromethane to give a crude solid after concentration. The crude product was purified by 12 g silica gel chromatography eluting with 0-10% methanol in ethyl acetate to afford 2-(3-{5-[5-(Azetidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-one as a light yellow solid (16 mg).

1. customThe reaction was degassed
2. filtrationThe reaction mixture was filtered
3. washthe filtercake was washed with methanol
4. concentrationThe combined filtrate and washes were concentrated
5. extractionextracted with ethyl acetate and water
6. customThe organic phase was separated
7. washwashed with brine
8. dry with materialdried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated
11. dissolutionThe residue was dissolved in ethyl acetate
12. additionHexane was added until precipitate
13. customwas formed
14. filtrationThe precipitate was filtered off
15. customto give crude product as a yellow solid
16. customThis crude product was purified by silica gel chromatography
17. customto give a yellow solid which
18. customthe resulting reaction mixture
19. stirringwas stirred over night at room temperature
20. temperatureheated to 40° C. for 4 hr
21. extractionextracted with dichloromethane
22. customto give a crude solid
23. concentrationafter concentration
24. customThe crude product was purified by 12 g silica gel chromatography
25. washeluting with 0-10% methanol in ethyl acetate