Cyclopropylboronic acid → 3-cyclopropyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole

Temperatur

0 °C

A 100 mL flask was charged with 1,4-dioxane/H2O (50 mL/10 mL). The flask was cooled to 0° C. under vacuum for 20 minutes. A 250 mL round bottom flask was charged with cyclopropylboronic acid (5.22 g, 60.8 mmol), 3-bromo-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (8.51 g, 24.3 mmol), palladium diacetate (0.218 g, 0.972 mmol) and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.997 g, 1.94 mmol). The flask was evacuated and back filled with N2 (repeated 3 times). The cold degassed dioxane/H2O mixture was added to the 250 mL flask, which was evacuated and back filled with argon (repeated 5 times). The reaction mixture was heated to 100° C. for 6 hours. The mixture was cooled to ambient temperature, filtered through a pad of Celite, and the filter pad was washed with H2O and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give a dark colored residue, which was dissolved in DCM (20 mL) and silica gel (20 g) was added. DCM was removed under reduced pressure. The crude product absorbed by silica gel was loaded onto a short pad of silica gel and eluted with EtOAc/hexanes (1:1). The desired fractions were concentrated under reduced pressure to give the product (7.55 g).

1. customThe flask was evacuated
2. additionback filled with N2 (repeated 3 times)
3. customThe cold degassed dioxane/H2O mixture
4. additionwas added to the 250 mL flask, which
5. customwas evacuated
6. additionback filled with argon (repeated 5 times)
7. temperatureThe reaction mixture was heated to 100° C. for 6 hours
8. temperatureThe mixture was cooled to ambient temperature
9. filtrationfiltered through a pad of Celite
10. washthe filter pad was washed with H2O and EtOAc
11. extractionThe aqueous layer was extracted with EtOAc
12. dry with materialThe combined organic phases were dried (Na2SO4)
13. concentrationconcentrated under reduced pressure
14. customto give a dark colored residue, which
15. additionsilica gel (20 g) was added
16. customDCM was removed under reduced pressure
17. customThe crude product absorbed by silica gel
18. washeluted with EtOAc/hexanes (1:1)
19. concentrationThe desired fractions were concentrated under reduced pressure

ORD-Eintrag

ord-9e6f172a703f44b6b67756e5a1cbd720

Quelldatensatz

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08841455B2