Potassium Carbonate → 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine

Temperature

90 °C

A mixture of 3,6-dichloropyridazine (20.1 g, 135 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (25.46 g, 122 mmol) and potassium carbonate (50.7 g, 367 mmol) in 1,4-dioxane (500 mL) and water (200 mL) under nitrogen was degassed by bubbling in nitrogen for 15 min. Dichlorobis(triphenylphosphine)palladium (II) (1.2%, 1 g, 1.4 mmol) was than added and nitrogen was bubbled in the mixture for another 10 min. The reaction mixture was stirred at 90° C. for 3 h, then cooled to room temperature and concentrated in vacuo to remove the majority of the 1,4-dioxane. The residue was partitioned between 1 N aqueous potassium carbonate (400 mL) and ethyl acetate (400 mL) and the phases separated. The aqueous layer was extracted with ethyl acetate (2×300 mL) and dichloromethane (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo. The residue was stirred in diethyl ether (150 mL) and the orange precipitate was filtered and dried to return the title compound (12.76 g, 65.6 mmol, 54% yield). The filtrate was concentrated onto silica gel and purified by flash chromatography on silica gel using a gradient of 0-50% ethyl acetate/hexane to return starting 3,6-dichloropyridazine as a white solid (9.9 g, 66.4 mmol, 49% yield).

1. customwas degassed
2. customby bubbling in nitrogen for 15 min
3. additionthan added
4. customnitrogen was bubbled in the mixture for another 10 min
5. temperaturecooled to room temperature
6. concentrationconcentrated in vacuo
7. customto remove the majority of the 1,4-dioxane
8. customThe residue was partitioned between 1 N aqueous potassium carbonate (400 mL) and ethyl acetate (400 mL)
9. customthe phases separated
10. extractionThe aqueous layer was extracted with ethyl acetate (2×300 mL) and dichloromethane (300 mL)
11. washThe combined organic layers were washed with brine
12. dry with materialdried over sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated in-vacuo
15. stirringThe residue was stirred in diethyl ether (150 mL)
16. filtrationthe orange precipitate was filtered
17. customdried

ORD record

ord-8313552576a046709942796d535dcd6b

Source dataset

uspto-grants-2011_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08071581B2