Cesium fluoride → HCID 178461600, compound

Temperature

80 °C

4-Chloro-6-fluoro-1H-indole (72 mg, 0.42 mmol) was dissolved in 4 mL of dioxane under argon. Bis(pinacolato)diboron (198 mg, 778 μmol), tricyclohexylphospine (19.8 mg, 71 μmol), bis(dibenzylidenacetone)palladium (20.3 mg, 35 μmol), and potassium acetate (104 mg, 1.06 mmol) were added under argon. The reaction was stirred for 24 hours at 80° C. The reaction mixture was cooled to room temperature and diluted with 30 mL of EtOAc. The organic layer was washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was filtered through a column (40 g SiO2; EtOAc/heptane in a gradient from 0/100 to 12/88) to yield a mixture, which was concentrated under reduced pressure, and then dissolved in 2 mL of acetonitrile and 0.2 mL of water under argon. 8-Bromo-2-((S)-3-methylmorpholin-4-yl-)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (100 mg, 153 μmol) was added, followed by cesium fluoride (25.8 mg, 170 μmol) and tetrakis(triphenylphospine)palladium (26 mg, 23 μmol). The reaction mixture was stirred at 135° C. for 2 hours in a sealed vial. The reaction mixture was cooled to room temperature and diluted with 40 mL of EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (10 g SiO2; tertbutylmethylether) to give the title compound as a foam (36 mg, 19% over 2 steps).

1. temperatureThe reaction mixture was cooled to room temperature
2. washThe organic layer was washed with 20 mL of brine
3. dry with materialdried over Na2SO4
4. filtrationfiltered
5. concentrationconcentrated under reduced pressure
6. filtrationThe residue was filtered through a column (40 g SiO2
7. customEtOAc/heptane in a gradient from 0/100 to 12/88) to yield a mixture, which
8. concentrationwas concentrated under reduced pressure
9. dissolutiondissolved in 2 mL of acetonitrile
10. stirringThe reaction mixture was stirred at 135° C. for 2 hours in a sealed vial
11. temperatureThe reaction mixture was cooled to room temperature
12. washThe organic layer was washed with brine
13. dry with materialdried over Na2SO4
14. filtrationfiltered
15. concentrationconcentrated
16. customThe residue was purified by column chromatography (10 g SiO2; tertbutylmethylether)

ORD record

ord-39fcc2fd6f284e548ab0415ad92aa2e5

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09334271B2