Chlorotrimethylsilane → (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate

Temperatur

60 °C

1,2-Dibromoethane (425 μL, 5.0 mmol) is added to a suspension of zinc powder (2.83 g, 43.2 mmol) in dry DMF (8 mL). The reaction mixture is heated at 60° C. for 10 min, then cooled to room temperature. TMSCl (500 μl, 4.0 mmol) is added (caution: exothermic!) and the resulting mixture is sonicated for 30 min. Zinc powder is allowed to settle and the supernatant is removed by syringe. DMF (8 mL) is added, followed by bromomethyl acetate (2.12 mL, 21.61 mmol). The mixture is stirred at 23° C. for 2.5 h. Zinc is allowed to settle and the solution of acetoxymethylzinc bromide is then transferred to a solution of 5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole (2.00 g, 7.20 mmol), palladium acetate (0.081 g, 0.360 mmol), and S-phos (0.355 g, 0.864 mmol) in DMF (10 mL) at 23° C. The resulting mixture is stirred at 23° C. for 15 h. Saturated aqueous NH4Cl (100 mL) is added and the mixture is then partitioned between EtOAc (150 mL) and water (150 mL). The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (60 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to give (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate.

1. temperaturecooled to room temperature
2. customthe resulting mixture is sonicated for 30 min
3. customthe supernatant is removed by syringe
4. additionDMF (8 mL) is added
5. stirringThe resulting mixture is stirred at 23° C. for 15 h
6. customthe mixture is then partitioned between EtOAc (150 mL) and water (150 mL)
7. extractionThe aqueous layer is extracted with EtOAc (2×100 mL)
8. washThe combined organic layers are washed with brine (60 mL)
9. dry with materialdried (Na2SO4)
10. concentrationconcentrated
11. customThe residue is purified by silica gel chromatography (0-100% EtOAc/heptane)

ORD-Eintrag

ord-fa039d5b6d61430db2ae60cf04b1721a

Quelldatensatz

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08541432B2