Reaktion #73402

Reaktionsgleichung

bromomethyl acetate

acetoxymethylzinc bromide

NH4Cl

1,2-Dibromoethane

5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole

S-phos

TMSCl

→

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

Lösungsmittel

DMF

DMF

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturcooled to room temperature
2. 2
   Sonstigethe resulting mixture is sonicated for 30 min
3. 3
   Sonstigethe supernatant is removed by syringe
4. 4
   workup.ADDITIONDMF (8 mL) is added
5. 5
   workup.STIRRINGThe resulting mixture is stirred at 23° C. for 15 h
6. 6
   Sonstigethe mixture is then partitioned between EtOAc (150 mL) and water (150 mL)
7. 7
   ExtraktionThe aqueous layer is extracted with EtOAc (2×100 mL)
8. 8
   WaschenThe combined organic layers are washed with brine (60 mL)
9. 9
   Trocknendried (Na2SO4)
10. 10
    Einengenconcentrated
11. 11
    SonstigeThe residue is purified by silica gel chromatography (0-100% EtOAc/heptane)

Vorschrift

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.

Quelle