反应详情

温度

90 °C

To a reactor equipped with overhead stirring, condenser, thermowell, and nitrogen inlet was charged water (H2O, 1.5 L), potassium carbonate (K2CO3, 1047 g, 7.58 mol, 2.45 equiv), 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 755 g, 2.66 mol), crude 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14, 822 g based on 100% conversion, 3.09 mol, 1.16 equiv) made as described above, and 1-propanol (6 L) at room temperature. The resulting reaction mixture was degassed three timed backfilling with nitrogen each time before being treated with tetrakis(triphenylphosphine)palladium(0) (9.2 g, 0.008 mol, 0.0026 equiv) at room temperature. The resulting reaction mixture was heated to gentle reflux (about 90° C.) for 1-4 hours. When the reaction was deemed complete by HPLC, the reaction mixture was concentrated under reduced pressure to remove solvents. The residue was then cooled to room temperature, diluted with ethyl acetate (9 L) and water (4 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×2.5 L). The combined organic layers were washed with water (2×2 L) and concentrated under reduced pressure to afford the crude 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (15), which was directly used in the subsequent acid-promoted de-protection reaction without further purification.

1. customTo a reactor equipped with overhead stirring, condenser
2. customat room temperature
3. customThe resulting reaction mixture
4. customwas degassed three
5. customThe resulting reaction mixture
6. temperaturewas heated
7. concentrationthe reaction mixture was concentrated under reduced pressure
8. customto remove solvents
9. temperatureThe residue was then cooled to room temperature
10. additiondiluted with ethyl acetate (9 L) and water (4 L)
11. customThe two layers were separated
12. extractionthe aqueous layer was extracted with ethyl acetate (2×2.5 L)
13. washThe combined organic layers were washed with water (2×2 L)
14. concentrationconcentrated under reduced pressure