反应详情

To a stirred solution of 4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (16.7 g, 60.9 mmol; obtained from Example 3, Step A) in DMF (250 mL) was added freshly ground potassium hydroxide (10.3 g, 183 mmol) followed by iodine (23.2 g, 91.4 mmol) under N2 at room temperature. The dark reaction was stirred at room temperature for 18 hours, covered by a foil to minimize light exposure. The reaction was then heated to 50° C. for 3 hours. The reaction was allowed to cool to room temperature. The crude reaction mixture was transferred via cannula into a stirred solution of 1-(chloromethyl)-4-methoxybenzene (11.1 g, 70.7 mmol) in DMF (100 mL) which was cooled in an ice bath under N2. The reaction was allowed to stir for 18 hours under N2 at room temperature. The mixture was then diluted with DCM (1 L) and washed with 5% aqueous Na2S2O3 (1 L). The aqueous phase was back-extracted with DCM (2×200 mL). The combined organic phases were washed with water (4×500 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was triturated with DCM (100 mL), and the undissolved solid removed by filtration. The filtrate was purified by Biotage Flash 65, eluting with 10% EtOAc/hexanes, 20% EtOAc/hexanes, then 30% EtOAc/hexanes to elute the desired product. The product was obtained as a pale yellow solid (16.6 g, 47%). 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=6 Hz, 1H), 8.16 (m, 2H), 7.38 (d, J=9 Hz, 2H), 7.34 (m, 1H), 6.84 (d, J=9 Hz, 2H), 6.36 (d, J=6 Hz, 1H), 5.63 (s, 2H), 3.77 (s, 3H).

1. customThe dark reaction
2. temperatureThe reaction was then heated to 50° C. for 3 hours
3. temperatureto cool to room temperature
4. customThe crude reaction mixture
5. temperaturewas cooled in an ice bath under N2
6. stirringto stir for 18 hours under N2 at room temperature
7. washwashed with 5% aqueous Na2S2O3 (1 L)
8. extractionThe aqueous phase was back-extracted with DCM (2×200 mL)
9. washThe combined organic phases were washed with water (4×500 mL)
10. dry with materialdried (Na2SO4)
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customThe resulting residue was triturated with DCM (100 mL)
14. customthe undissolved solid removed by filtration
15. customThe filtrate was purified by Biotage Flash 65
16. washeluting with 10% EtOAc/hexanes, 20% EtOAc/hexanes
17. wash30% EtOAc/hexanes to elute the desired product