反应详情

温度

75 °C

To a 3 L flask with mechanical stirring was added ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate, T2 (100 g, 225 mmol), (4-chloro-2-fluorophenyl)boronic acid (25.5 g, 146 mmol) and Pd(dppf)2Cl2 (4.93 g, 6.74 mmol). The flask was purged with N2, then degassed 2-methyltetrahydrofuran (1 L) and 3 M aq K3PO4 (225 mL, 674 mmol) were added. The reaction mixture was heated to 75° C. and stirred at this temperature for 30 min. Additional (4-chloro-2-fluorophenyl)boronic acid (25.5 g, 146 mmol) was added and the reaction was allowed to heat for 1.5 h. The mixture was allowed to cool to rt and the aqueous layer was separated. The organic layer was passed through a celite pad and placed back in the reaction vessel. Lithium hydroxide (28 g, 667 mmol) in water (700 mL) was added and the mixture was heated to 50° C. and stirred at this temperature for 1 h. The mixture was allowed to cool and the aqueous layer separated. Celite was added to the aqueous layer and the mixture was filtered through a plug of celite. The filtrate was placed in a flask with overhead stirrer and carefully acidified with 4 M aq HCl and heated to 50° C. with stirring until a precipitate formed. The solid was collected via filtration and dried under vacuum to afford the title compound as a tan solid (68.7 g, 74%). MS (LCMS) m/z 420.6 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (s, 3H) 2.18 (ddd, J=13.17, 10.24, 5.07 Hz, 1H) 2.41-2.45 (m, 1H) 3.10-3.19 (s, 3H) 3.87-4.08 (m, 2H) 6.47 (d, J=7.02 Hz, 1H) 7.42 (dd, J=8.39, 1.95 Hz, 1H) 7.48-7.56 (m, 1H) 7.60 (dd, J=9.95, 1.95 Hz, 1H) 8.06 (d, J=6.05 Hz, 1H).

1. customThe flask was purged with N2
2. stirringstirred at this temperature for 30 min
3. temperatureto heat for 1.5 h
4. temperatureto cool to rt
5. customthe aqueous layer was separated
6. temperaturethe mixture was heated to 50° C.
7. stirringstirred at this temperature for 1 h
8. temperatureto cool
9. customthe aqueous layer separated
10. additionCelite was added to the aqueous layer
11. filtrationthe mixture was filtered through a plug of celite
12. customThe filtrate was placed in a flask with overhead stirrer
13. temperatureheated to 50° C.
14. stirringwith stirring until a precipitate
15. customformed
16. filtrationThe solid was collected via filtration
17. customdried under vacuum