反应详情

温度

100 °C

A single necked round bottom flask (250 mL) equipped with a magnetic stir bar was charged with tert-butyl 5-bromo-1H-indazole-carboxylate (4.0 g, 13.4 mmol) dissolved in 1,4-dioxane (130 mL), 2-chloro-3-pyridine boronic acid pinacol ester (4 g, 16.7 mmol), Pd(PPh3)4 (1.5 g, 1.3 mmol) and 2M aq.Na2CO3 (20 mL, 40 mmol) under nitrogen atmosphere. The rubber septum was replaced with reflux condenser containing three-way stopcock equipped with argon filled balloon. The reaction contents were stirred and air was removed from the closed reaction system by vacuum and back filled with argon. Following three cycles of degassing, the reaction mixture was heated at 100° C. (oil-bath) under argon. Inflated argon balloon was emptied, refilled with argon and remounted in the course of reaction. The initial pale yellow heterogeneous reaction mixture turned to clear biphasic off-brown solution. After 18 h with no additional change in the proportion of the product (62%) as analyzed by LC/MS, the reaction mixture was cooled to room temperature. Upon concentration of the reaction mixture, EtOAc/water (200 mL/75 mL) was transferred to the concentrate and stirred for 30 min. The organic layer was separated and the aqueous layer extracted with EtOAc (100 mL×2). MgSO4 (20g) and Celite® (20g) were added to combined organic layers and the contents suction filtered after stirring for 1 h. The filter cake was washed with EtOAc (300 mL) and the combined filtrates concentrated by rotary evaporator under vacuum. The crude concentrate was dissolved in 1% MeOH/CH2Cl2 and absorbed on silica gel (20g) by evaporating the solvent followed by drying. Subsequent purification by flash silica gel column purification of the dry powder (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAC/hexanes eluting solvent) provided 5-(2-chloropyridin-3-yl)-1H-indazole (1.5 g, 47%) as a white crystalline solid after concentration of the desired product fractions. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 8.41 (dd, 1H, J=1.8 and 4.7 Hz), 8.13 (s, 1H), 7.90 (dd, 1H, J=1.7 and 4.7 Hz), 7.84 (s, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.51 (dd, 1H, J=4.7 and 7.3 Hz), 7.42 (dd, 1H, J=1.4 and 8.5 Hz). LCMS: 95%, MS (m/e) 230 (MH+).

1. customA single necked round bottom flask (250 mL) equipped with a magnetic stir bar
2. temperaturewith reflux condenser
3. additioncontaining three-way stopcock
4. customequipped with argon filled balloon
5. customThe reaction contents
6. customair was removed from the closed reaction system by vacuum
7. additionback filled with argon
8. customof degassing
9. additionrefilled with argon
10. customremounted in the course of reaction
11. temperaturethe reaction mixture was cooled to room temperature
12. concentrationconcentrate
13. stirringstirred for 30 min
14. customThe organic layer was separated
15. extractionthe aqueous layer extracted with EtOAc (100 mL×2)
16. additionMgSO4 (20g) and Celite® (20g) were added
17. filtrationthe contents suction filtered
18. stirringafter stirring for 1 h
19. washThe filter cake was washed with EtOAc (300 mL)
20. concentrationthe combined filtrates concentrated by rotary evaporator under vacuum
21. concentrationThe crude concentrate
22. dissolutionwas dissolved in 1% MeOH/CH2Cl2
23. customabsorbed on silica gel (20g)
24. customby evaporating the solvent
25. customby drying
26. customSubsequent purification
27. customby flash silica gel column purification of the dry powder (Combiflash® companion System® with RediSep® silica gel column 120 g, 30-70% EtOAC/hexanes eluting solvent)