反应详情

A solution of 6-Bromo-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole (15.9 g, 39.8 mmol) in 9:1 methanol:water (300 mL) was degassed for 10 min with an ultrasonic bath. Carbon monoxide gas was then bubbled through the solution for 2 min. To the resulting solution was added, successively, potassium carbonate (16.5 g, 119 mmol), 1,3-bis(diphenylphosphino)propane (0.82 g, 1.99 mmol), and palladium(II) acetate (0.45 g, 1.99 mmol). A balloon of CO with a purge valve was attached to the reaction flask, and the flask was evacuated and recharged five times with CO, and kept under balloon pressure of CO. The flask was heated in an oil bath set to 60° C. and stirred for 17 hr. The mixture was then cooled in an ice bath and acidified with 6M HCl to an apparent pH of <2. The resulting mixture was transferred to a separatory funnel and diluted with ether (500 mL) and water (250 mL). After shaking, the organic layer was stirred with activated charcoal (6 g) at ambient temperature for 15 min, then filtered through a glass microfiber filter to remove the charcoal and palladium residues. The filtrate was extracted with 1M NaOH (300 mL). The aqueous layer was stirred and acidified to pH<2 with conc. HCl. After stirring for a few minutes, a precipitate formed, which was collected by filtration, washed with water, and dried under vacuum to afford the title compound as a light tan powder (10.8 g, 74%).

1. customCarbon monoxide gas was then bubbled through the solution for 2 min
2. additionTo the resulting solution was added
3. customA balloon of CO with a purge valve was attached to the reaction flask
4. customthe flask was evacuated
5. temperatureThe flask was heated in an oil bath
6. customset to 60° C.
7. temperatureThe mixture was then cooled in an ice bath
8. customThe resulting mixture was transferred to a separatory funnel
9. additiondiluted with ether (500 mL) and water (250 mL)
10. stirringAfter shaking
11. stirringthe organic layer was stirred with activated charcoal (6 g) at ambient temperature for 15 min
12. filtrationfiltered through a glass microfiber
13. filtrationfilter
14. customto remove the charcoal and palladium residues
15. extractionThe filtrate was extracted with 1M NaOH (300 mL)
16. stirringThe aqueous layer was stirred
17. stirringAfter stirring for a few minutes
18. customa precipitate formed
19. filtrationwhich was collected by filtration
20. washwashed with water
21. customdried under vacuum