反应详情

A three necked round bottom flask equipped with an internal thermometer and an overhead stir motor was charged with 600 mL of THF and chilled to −78° C. t-BuLi (1.7 M in THF, 200 mL, 0.340 mol) was added to the flask, and the mixture was stirred for 15 minutes. 5-Bromo-3-methyl-1H-indazole (22.4 g, 0.106 mol) in 200 mL THF was then added dropwise via an addition funnel. The rate of addition was closely monitored to make sure that the internal temperature remained below −70° C. The resulting orange solution was stirred for 30 minutes, at which point CO2 was bubbled through the mixture. A white precipitate was observed. After 20 minutes, the ice bath was removed and the temperature was allowed to warm to room temperature. The resulting mixture was stirred for an additional 30 minutes. Water was then added to the mixture (40 mL initially followed by a further 200 mL). The biphasic mixture was partially concentrated under reduced pressure, removing about 75% of the original organic portion. The biphasic solution was then transferred to an addition funnel, and the organic phase was extracted with 100 mL of 2M NaOH. The combined aqueous extracts were washed with ether and then acidified to pH=2.0 with concentrated HCl. A precipitate began to form, and the mixture was cooled to 0° C. to complete the precipitation. The resulting solid was filtered, washed with 1M HCl, and dried under reduced pressure at 160° C. over phosphorus pentoxide, affording 3-methyl-1H-indazole-5-carboxylic acid (18.1 g, 96% yield) as a pink/beige solid. LCMS (API-ES) m/z (%): 177.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 2.61 (s, 3H) 3.33 (b, 2H), 7.52 (d, J=6.0 Hz, 1H), 8.05 (d, J=6.0 Hz, 1H), 8.50 (s, 1H).

1. customA three necked round bottom flask equipped with an internal thermometer
2. additionwas added to the flask
3. stirringthe mixture was stirred for 15 minutes
4. additionThe rate of addition
5. customremained below −70° C
6. customwas bubbled through the mixture
7. customthe ice bath was removed
8. stirringThe resulting mixture was stirred for an additional 30 minutes
9. additionWater was then added to the mixture (40 mL
10. concentrationThe biphasic mixture was partially concentrated under reduced pressure
11. customremoving about 75% of the original organic portion
12. customThe biphasic solution was then transferred to an addition funnel
13. extractionthe organic phase was extracted with 100 mL of 2M NaOH
14. washThe combined aqueous extracts were washed with ether
15. customto form
16. temperaturethe mixture was cooled to 0° C.
17. customthe precipitation
18. filtrationThe resulting solid was filtered
19. washwashed with 1M HCl
20. dry with materialdried under reduced pressure at 160° C. over phosphorus pentoxide