反应详情

To a suspension of tert-butyl 1-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-5-fluoro-4-pyridyl]piperidine-4-carboxylate 28 (69.7 g, 147.2 mmol) in DCM (348.5 mL) and triethylsilane (18.83 g, 25.87 mL, 161.9 mmol) was added TFA (151.1 g, 102.1 mL, 1.325 mol) (mixture sets solid on initial addition of TFA then goes into solution after complete addition). Resulting orange solution was stirred at room temperature overnight. Additional TFA (16.78 g, 11.34 mL, 147.2 mmol) was added and the mixture stirred at room temperature for 2 h. Mixture then heated at 40° C. for 20 mins to force reaction to completion. Mixture was concentrated in vacuo, chloroform (300 mL) was added and mixture again concentrated in vacuo to leave an orange solid suspension. Mixture triturated in DCM (approx. 200 mL), stirred for 20 mins then solid collected by filtration, washed with minimal DCM and dried by suction to leave a yellow solid. Filtrate was concentrated in vacuo, residue re-slurried in DCM (approx 50 mL), stirred for 20 mins then solid collected by filtration, washed with minimal DCM and dried by suction to leave a yellow solid which was combined with first crop of solid. Solid dried under vacuum overnight to leave desired product 29 as a yellow solid (82.8 g, 96%). 1H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.59 (s, 1H), 9.50 (dd, 1H), 8.84 (dd, 1H), 8.33 (d, 1H), 3.13-3.10 (m, 4H), 2.57-2.47 (masked signal, 1H) and 2.08-1.93 (m, 4H). MS (ES+) 418.1.

1. additionafter complete addition)
2. customResulting orange solution
3. stirringthe mixture stirred at room temperature for 2 h
4. temperatureMixture then heated at 40° C. for 20 mins
5. customreaction to completion
6. concentrationMixture was concentrated in vacuo, chloroform (300 mL)
7. additionwas added
8. concentrationmixture again concentrated in vacuo
9. customto leave an orange solid suspension
10. customMixture triturated in DCM (approx. 200 mL)
11. stirringstirred for 20 mins
12. filtrationsolid collected by filtration
13. washwashed with minimal DCM
14. customdried by suction
15. customto leave a yellow solid
16. concentrationFiltrate was concentrated in vacuo, residue re-slurried in DCM (approx 50 mL)
17. stirringstirred for 20 mins
18. filtrationsolid collected by filtration
19. washwashed with minimal DCM
20. customdried by suction
21. customto leave a yellow solid which
22. customSolid dried under vacuum overnight