反应详情

温度

76 °C

4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (456.7 mg, 0.6026 mmol) was dissolved in trifluoroacetic acid (9.5 mL) and the reaction flask was fitted with a reflux condenser and put in a preheated oil bath (75-77° C.) and stirred for 16 h. The reaction was cooled to room temperature and concentrated. The reaction was diluted with DCM (40 mL) and treated with saturated sodium bicarbonate and 5 N NaOH to raise the pH of the aqueous phase to about 8. Then, the layers were separated and the aqueous phase was extracted with DCM and 10:1 DCM/MeOH. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH. The solid was not >95% pure by HPLC, so the filtrate and solid were combined, concentrated, and purified on a silica gel column according to the procedure described by Still et al. (Journal of Organic Chemistry, 1978, 43, 2923-2925) using this eluent system: 30:1 DCM/2 N ammonia in MeOH to 20:1 DCM/2 N ammonia in MeOH to 15:1 DCM/2 N ammonia in MeOH to 5:1 DCM/2 N ammonia in MeOH. The fractions with product were collected, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH, collected, and dried under high vacuum to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (194.7 mg, 62% yield) as a yellow powder. 1H NMR (CDCl3, 400 MHz) δ 11.93 (s, 1H), 8.71 (d, J=2.54 Hz, 1H), 8.31 (t, J=2.25 Hz, 1H), 8.27 (d, J=2.35 Hz, 1H), 8.05 (d, J=2.15 Hz, 1H), 5.42 (br s, 2H), 4.04 (s, 3H), 3.56 (quartet, J=6.65 Hz, 1H), 3.24 (t, J=4.69 Hz, 4H), 2.78 (s, 3H), 2.68-2.54 (m, 7H), 1.44 (t, J=6.85 Hz, 3H). m/z (ESI, pos. ion) 518 (M+H)+.

1. customthe reaction flask was fitted with a reflux condenser
2. customput in a preheated oil bath
3. temperatureThe reaction was cooled to room temperature
4. concentrationconcentrated
5. additionThe reaction was diluted with DCM (40 mL)
6. additiontreated with saturated sodium bicarbonate and 5 N NaOH
7. temperatureto raise the pH of the aqueous phase to about 8
8. customThen, the layers were separated
9. extractionthe aqueous phase was extracted with DCM and 10:1 DCM/MeOH
10. dry with materialdried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated
13. additiontreated with MeOH
14. filtrationfiltered
15. washThe solid was washed with MeOH
16. concentrationconcentrated
17. custompurified on a silica gel column
18. customThe fractions with product were collected
19. concentrationconcentrated
20. additiontreated with MeOH
21. filtrationfiltered
22. washThe solid was washed with MeOH
23. customcollected
24. customdried under high vacuum