反应详情

温度

70 °C

To a slurry of 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine hydrochloride (7.50 g, 15.0 mmol) and water (100 mL) is added sodium hydroxide solution (10 N, 2.0 mL, 20 mmol) dropwise. Then, fumaric acid (3.48 g, 30 mmol) is added. The mixture is stirred for about 15-20 min and then heated to about 65-75° C. and stirred until all of the solid dissolves. The solution is filtered and the filtrate is cooled to about 0-5° C. over about 1 h. The mixture is stirred for 1 h and then filtered and the collected solid washed with cold water and isopropanol. The solid is dried under vacuum at about 60° C./10 mmHg for about 20 h to give a white solid (6.54 g, 75%) in anhydrous form. A portion of the compound is placed in a drying dish at 80-100% relative humidity (RH) and room temperature for about 24 h. The compound absorbed 5.8% water forming a dihydrate which is stable at room temperature and at 5-100% relative humidity (RH). 1H NMR (CDCl3): δ 8.43 (s, 1H), 6.86 (d, 2H, J=10.2 Hz), 6.51 (s, 2H), 5.84 (m, 1H), 4.15 (t, 2H, J=7.9 Hz), 3.04 (t, 2H, J=7.2 Hz), 2.57 (s, 3H), 2.08 (m, 2H), 1.33 (d, J=6.7, 3H).

1. stirringstirred until all of the solid
2. dissolutiondissolves
3. filtrationThe solution is filtered
4. temperaturethe filtrate is cooled to about 0-5° C. over about 1 h
5. stirringThe mixture is stirred for 1 h
6. filtrationfiltered
7. washthe collected solid washed with cold water and isopropanol
8. customThe solid is dried under vacuum at about 60° C./10 mmHg for about 20 h