反应详情

温度

60 °C

To a suspension of NaH (40.9 g, 1.02 mol, 60% in oil) in anhydrous THF (750 mL) is added 3-methylamino-propan-1-ol (115 g, 1.21 mol) at about 20-30° C. dropwise over 30 min. The mixture is stirred for 30 min. Then, a solution of [5-chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-((1S)-2,2,2-trifluoro-1-methyl-ethyl)-amine (150 g, 0.379 mol) in THF (150 mL) is added slowly over 15 min. The mixture is heated to 60° C. and stirred for 16 h, then cooled to 0-6° C. Cold water (1500 mL) is added dropwise while maintain the temperature between 10±3° C. THF is removed by distillation. The reaction mixture is extracted with t-butylmethyl ether (TBME, 2×1000 mL) and to the separated aqueous phase is added in portions succinic acid (296 g, 2.51 mol) is added in portions and followed by addition of TBME (1000 mL). The mixture is cooled to 3±3° C. and stirred for 1 h. The crude solid product is filtered, washed with cold water (150 mL) and TBME (2×400 mL). The wet solid is dissolved into water (2000 mL) at about 75° C. The solution is filtered at 60-70° C. and cooled to 0° C. over 1 h and stirred for 1 h at this temperature. The solid is filtered and dried at 35° C./10 mmHg for 20 h to give a white solid in anhydrous form (175 g, 80%, >99% HPLC area purity and 99% ee). A small portion of the anhydrous compound is placed in a drying dish of 80%-100% relative humidity at about 20° C. to about 30° C. for 24 h. It absorbed 5.8% wt of water and stopped. This dihydrate is stable at about 20° C. to about 30° C. and at 5%-100% relative humidity. 1H NMR (CDCl3): δ 10.2 (bs, 1H), 8.26 (s, 1H), 6.80 (d, 2H, J=10.5 Hz), 5.79 (m, 1H), 4.13 (t, 2H, J=6.3 Hz), 3.03 (t, 2H, J=7.2 Hz), 2.57 (s, 3H), 2.35 (s, 4H), 2.07 (m, 2H), 1.27 (d, J=6.0, 3H).

1. stirringstirred for 16 h
2. temperaturecooled to 0-6° C
3. temperaturewhile maintain the temperature between 10±3° C
4. customTHF is removed by distillation
5. extractionThe reaction mixture is extracted with t-butylmethyl ether (TBME, 2×1000 mL) and to the separated aqueous phase
6. additionis added in portions
7. temperatureThe mixture is cooled to 3±3° C.
8. stirringstirred for 1 h
9. filtrationThe crude solid product is filtered
10. washwashed with cold water (150 mL) and TBME (2×400 mL)
11. dissolutionThe wet solid is dissolved into water (2000 mL) at about 75° C
12. filtrationThe solution is filtered at 60-70° C.
13. temperaturecooled to 0° C. over 1 h
14. stirringstirred for 1 h at this temperature
15. filtrationThe solid is filtered
16. customdried at 35° C./10 mmHg for 20 h
17. customto give a white solid in anhydrous form (175 g, 80%, >99% HPLC area purity and 99% ee)
18. waitA small portion of the anhydrous compound is placed in a drying dish of 80%-100% relative humidity at about 20° C. to about 30° C. for 24 h
19. customIt absorbed 5.8% wt of water
20. customis stable at about 20° C. to about 30° C. and at 5%-100% relative humidity