反应详情

温度

50 °C

To a 3-necked, 3 L, round-bottomed flask equipped with a nitrogen line, temperature probe, heating mantle, reflux condenser, mechanical stirrer, and 1 N aq. NaOH scrubber were added 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 12, 120.98 g, 75 wt %, 90.74 g actual, 438 mmol) and toluene (1 L). The mixture was warmed to 50° C. for 1 h with stirring. The mixture was then cooled to 25° C. and thionyl chloride (47.9 mL, 657 mmol) was added. The mixture was warmed back to 50° C. and held for 1 h. During this time, in a separate 5 L jacketed reactor equipped with a mechanical stirrer and temperature probe were added toluene (600 mL), aqueous sodium carbonate (185.7 g, 1.75 mol in 1.6 L water), and 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.HOAc (Intermediate 23, 122 g, 438 mmol). This biphasic mixture was cooled to 0° C. After cooling to 0° C., the original slurry was poured through a filter and over the stirring biphasic mixture of amine and aqueous sodium carbonate. The mixture was allowed to warm to room temperature. After 2 h, additional 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.HOAc (4 g, 14 mmol) was added and the mixture was stirred for 30 additional minutes. At the end of this period, the layers were separated and 100 mL of methanol were added to the organic layer. The organic layer was dried over MgSO4, filtered, and concentrated to a white solid. This solid was taken up in ethanol (1.4 L) and warmed to 77° C. The mixture was then cooled to 55° C. and seeded with previously crystallized material. (Note: The seeds were generated from slurrying the initial product in 2-propanol at room temperature [100 mg/mL]). The mixture was cooled to room temperature at a rate of 5° C. per hour. After stirring at room temperature for 14 h, the mixture was filtered and dried to provide the final product as a white crystalline solid (136.84 g, 74%). 1H NMR (400 MHz, CDCl3): 7.88-7.78 (m, 1.78H), 7.75-7.69 (s, 1.22H), 7.51-7.43 (m, 1H), 7.17-7.11 (m, 1H), 6.30-6.28 (m, 1H), 4.03-3.48 (m, 7H), 3.29-3.21 (m, 1H), 3.15-2.92 (m, 2H), 2.30 (s, 6H). MS (ESI) mass calcd for C21H22FN7O, 407.19; m/z found, 408 [M+H]+. Anal. calcd. for C21H22FN7O C, 61.90; H, 5.44; N, 24.06. found C, 61.83; H, 5.42; N, 24.08.

1. customTo a 3-necked, 3 L, round-bottomed flask equipped with a nitrogen line, temperature probe
2. temperatureheating mantle
3. temperaturereflux condenser, mechanical stirrer
4. temperatureThe mixture was then cooled to 25° C.
5. temperatureThe mixture was warmed back to 50° C.
6. customequipped with a mechanical stirrer
7. temperatureThis biphasic mixture was cooled to 0° C
8. temperatureAfter cooling to 0° C.
9. additionthe original slurry was poured through
10. filtrationa filter and over the stirring biphasic mixture of amine and aqueous sodium carbonate
11. temperatureto warm to room temperature
12. waitAfter 2 h
13. stirringthe mixture was stirred for 30 additional minutes
14. customAt the end of this period, the layers were separated
15. addition100 mL of methanol were added to the organic layer
16. dry with materialThe organic layer was dried over MgSO4
17. filtrationfiltered
18. concentrationconcentrated to a white solid
19. temperaturewarmed to 77° C
20. temperatureThe mixture was then cooled to 55° C.
21. customat room temperature
22. temperatureThe mixture was cooled to room temperature at a rate of 5° C. per hour
23. stirringAfter stirring at room temperature for 14 h
24. filtrationthe mixture was filtered
25. customdried