反应详情

温度

5 °C

{[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5A, 646 g, 71% free amine equivalent), 6-trifluormethylnicotinic acid (429.7 g), diisopropylethylamine (1500 mL) and tetrahydrofuran (5.1 L) were placed in a flask equipped with an addition funnel, thermometer, and nitrogen inlet. The mixture was stirred vigorously for 10-15 min. The mixture was cooled to ˜5° C. and propylphosphonic anhydride (3.2 L of 50 wt % solution) added slowly. The mixture was stirred at ˜15° C. for 2 hrs. The mixture was cooled to ˜5° C. and quenched by the addition of water (505 mL) slowly. The pH was adjusted to 5-6 by adding 20 wt % K3PO4 (2.9 L). The mixture was diluted with EtOAc (3.2 L) and the temperature adjusted to 15-20° C. The phases were separated and the organic mixture was washed sequentially with water (1.5 L) and then 5 wt % sodium bicarbonate solution (2.6 L). The mixture was filtered and the solvent removed to minimum volume under vacuum. Isopropyl alcohol (2.0 L) was added and the mixture filtered, and the solvent removed under vacuum two times. Isopropyl alcohol (980 mL) was added and the mixture heated to 70-80° C. Water (1.5 L) was added while maintaining temperature above 65° C. and monitoring turbidity. The temperature was adjusted to 65° C., seeded with product (4.5 g) and the mixture held at 65° C. for 30 min. The mixture was cooled to ˜5° C. overnight and the product was isolated by filtration, washing the solids with cold 10% IPA in water (1 L), then dried in a vacuum oven to give the title compound (529 g);

1. customequipped with an addition funnel
2. stirringThe mixture was stirred at ˜15° C. for 2 hrs
3. temperatureThe mixture was cooled to ˜5° C.
4. customquenched by the addition of water (505 mL) slowly
5. additionby adding 20 wt % K3PO4 (2.9 L)
6. additionThe mixture was diluted with EtOAc (3.2 L)
7. customadjusted to 15-20° C
8. customThe phases were separated
9. washthe organic mixture was washed sequentially with water (1.5 L)
10. filtrationThe mixture was filtered
11. customthe solvent removed to minimum volume under vacuum
12. additionIsopropyl alcohol (2.0 L) was added
13. filtrationthe mixture filtered
14. customthe solvent removed under vacuum two times
15. additionIsopropyl alcohol (980 mL) was added
16. temperaturethe mixture heated to 70-80° C
17. additionWater (1.5 L) was added
18. temperaturewhile maintaining temperature above 65° C. and monitoring turbidity
19. customwas adjusted to 65° C.
20. waitthe mixture held at 65° C. for 30 min
21. temperatureThe mixture was cooled to ˜5° C. overnight
22. customthe product was isolated by filtration
23. washwashing the solids with cold 10% IPA in water (1 L)
24. customdried in a vacuum oven