反应详情

温度

75 °C

A 250 mL round bottom flask equipped with an overhead stirrer, heating mantle and thermocouple, was charged with 31.5 mL of isopropanol (IPA), 13.5 mL water, 15.0 g (36.9 mmol) of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine freebase and 4.25 g (36.9 mmol) of 85% aqueous phosphoric acid. The mixture was heated to 75° C. A thick white precipitate formed at lower temperatures but dissolved upon reaching 75° C. The solution was cooled to 68° C. and then held at that temperature for 2 h. A slurry bed of solids formed during this age time [the solution can be seeded with 0.5 to 5 wt % of small particle size (alpine milled) monohydrate]. The slurry was then cooled at a rate of 4° C./h to 21° C. and then held overnight. 105 mL of IPA was then added to the slurry. After 1 h the slurry was filtered and washed with 45 mL EPA. The solids were dried on the frit with open to air. The solids were found to greater than 99.8% pure by HPLC area percentage (HPLC conditions same as those given above).

1. customA 250 mL round bottom flask equipped with an overhead stirrer
2. temperatureheating mantle
3. customA thick white precipitate formed at lower temperatures
4. dissolutiondissolved
5. customupon reaching 75° C
6. temperatureThe solution was cooled to 68° C.
7. customA slurry bed of solids formed during this age time [the solution
8. temperatureThe slurry was then cooled at a rate of 4° C./h to 21° C.
9. waitheld overnight
10. filtrationAfter 1 h the slurry was filtered
11. washwashed with 45 mL EPA
12. customThe solids were dried on the frit with open to air