反应详情

温度

8.5 °C

IPA solution (total of 70 ml) containing (2R,4S)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-[(8aS)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-piperidinecarboxamide (10.01 g) and (2R,4 R)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-[(8aS)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-piperidinecarboxamide (4.27 g) was diluted with IPA (23.8 ml). Maleic acid (2.85 g) in IPA (21 ml) was added, was washed in with IPA (2.8 ml) and was seeded with orvepitant maleate A (10 mg). The slurry was stirred for 1 hour. Isooctane (95 ml) was added dropwise over 15 minutes and the slurry was stirred for a further 1 hour. The mixture was cooled to 7-10° C. and was filtered, washed with a 1:1 mixture of IPA and isooctane and was dried in vacuo at about 50° C. Yield 10.88 g. 2.0 g of this was dissolved in IPA (20 ml), was heated to give a clear colourless solution, allowed to cool to about 50° C., seeded (10 mg of example 3 Form 1) and was then allowed to cool. This gave a very thick unstirrable slurry which was reheated to give a solution. Isooctane (20 ml) was added at 60° C., cooled to about 50° C. and was reseeded (10 mg example 3 Form 1). The hazy solution was stirred overnight at about 50° C. and was allowed to cool to about 20° C. After 5 hours, the solid was collected by vacuum filtration, was washed with a mixture of 1:1 of IPA and iso-octane (2×2 ml, 2×1 ml) and was dried in vacuum at 50° C. Yield 1.546 g.

1. washwas washed in with IPA (2.8 ml)
2. additionIsooctane (95 ml) was added dropwise over 15 minutes
3. stirringthe slurry was stirred for a further 1 hour
4. filtrationwas filtered
5. washwashed with a 1:1 mixture of IPA and isooctane
6. customwas dried in vacuo at about 50° C
7. dissolution2.0 g of this was dissolved in IPA (20 ml)
8. temperaturewas heated
9. customto give a clear colourless solution
10. temperatureto cool to about 50° C.
11. temperatureto cool
12. customThis gave a very thick unstirrable slurry which
13. customto give a solution
14. temperaturecooled to about 50° C.
15. stirringThe hazy solution was stirred overnight at about 50° C.
16. temperatureto cool to about 20° C
17. waitAfter 5 hours
18. filtrationthe solid was collected by vacuum filtration
19. washwas washed with a mixture of 1:1 of IPA and iso-octane (2×2 ml, 2×1 ml)
20. customwas dried in vacuum at 50° C