反应详情

温度

15 °C

The 2-({(3aR,4S,6R,6aS)-6-[7-{[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}oxy)ethanol solution from above was cooled to 15° C., a solution of concentrated aqueous hydrochloric acid (465 kg) in methanol (623 kg), also tempered to 15° C., was charged. The reaction was stirred at 15° C. until the conversion criterion was fulfilled (>97%) and the phases were allowed to separate. The methanol-water layer, containing the product, was added to sodium bicarbonate (404 kg) in water (749 kg), keeping the temperature below 22° C. When pH≧6 the aqueous layer was extracted with ethylacetate (756 kg) and the phases were separated. The water layer was again washed with ethylacetate (1080 kg) whereafter the aqueous layer was discharged. The ethylacetate layers were combined and washed once with water (490 kg). The water content in the remaining ethylacetate solution was decreased to ≦0.8% (w/w) by vacuum distillation at 50° C., followed by a clear filtration and the concentration was adjusted to 6.2 L/kg 2-[((3aR,4S,6R,6aS)-6-{[5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol. The mixture was heated to 50° C. and then iso-octane was added (1152 kg) during 45 minutes. The slurry was cooled to 0° C. during 2.5 hours and then kept at this temperature for 3.5 hours. The product was isolated and washed with a cold (<5° C.) mixture of ethylacetate (722 kg) and iso-octane (828 kg). Finally, the isolated product was dried under vacuum to give the title compound as a white solid (203 kg, 90% calculated from 2-[((3aR,4S,6R,6aS)-6-{[5-Amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol).

1. customalso tempered to 15° C.
2. additionwas charged
3. customto separate
4. additionThe methanol-water layer, containing the product
5. additionwas added to sodium bicarbonate (404 kg) in water (749 kg)
6. customthe temperature below 22° C
7. extractionWhen pH≧6 the aqueous layer was extracted with ethylacetate (756 kg)
8. customthe phases were separated
9. washThe water layer was again washed with ethylacetate (1080 kg) whereafter the aqueous layer
10. washwashed once with water (490 kg)
11. distillationThe water content in the remaining ethylacetate solution was decreased to ≦0.8% (w/w) by vacuum distillation at 50° C.
12. filtrationfollowed by a clear filtration
13. concentrationthe concentration
14. temperatureThe mixture was heated to 50° C.
15. additioniso-octane was added (1152 kg) during 45 minutes
16. temperatureThe slurry was cooled to 0° C. during 2.5 hours
17. customThe product was isolated
18. washwashed with a cold (<5° C.) mixture of ethylacetate (722 kg) and iso-octane (828 kg)
19. customFinally, the isolated product was dried under vacuum