反应详情

The manufacture and synthesis Ribavirin (ICN Pharmaceuticals, Costa Mesa Calif.) are described in U.S. Pat. No. 4,211,771, incorporated herein by reference. A dry 1 L ml 3-neck round bottom flask, equipped with a stir bar, gas inlet adapter, and thermometer, was charged with 50 g Ribavirin (0.204 moles), 500 ml trimethyl phosphate, and 0.367 ml de-ionized water (0.0204 moles). The mixture was cooled under nitrogen with an ice/water bath. When the temperature reached 10° C., 23.3 ml phosphorous oxychloride was added, the flask was removed from the ice bath, and the mixture was stirred under nitrogen. After 30 min., the flask was cooled in the ice/water bath. When the temperature reached 10° C., the mixture was poured into a 2 L beaker containing 1000 ml ice water. The pH was adjusted to pH=9.0 using 4 M LiOH and the mixture was stirred overnight. After final adjustment to pH 9, the white precipitate that has formed is filtered away using a 0.2 mm filter. The mixture was evaporated at 40° C. under reduced pressure to 1 L. The solution was added to 1 L hot ethanol dropwise. The white precipitate was collected on a 2 L glass fritted funnel, coarse grade, washing the solid with two 100 ml portions of ethanol, re-suspending the solid each time. The product was dried under vacuum overnight, yield: 89 g. The solid was dissolved in 200 ml de-ionized water, and 5 g activated carbon was added. The mixture was filtered through a 0.2 mm filter, washing the carbon with 50 ml de-ionized water. The filtered solution was added dropwise to 1200 ml hot ethanol The mixture was cooled to room temperature, and the precipitate was collected on the 2 L glass fritted funnel. The solid was washed with 2×100 ml ethanol in the funnel, and dried under vacuum. Yield: 66.6 g. The dried product was dissolved in 200 ml de-ionized water. Amberlite IR-120 H.C.P. resin (H+ form) was added until the pH of the mixture reached pH=2.18. The resin was filtered off using a 0.2 mm filter, and the final solution was lyophilized. Yield: 54.8 g (0.160 moles), 78.5%, Ribavirin 5'-monophosphate. Elemental analysis indicates the product contains 1 mole water/mol ribavirin 5'-monophosphate.

1. customA dry 1 L ml 3-neck round bottom flask, equipped with a stir bar, gas inlet adapter
2. temperatureThe mixture was cooled under nitrogen with an ice/water bath
3. customreached 10° C.
4. customthe flask was removed from the ice bath
5. temperaturethe flask was cooled in the ice/water bath
6. customreached 10° C.
7. additionthe mixture was poured into a 2 L beaker
8. additioncontaining 1000 ml ice water
9. stirringthe mixture was stirred overnight
10. customAfter final adjustment to pH 9, the white precipitate that has formed
11. filtrationis filtered away
12. filtrationfilter
13. customThe mixture was evaporated at 40° C. under reduced pressure to 1 L
14. additionThe solution was added to 1 L hot ethanol dropwise
15. customThe white precipitate was collected on a 2 L glass fritted funnel
16. washcoarse grade, washing the solid with two 100 ml portions of ethanol
17. customThe product was dried under vacuum overnight, yield: 89 g
18. dissolutionThe solid was dissolved in 200 ml de-ionized water
19. addition5 g activated carbon was added
20. filtrationThe mixture was filtered through a 0.2 mm
21. filtrationfilter
22. washwashing the carbon with 50 ml de-ionized water
23. additionThe filtered solution was added dropwise to 1200 ml hot ethanol The mixture
24. customthe precipitate was collected on the 2 L glass fritted funnel
25. washThe solid was washed with 2×100 ml ethanol in the funnel
26. customdried under vacuum
27. dissolutionThe dried product was dissolved in 200 ml de-ionized water
28. additionresin (H+ form) was added until the pH of the mixture
29. filtrationThe resin was filtered off
30. filtrationfilter