Chlorotrimethylsilane → Azacytidine

A mixture of 5-azacytosine, HMDS, and TMSCl in acetonitrile is heated to reflux for 20 hours under an inert atmosphere. TMS-triflate and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose are then added directly to the silylated 5-azacytosine in acetonitrile. The addition is performed at ambient temperature and under an inert atmosphere. The reaction mixture is maintained under stirring for 20 hours, then the acetonitrile is removed under vacuum. The solids are then dissolved in dichloromethane, and the mixture is poured over a pre-cooled (0–5° C.) sodium bicarbonate solution (10%). The resulting mixture is extracted with dichloromethane. The combined organic extract is washed with cooled (0–5° C.) 10% sodium bicarbonate and brine, then dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuum to dryness. The off-white foam is dissolved in methanol and treated with a solution of 25% sodium methoxide in methanol. The suspension is stirred at ambient temperature for 15 hours, then the solid is filtered off, washed with methanol and anhydrous ether, then dried in vacuum. The crude 5-azacytidine is further purified from DMSO and methanol (for details see Example 4).

1. temperatureis heated
2. temperatureto reflux for 20 hours under an inert atmosphere
3. additionThe addition
4. customis performed at ambient temperature and under an inert atmosphere
5. temperatureThe reaction mixture is maintained
6. customthe acetonitrile is removed under vacuum
7. dissolutionThe solids are then dissolved in dichloromethane
8. additionthe mixture is poured over
9. temperaturea pre-cooled (0–5° C.) sodium bicarbonate solution (10%)
10. extractionThe resulting mixture is extracted with dichloromethane
11. extractionThe combined organic extract
12. washis washed
13. temperaturewith cooled (0–5° C.) 10% sodium bicarbonate and brine
14. dry with materialdried over magnesium sulfate
15. filtrationfiltered
16. concentrationthe filtrate concentrated in vacuum to dryness
17. dissolutionThe off-white foam is dissolved in methanol
18. additiontreated with a solution of 25% sodium methoxide in methanol
19. stirringThe suspension is stirred at ambient temperature for 15 hours
20. filtrationthe solid is filtered off
21. washwashed with methanol and anhydrous ether
22. customdried in vacuum
23. customThe crude 5-azacytidine is further purified from DMSO and methanol (for details see Example 4)

ORD record

ord-34b915492fe3408d8912bf3c8e6c5810

Source dataset

uspto-grants-2006_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07038038B2