Chlorotrimethylsilane → Azacytidine

Temperature

2.5 °C

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. extractionThe resulting mixture is extracted with dichloromethane
10. extractionThe combined organic extract
11. washis washed
12. temperaturewith cooled (0-5° C.) 10% sodium bicarbonate and brine
13. dry with materialdried over magnesium sulfate
14. filtrationfiltered
15. concentrationthe filtrate concentrated in vacuum to dryness
16. dissolutionThe off-white foam is dissolved in methanol
17. additiontreated with a solution of 25% sodium methoxide in methanol
18. stirringThe suspension is stirred at ambient temperature for 15 hours
19. filtrationthe solid is filtered off
20. washwashed with methanol and anhydrous ether
21. customdried in vacuum
22. customThe crude 5-azacytidine is further purified from DMSO and methanol (for details see Example 4)

ORD record

ord-535c4632dc8145bfa1a68cb2f4c5cc0b

Source dataset

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07858774B2