Sodium Hydroxide → Azacytidine

HRID 1777282Notes

Reaction equation

HRID 1777282 reaction equation
FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.[NH:16]1[CH:23]=[N:22][C:20]([NH2:21])=[N:19][C:17]1=[O:18].C(O[CH:28]1[O:40][C@H:39]([CH2:41][O:42]C(=O)C)[C@@H:34]([O:35]C(=O)C)[C@H:29]1[O:30]C(=O)C)(=O)C.C(=O)(O)[O-].[Na+].[OH-].[Na+].C[O-].[Na+]>C(#N)C.O.CO.[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[CH:23]1[N:16]([C@@H:28]2[O:40][C@H:39]([CH2:41][OH:42])[C@@H:34]([OH:35])[C@H:29]2[OH:30])[C:17](=[O:18])[N:19]=[C:20]([NH2:21])[N:22]=1

Participants

12

Reactant 6

HCID 14798Sodium HydroxideHCID 94358Bis(trimethylsilyl)trifluoroacetamideHCID 516892Sodium BicarbonateHCID 9797055D-Ribofuranose, 1,2,3,5-tetraacetateHCID 10942334Sodium MethoxideHCID 178508820HCID 178508820, compound

Product 1

HCID 9444AzacytidineYield 36.7%

Reagents, catalysts & solvents 5

HCID 24193Titanium TetrachlorideCatalystHCID 887MethanolSolvent2×HCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent2×HCID 6344DichloromethaneSolvent

Procedure

34.7 mL of BSTFA are added to a suspension of 6.3 g of azacytosine in 126 mL of acetonitrile. The mixture is brought to 50° C. and it is stirred for 90 minutes. 7 mL titanium tetrachloride and then a solution of 16.7 g of 1,2,3,5-tetra-O-acetyl-D-ribofuranose in 33 mL of acetonitrile are added to the limpid solution, in about ten minutes. Stirring is maintained for 120 minutes, it is cooled to room temperature and it is slowly poured onto a mixture constituted by 500 ml of dichloromethane and 330 mL of water into which 9.5 g of sodium bicarbonate had been previously dissolved. Stirring is carried out for 15 minutes and the pH is adjusted to pH=4.5 using 30% sodium hydroxide in water. It is filtered on earth filter, the mixture is left to settle and phases are separated. The aqueous phase is washed twice using 125 ml of dichloromethane for each washing. The organic phases which are anhydrified by treating them with anhydrous calcium chloride are combined. Concentration is carried out at low pressure until a viscous residue is obtained. The residue is recovered with 250 mL of methanol, it is concentrated once again at low pressure until a viscous residue is obtained. 250 mL of methanol are added, it is heated to 50° C. and 15 mL of a 10% solution of sodium methylate in methanol are added. It is stirred for 1 hour, it is cooled to room temperature, it is stirred to complete precipitation and the solid is filtered by washing it on the filter with methanol. 4.7 g of azacitidine with HPLC purity (UV 254 nm) of 97.2% are obtained after drying at low pressure.

Workup

  1. customis brought to 50° C.
  2. stirringStirring
  3. temperatureis maintained for 120 minutes
  4. additionit is slowly poured onto a mixture
  5. dissolutionhad been previously dissolved
  6. stirringStirring
  7. waitis carried out for 15 minutes
  8. filtrationIt is filtered on earth
  9. filtrationfilter
  10. waitthe mixture is left
  11. customphases are separated
  12. washThe aqueous phase is washed twice
  13. additionby treating them with anhydrous calcium chloride
  14. concentrationConcentration
  15. customis obtained
  16. customThe residue is recovered with 250 mL of methanol, it
  17. concentrationis concentrated once again at low pressure until a viscous residue
  18. customis obtained
  19. temperatureit is heated to 50° C.
  20. stirringIt is stirred for 1 hour
  21. temperatureit is cooled to room temperature
  22. stirringit is stirred to complete precipitation
  23. filtrationthe solid is filtered
  24. washby washing it on the
  25. filtrationfilter with methanol

Sources & evidence

ORD record
ord-2e7200ae6d9e452f8e6004fd93d3dacd
Source dataset
uspto-grants-2016_02
Patent number
US09266863B2

Reaction notes

Loading…