Synthesis of 5-Azacytidine
The present invention provides a method for the preparation of 5-azacytidine, wherein 5-azacytidine is represented by the structure: The method involves the silylation of 5-azacytosine, followed by the coupling of silylated 5-azacytosine to a protected β-D-ribofuranose derivative. The coupling reaction is catalyzed by trimethylsilyl trifluoromethanesulfonate (TMS-Triflate).
1 - 30 . (canceled)
31 . A method of preparing 5-azacytidine comprising the steps of:
a) reacting 5-azacytidine with at least one silylating reagent to yield silylated 5-azacytidine;
b) adding directly to the reaction mixture of a), a non-metallic Lewis acid catalyst and protected β-D-ribofuranose; and
c) deprotecting and desilylating the product of step b).
32 . The method of claim 31 wherein each said silylating reagent is a trimethylsilyl (TMS) reagent.
33 . The method of claim 31 wherein each said silylating reagent is selected from the group consisting of hexamethyldisilizane (HMDS) and chlorotrimethylsilane (TMSCl).
34 . The method of claim 31 wherein the silylation reaction step in a) is carried out in the presence of ammonium sulfate.
35 . The method of claim 31 wherein the silylation reaction step in a) is carried out in the presence of a dry organic solvent.
36 . The method of claim 35 wherein said dry organic solvent is a polar solvent.
37 . The method of claim 36 wherein said polar solvent is acetonitrile.
38 . The method of claim 31 wherein said protected ribofuranose is selected from the group consisting of:
39 . The method of claim 31 further comprising:
d) recrystallizing the product from step c).
40 . The method of claim 39 wherein step e) comprises:
i) dissolving the product form step c) in dimethylsulfoxide;
ii) adding methanol to the solution of i); and
iii) isolating the recrystallized product.