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Process for preparation of Azacitidine

IP.com Disclosure Number: IPCOM000244609D
Publication Date: 2015-Dec-29
Document File: 2 page(s) / 34K

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The IP.com Prior Art Database


A method for preparation of Azacitidine is described in which the intermediate of formula (IV) is isolated as solid and associated impurities are removed during isolation. The isolated intermediate is converted to Azacitidine having purity conforming to regulatory specification. Prior art processes provide Azacitidine requiring successive purifications as compound (IV) is difficult to isolate and thus all the impurities get carried over to the final product Azacitidine.

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Process for preparation of Azacitidine


Azacitidine, chemically known as 4-Amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one is a chemical analogue of cytidine, and a nucleoside metabolic inhibitor indicated for the treatment of myelodysplastic syndrome (MDS).

Azacitidine (I)                                                          

A review of the prior art processes indicated that the intermediate compound (IV) was difficult to isolate and thus the impurities formed in the reaction got carried over to the final drug substance, azacitidine, which needed to be purified repeatedly for conforming to regulatory guidelines and also for obtaining the desired therapeutic effect. Herein, Scheme-1 describes a process for preparation of Azacitidine (I) which proceeds via the isolation of compound (IV) during which associated impurities are removed, further deprotection using methanolic ammonia gave azacitidine with the desired purity.

Scheme-1: Synthesis of Azacitidine (I)

Example 1:       Preparation of N-trimethylsilyltriacetyl azacitidine (compound IV)

Hexamethyldisilazane (HMDS; 600 ml) was added to a stirred mixture of acetonitrile (400 ml) and 5-azacytosine (100 g) at 25 to 35°C. Ammonium sulfate (3 g) was added to the stirred mixture and heated to 75 to 85°C with continued stirring, till completion of the reaction as monitored b...