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Publication Date: 2010-Sep-22

Publishing Venue

The Prior Art Database


The present invention relates to improved processes for preparing 1-(2'-deoxy-b-L-ribofuranosyl)thymine derivatives, which thymine derivatives can be intermediates useful for the synthesis of telbivudine, or can be telbivudine itself. Additionally, the present invention provides telbivudine of improved purity suitably when prepared by processes according to the invention. The present invention further provides novel monoprotected derivatives of telbivudine that have potential utility as reference markers and standards in the pharmaceutical field.

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PROCESS FOR PREPARING 1-(2’-deoxy-b-L-ribofuranosyl)thymine

Background of the invention

[0001]               Telbivudine, which is a compound of formula (I) below, is the international commonly accepted non-proprietary name for 1-[(2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-5-methyl-1H-pyrimidine-2,4-dione (which also has a number of conventional names, such as β-L-2’-deoxythymidine, β-L-thymidine, and β-L-dT).  Telbivudine has an empirical formula of C10H14N2O5, and a molecular weight of 242.23 g/mol.


[0002]               Telbivudine is a thymine nucleoside analogue with selective activity against the hepatitis B virus (HBV). In the

United States

, telbivudine is marketed under the name TYZEKATM, and is indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases or histologically active disease.

[0003]               Telbivudine was first described in Coll.


Chem. Commun., Vol. 29, p. 2809 (1964). Furthermore, there are a number of synthetic processes reported in the literature for preparing telbivudine. For example,


patent application publication Nos. US2004/063926, US2004/266996 and US2005/059632, make use of compounds of formula (V), wherein X is an acyl- or aroyl-type hydroxyl protecting group, as the key intermediate compounds for preparing telbivudine via a hydroxyl deprotection reaction as shown in Scheme 1.

Scheme 1

[0004]               In particular, the deprotection reaction described in these references is carried out either in the presence of sodium methoxide in methanol or in the presence of a methanolic solution saturated with ammonia. However, the two deprotection reactions described therein suffer from important drawbacks, which make them unsuitable for industrial use. Namely, the use of sodium methoxide as a base in the reaction requires the subsequent use of ion-exchange resins, such as Dowex-50 strong cation-exchange (H+) resins, in order to eliminate the sodium cations present in the reaction mixture. Said resins are not suitable for scale-up since they are expensive, require the use of special installations such as ion-exchange columns, and high volumes of solvent, and hence render inefficient preparation of telbivudine product especially at industrial scale. Furthermore, the use of ammonia is also not desirable for scale-up since it is a highly toxic reagent which causes health and environmental problems, is inconvenient to work with at industrial scale and typically exhibits long reaction times of 48 hours or more.

[0005]               In addition, there are different synthetic strategies in the literature for the preparation of compounds of formula (V), as key intermediates for the synthesis of telbivudine. For example,


patent application publication Nos. US2004/266996 and US2005/059632, describe the preparation of 1-(


,5’-di-O-p-toluoyl-2’-deoxy-b-L-ribofuranosyl)thymine (a compound of formula Va as shown belo...