Process for producing 5-fluoro-1-(2R, 5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine

1. An improved process for producing 5-Fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine of Formula I and its pharmaceutically acceptable salts,

the process comprising the steps of:

a. reducing the compound (2R,5S)-5-(4-Amino-5-fluoro-2-oxo-2H pyrimidin-1-yl)-[1,3]-oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl-1R-cyclohexyl Ester) of Formula II employing a reducing agent;

to obtain the compound (2R-Cis)-2-hydroxymethyl-5-(5 fluoro cytosine-yl)-1,3-oxathiolane of Formula III;

b. followed by in_situ salification of compound (2R-Cis)-2-hydroxymethyl-5-(5′fluoro cytosine-1′-yl)-1,3-oxathiolane of Formula III employing a mineral acid or sulfonic acid in presence of an organic solvent to give compound (2R-Cis)-2-hydroxymethyl-5-(5′fluoro cytosine-1′-yl)-1,3-oxathiolane salt of Formula IV,

wherein X is mineral acid or sulfonic acid; and

c. neutralizing the compound of Formula IV employing an organic solvent in presence of an organic amine base to obtain 5-Fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine of Formula I.

2. The process according to claim 1 , wherein the reducing agent is sodium borohydride.

3. The process according to claim 1 , wherein the organic solvent used in step (b) is selected from alcohols.

4. The process according to claim 3 , wherein the alcohol is selected from methanol, isopropanol or mixtures thereof.

5. The process according to claim 1 , wherein the mineral acid or sulfonic acid is selected from hydrochloric acid, hydrobromic acid and methane sulfonic acid.

6. The process according to claim 5 , wherein the mineral acid is hydrochloric acid.

7. The process according to claim 1 , wherein the organic solvent used in step (c) is selected from alcohols and chlorinated solvents or mixtures thereof.

8. The process according to claim 7 , wherein the organic solvent is selected from methanol, methylene chloride and chloroform.

9. The process according to claim 1 , wherein the organic amine bases is selected form triethylamine, and N,N-diisopropylethylamine.

10. The Process according to claim 1 , wherein compound of Formula IV is (2R-Cis)-2-hydroxymethyl-5-(5 fluorocytosine-1-yl)-1,3-oxathiolane hydrochloride.

11. An improved process for producing 5-Fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine of Formula I and its pharmaceutically acceptable salts,

the process comprising the steps of:

a. reducing the compound (2R,5S)-5-(4-Amino-5-fluoro-2-oxo-2H pyrimidin-1-yl)-[1,3]-oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl-1R-cyclohexyl Ester) of Formula II employing a reducing agent;

to obtain the compound (2R-Cis)-2-hydroxymethyl-5-(5′fluoro cytosine-yl)-1,3-oxathiolane of Formula III;

b. followed by in_situ salification of compound (2R-Cis)-2-hydroxymethyl-5-(5′fluoro cytosine-1′-yl)-1,3-oxathiolane of Formula III employing a mineral acid in presence of an organic solvent to give compound (2R-Cis)-2-hydroxymethyl-5-(5′fluoro cytosine-1′-yl)-1,3-oxathiolane salt of Formula IV,

wherein X is organic acid or mineral acid; and

c. neutralizing the compound of Formula IV employing an organic solvent in presence of an organic amine base to obtain 5-Fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine of Formula I.

12. An improved process for producing 5-Fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine of Formula I and its pharmaceutically acceptable salts,

the process comprising the steps of:

a. reducing the compound (2R,5S)-5-(4-Amino-5-fluoro-2-oxo-2H pyrimidin-1-yl)-[1,3]-oxathiolane-2-carboxylic acid, 2S-isopropyl-5R-methyl-1R-cyclohexyl Ester) of Formula II employing a reducing agent;

to obtain the compound (2R-Cis)-2-hydroxymethyl-5-(5′fluoro cytosine-yl)-1,3-oxathiolane of Formula III;

b. followed by in_situ salification of compound (2R-Cis)-2-hydroxymethyl-5-(5′fluoro cytosine-1′-yl)-1,3-oxathiolane of Formula III employing an organic acid or mineral acid in presence of an organic solvent to give compound (2R-Cis)-2-hydroxymethyl-5-(5′fluoro cytosine-1′-yl)-1,3-oxathiolane salt of Formula IV;

wherein X is organic acid or mineral acid; and

c. neutralizing the compound of Formula IV employing an organic solvent in presence of an organic amine base to obtain 5-Fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine of Formula I.