Process and methods for the preparation of optically active cis-2-hydroxymethyl-4- (cytosin-1'-yl)-1,3-oxathiolane or pharmaceutically acceptable salts thereof

1. A process for producing crystalline (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane comprising:

a) reacting cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane with a chiral acid and an achiral acid to produce a diastereomeric salt and an a enantiomeric salt, wherein said chiral acid is (1R)-(−)-10-camphorsulfonic acid, and the reaction produces a chiral acid salt which is a mixture of (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid and (+)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid and (+)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid,

wherein cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is reacted with a half quantity molar amount of (1R)-(−)-10-camphorsulfonic acid, said molar amount being with regard to cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane;

b) recovering said (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid; and

c) converting said (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid into said crystalline (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane;

wherein a) is performed in the presence of an aqueous/organic solvent mixture, and

the overall yield of (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is at least 25%.

2. A process according to claim 1 , wherein said achiral acid is hydrochloric acid.

3. A process according to claim 2 , wherein step a) is performed in the presence of a mixture of isopropyl alcohol and water as the solvent mixture.

4. A process according to claim 3 , wherein the resultant amount of (−)-cis-2-hydroxymethyl-4-(cytosin-1-yl)-1,3-oxathiolane•(1R)-(−)- 10-camphorsulfonic acid in step a) is at least 90.9% based on the total amount of chiral acid salt obtained.

5. A process according to claim 3 , wherein the yield of chiral acid salt obtained in step a) is at least 36%.

6. A process according to claim 3 , wherein the yield of chiral acid salt obtained in step a) is at least 52.6%.

7. A compound which has the formula:

(−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonate;

(−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1S)-(+)-10-camphorsulfonate;

(+)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonate; or

(+)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1S)-(+)-10-camphorsulfonate.

8. A process according to claim 1 , wherein in a) cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is reacted with a half quantity molar amount of said achiral acid, said molar amount being with regard to cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane.

9. A process according to claim 8 , wherein said achiral acid is hydrochloric acid.

10. A process according to claim 1 , wherein step a) is performed in the presence of a mixture of a mixture of methanol and water as the solvent mixture.

11. A process according to claim 10 , wherein the yield of chiral acid salt obtained in step a) is at least 78.7%.

12. A process according to claim 1 , wherein (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is obtained at an enantiomeric excess of 60% or higher, based on.

13. A process according to claim 1 , (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is obtained at an enantiomeric excess of 70% or higher.

14. A process according to claim 1 , wherein (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is obtained at an enantiomeric excess of 80% or higher.

15. A process according to claim 1 , wherein (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is obtained at an enantiomeric excess of 90% or higher.

16. A process according to claim 1 , wherein (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is obtained at an enantiomeric excess of 95% or higher.

17. A process according to claim 1 , wherein the (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is obtained at an enantiomeric excess of 98% or higher.

18. A process according to claim 1 , wherein (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is obtained at an enantiomeric excess of 99% or higher.

19. A process according to claim 1 , further comprising the step of removing the excess (1R)-(−)-10-camphorsulfonic acid before recovering the diastereomeric salt (−)-cis-2-hydroxymethyl-4- (cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid.

20. A process for resolving cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane comprising:

a) dissolving cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane in an aqueous/organic solvent, in the presence of an achiral acid and the chiral acid (1R)-(−)-10-camphorsulfonic acid, and the heating the resultant solution to obtain a solution containing the diastereomeric salts (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid and (+)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid;

b) cooling the heated solution to and recovering the resultant solid product, which contains an excess amount of (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid, relative to the amount of (+)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid; and

c) converting said (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane•(1R)-(−)-10-camphorsulfonic acid into said (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane;

wherein the overall yield of (−)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-oxathiolane is at least 25%.

21. A process according to claim 20 , wherein in a) said resultant solution is heated to a temperature between room temperature and 50° C.

22. A process according to claim 20 , wherein in c) said heated solution is cooled to a temperature between room temperature to −10° C.