Methods of preparing substituted nucleoside analogs
Disclosed herein are methods of preparing a nucleoside analog (I) by a reaction that includes an intermediate (GG): Nucleoside analog (I) is useful in treating diseases and/or conditions such as viral infections.
1. A method of preparing a compound (I), or a pharmaceutically acceptable salt thereof, wherein the method comprises making the compound (GG), wherein compound (I) and compound (GG) have the following structures:
wherein:
R 2 is trifluoromethanesulfonyl (Tf); and
R 3 is a silyl group or a triarylmethyl group.
2. The method of claim 1 , wherein R 3 is a silyl group and the silyl group is selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl, [2-(trimethyl silyl)ethoxy]methyl, tetraisopropyldisilylene (TIPDS) and di-tert-butyldimethylsilylene (DTBS).
3. The method of claim 2 , wherein the silyl group is a triisopropylsilyl (TIPS) group.
4. The method of claim 1 , wherein R 3 is a triarylmethyl group and the triarylmethyl group is selected from the group consisting of trityl, monomethoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr) and 4,4′,4″-trimethoxytrityl (TMTr).
5. The method of claim 1 , further comprising chlorinating the 4′-position of compound (GG) to form compound (HH):
wherein:
R 2 is trifluoromethanesulfonyl (Tf); and
R 3 is a silyl group or a triarylmethyl group.
6. The method of claim 5 , wherein the chlorinating reagent is LiCl.
7. The method of claim 5 , further comprising cleaving the 7-membered ring of compound (HH) via a hydrolysis reaction to form compound (II):
wherein: R 3 is a silyl group or a triarylmethyl group.
8. The method of claim 7 , wherein the 7-membered ring is cleaved by contacting with an acid.
9. The method of claim 8 , wherein the acid is HCl or diluted sulfuric acid.
10. The method of claim 7 , further comprising removing the group attached to the 3′-oxygen of compound (II) to form compound (JJ):
wherein: R 3 is a silyl group or a triarylmethyl group.
11. The method of claim 10 , wherein the silyl group is removed by contacting with a fluoride source.
12. The method of claim 11 , wherein the fluoride source is selected from the group consisting of tetrabutylammonium fluoride, pyridine.HF, triethylamine trihydrofluoride, hydrofluoric acid, tris(dimethylamino)sulfonium difluorotrimethylsilicate, SiF 4 and ammonium fluoride.
13. The method of claim 12 , wherein the fluoride source is tetra-n-butylammonium fluoride.
14. The method of claim 10 , further comprising adding an acyl group at each of the 3′-position and the 5′-position of compound (JJ) to form compound (KK):
15. The method of claim 14 , wherein the acyl groups are added via an esterification reaction by contacting with isobutyric anhydride.
16. The method of claim 14 , further comprising contacting with 4-dimethylaminopyridine as a catalyst.
17. The method of claim 14 , further comprising converting the uracil of compound (KK) to a cytosine and forming compound (I), or a pharmaceutically acceptable salt thereof:
18. The method of claim 1 , further comprising cyclizing compound (FF) to form compound (GG):
wherein:
R 1 and R 2 are each trifluoromethanesulfonyl (Tf); and
R 3 is a silyl group or a triarylmethyl group.
19. The method of claim 18 , wherein the cyclization is performed in the presence of an amidine reagent.
20. The method of claim 19 , wherein the amidine reagent is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
21. The method of claim 18 , wherein the cyclization is conducted in a polar aprotic solvent.
22. The method of claim 18 , further comprising protecting each of the 4′-position and 5′-position of compound (EE) with a triflate and obtaining compound (FF):
wherein:
R 1 and R 2 are each trifluoromethanesulfonyl (Tf); and
R 3 is a silyl group or a triarylmethyl group.
23. The method of claim 22 , further comprising a base catalyzed condensation reaction with formaldehyde and reduction of an aldehyde attached to the 4′-carbon of compound (DD) to form compound (EE):
wherein: R 3 is a silyl group or a triarylmethyl group.
24. The method of claim 23 , wherein the reducing agent is NaBH 4 .
25. The method of claim 23 , further comprising oxidizing the 5′-OH group of compound (CC) to a 5′-aldehyde group and forming compound (DD):
wherein: R 3 is a silyl group or a triarylmethyl group.
26. The method of claim 25 , wherein the oxidation conditions are Swern oxidation conditions.
27. The method of claim 25 , further comprising removing the silyl group attached to the 5′-oxygen of compound (BB) to form compound (CC):
wherein:
R A is a silyl group; and
R 3 is a silyl group or a triarylmethyl group.
28. The method of claim 27 , wherein R 3 is a silyl group and each silyl group is selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl, [2-(trimethylsilyeethoxy]methyl, tetraisopropyldisilylene (TIPDS) and di-tert-butyldimethylsilylene (DTBS).
29. The method of claim 28 , wherein each silyl group is a triisopropylsilyl (TIPS) group.
30. The method of claim 27 , further comprising protecting the 5′-OH group of compound (AA) with a silyl group and the 3′-OH group of compound (AA) with a silyl group or a triarylmethyl group to form compound (BB):
wherein:
R A is a silyl group; and
R 3 is a silyl group or a triarylmethyl group.
31. The method of claim 30 , wherein R 3 is a silyl group and each silyl group is selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl, [2-(trimethylsilypethoxy]methyl, tetraisopropyldisilylene (TIPDS) and di-tert-butyldimethylsilylene (DTBS).
32. The method of claim 31 , wherein each silyl group is a triisopropylsilyl (TIPS) group.
33. The method of claim 30 , wherein R 3 is a triarylmethyl group and the triarylmethyl group is selected from the group consisting of trityl, monomethoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr) and 4,4′,4″-trimethoxytrityl (TMTr).
34. The method of claim 1 , wherein compound (I) is purified by contacting with isopropyl acetate and heptane.
35. The method of claim 1 , wherein compound (I) is purified by contacting with methanol and water.
36. A compound having the following structure (GG)
wherein:
R 2 is a trifluoromethanesulfonyl (Tf); and
R 3 is a silyl group.
37. The compound of claim 36 , wherein the silyl group is triisopropylsilyl (TIPS).
38. The method of claim 25 , wherein the oxidizing conditions are Moffatt oxidation conditions or modified Moffatt oxidation conditions.
39. The method of claim 5 , wherein R 3 is a triisopropylsilyl (TIPS) group.
40. The method of claim 7 , wherein R 3 is a triisopropylsilyl (TIPS) group.
41. The method of claim 10 , wherein R 3 is a triisopropylsilyl (TIPS) group.
42. The method of claim 18 , wherein R 3 is a triisopropylsilyl (TIPS) group.
43. The method of claim 22 , wherein R 3 is a triisopropylsilyl (TIPS) group.
44. The method of claim 23 , wherein R 3 is a triisopropylsilyl (TIPS) group.
45. The method of claim 25 , wherein R 3 is a triisopropylsilyl (TIPS) group.