Process for the production of 3'-nucleoside prodrugs

• US 20040181051A1
• Filed: 12/23/2003
• Published: 09/16/2004
• Est. Priority Date: 12/23/2002
• Status: Abandoned Application

• Current Assignee: Adel M. Moussa, Richard Storer, Steven Mathieu
• Original Assignee: Adel M. Moussa, Richard Storer, Steven Mathieu
• Inventors: Moussa, Adel M., Storer, Richard, Mathieu, Steven
• Application Number:
  US10/746,395
• Publication Number:
  US 20040181051A1
• Time in Patent Office: Days
• US Class Current: 536/27.1
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Abstract

Provided is a single-step process for the selective 3′-acylation of a ribofuranosyl 2′ or 3′-branched nucleoside. These compounds are useful as antiviral agents, and in particular, can be used to treat Flaviviridae infections in a host in need thereof.

Claims

1. A process for selectively esterifying the 3′

hydroxyl position of a 2′

-branched ribofuranosyl nucleoside, optionally in a one pot system, comprising reacting;

a) a 2′

branched ribofuranosyl nucleoside,

b) an optionally protected organic acid;

c) a coupling reagent; and

d) base, optionally in the presence of a base catalyst.

2. The process of claim 1, wherein the 2′

branched ribofuranosyl nucleoside is a 2′

-C-methyl branched nucleoside of the formula;

3. The process of claim 2, wherein the Base is a pyrimidine base.

4. The process of claim 2, wherein the pyrimidine base is selected from the group consisting of thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-aza-pyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, C⁵-alkylpyrimidines, C⁵-benzylpyrimidines, C⁵-halopyrimidines, C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine, C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine, C⁵-nitropyrimidine, and C⁵-aminopyrimidine.

5. The process of claim 3, wherein the pyrimidine base is selected from the group consisting of

6. The process of claim 2, wherein the Base is a purine base.

7. The process of claim 6, wherein the purine base is selected from the group consisting of N⁶-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-thioalkyl purine, N²-alkylpurines, N²-alkyl-6-thiopurines, N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.

8. The process of claim 6, wherein the purine base is selected from the group consisting of

9. The process of claim 16, wherein the Base is a pyrrolopyrimidine.

10. The process of claim 16, wherein the Base is a triazolopyridine, an imidazolopyridine, or a pyrazolopyrimidine.

11. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

12. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

13. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

14. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

15. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

16. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

17. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

18. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

19. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

20. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

21. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

22. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

23. The process of claim 1 wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

24. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

25. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

26. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

27. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

28. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

29. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

30. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

31. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

32. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

33. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

34. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

35. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

36. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

37. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

38. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

39. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

40. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

41. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

42. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

43. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

44. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

45. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

46. The process of claim 1, wherein the 2′

-C-methyl branched nucleoside to be selectively esterified at the 3′

-position is

47. The process of claim 1, wherein the optionally protected organic acid is an optionally protected amino acid.

48. The process of claim 50, wherein the optionally protected amino acid is an optionally protected L-valinoyl.

49. The process of claim 51, wherein the optionally protected L-valinoyl is Boc-L-valinoyl.

50. The process of claim 1, wherein the coupling reagent is selected from the group consisting of EDC (1-[3-(dimethylamino)-propyl]-3-ethyl-carbodiimide hydrochloride);

CDI (carbonyldiimidazole), BOP reagent (benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate), and Mitsunobu reagents with triphenylphosphine.

51. The process of claim 1, wherein the coupling reagent is a carbodiimide.

52. The process of claim 51, wherein the coupling reagent is CDI.

53. The process of claim 1, wherein the base is selected from the group consisting of TEA (triethylamine), diisopropylethylamine, and N-ethylmorpholine.

54. The process of claim 1, wherein the base is a tertiary amine.

55. The process of claim 54, wherein the tertiary amine is triethylamine.

56. The process of claim 1, wherein the base catalyst is DMAP.

57. The process of claim 1, wherein the molar ratio of the optionally protected organic acid and the nucleoside is 1.0 to 1.5.

58. The process of claim 57, wherein the molar ratio 1.0 to about 1.2.

59. The process of claim 1, wherein the molar ratio of the coupling agent and the nucleoside is 1.0 to 1.5.

60. The process of claim 59, wherein the molar ratio is 1.0 to 1.2.

61. The process of claim 1, wherein the reaction is conducted at a temperature of at least 80°

C. for at least 20 minutes.

62. The process of claim 61, wherein the reaction occurs under argon gas.

63. The process of claim 1, wherein the 2′

-branched ribofuranosyl nucleoside is solubilized in a solvent.

73. The process of claim 1, wherein the reaction occurs in a solvent or mixture of solvents selected from the group consisting of polar aprotic solvent.

74. The process of claim 73, wherein the solvent is selected from the group consisting of acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, dichloromethane, dichloroethane, diethyl ether, pyridine, dimethylformamide (DMF), DME, dimethylsulfoxide (DMSO), dimethylacetamide, and combination thereof.

64. A process for selectively esterifying the 3′

hydroxyl position of a 2′

-branched ribofuranosyl nucleoside comprising;

a) heating a first solution of a 2′

branched ribofuranosyl nucleoside in an organic solvent at temperature and for a time sufficient to dissolve the nucleoside;

b) adding a tertiary amine and a base catalyst to the first solution; and

c) adding a second solution, comprising a protected amino acid and a carbodiimide coupling reagent in an organic solvent, to the first solution.

65. The process of claim 64 wherein in step a) the first solution is heated to at least 80°

C. for at least 20 minutes.

66. The process of claim 64 wherein in step c) the first solution is maintained at a temperature of at least 80°

C., and the second solution is added over a time period of at least one hour.

67. The process of claim 66, further comprising heating the combined first and second solutions at a temperature of at least 80°

C. for at least about one half hour.

68. The process of claim 64, wherein the organic solvent in the first solution is DMF.

69. The process of claim 64, wherein the organic solvent in the second solution is THF or DMF.

70. The process of claim 64, further comprising neutralizing the product solution with an acid.

71. The process of claim 64, wherein the tertiary amine is triethylamine and the base catalyst is DMAP.

72. The process of claim 64, wherein the protected amino acid is a protected L-valinoyl amino acid.