Synthesis of [2.2.1]bicyclo nucleosides

• US 20030092905A1
• Filed: 12/16/2002
• Published: 05/15/2003
• Est. Priority Date: 03/24/1999
• Status: Active Grant

• Current Assignee: Qiagen GmbH (Qiagen NV)
• Original Assignee: Exiqon A/S (Qiagen NV)
• Inventors: Fensholdt, Jef, Kochkine, Alexei, Pfundheller, Henrik M.
• Granted Patent: US 6,734,291 B2
• Time in Patent Office: Days
• US Class Current: 536/27.1
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

A synthesis of [2.2.1]bicyclo nucleosides which is shorter and provides higher overall yields proceeds via the key intermediate of the general formula III, wherein R₄ and R₅ are, for instance, sulfonates and R₇ is, for instance, a halogen or an acetate. From compounds of the general formula II, such as 3-O-aryl-4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose, intermediates of the general formula III are suitable for coupling with silylated nucleobases. Upon one-pot base-induced ring-closure and desulfonation of the formed [2.2.1]bicyclo nucleoside, a short route to each the LNA (Locked Nucleic Acid) derivatives of adenosine, cytosine, uridine, thymidine and guanidine is demonstrated. The use of the 5′-sulfonated ring-closed intermediate also allows for synthesis of 5′-amino- and thio-LNAs.

Claims

1. A method for the synthesis of a novel intermediate of the general formula II:

2. A method according to claim 1, wherein R₁ is selected from benzyl, o-, m-, and p-methylbenzyl, 2-chlorobenzyl, 4-phenylbenzyl, tetrahydropyran-2-yl, benzoyl and phenyl.

3. A method according to claim 2, wherein R₁ is benzyl.

4. A method according to any of claims 1-3, wherein each of the substituents R₂ and R₃ independently represent hydrogen methyl, trifluoromethyl, ethyl, propyl, iso-propyl, butyl, t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, phenyl, benzyl, phenylethyl, o-, m-, and p-methylbenzyl, 2-chlorobenzyl, or R₂ and R₃ together designate 1,5-pentylene.

5. A method according to any of claims 1-4, wherein each of the substituents R₂ and R₃ independently represent hydrogen, methyl, phenyl, benzyl, phenylethyl, preferably methyl.

6. A method according to any of claims 1-4, wherein each of the substituents R₂ and R₃ are methyl.

7. A method according to claims 1-6, wherein R′

is selected from methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, propyl, iso-propyl, butyl, nonafluorobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, o-, m- or p-methylbenzyl, 2-chlorobenzyl, phenyl, o-, m- or p-bromophenyl, p-nitrophenyl, and X is selected from halogen, such as fluoro, chloro, bromo, and iodo.

8. A method according to claim 7, wherein R′

SO₂X is selected from methanesulfonyl chloride, trifluoromethanesulfonyl chloride, ethanesulfonyl chloride, 2,2,2-trifluoroethanesulfonyl chloride, propanesulfonyl chloride, iso-propanesulfonyl chloride, butanesulfonyl chloride, nonafluorobutanesulfonyl chloride, cyclopentanesulfonyl chloride, hexanesulfonyl chloride, cyclohexanesulfonyl chloride, α

-toluenesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride and p-nitrobenzenesulfonyl chloride.

9. A method according to claim 8, wherein R′

SO₂X is selected from methanesulfonyl chloride, trifluoromethanesulfonyl chloride, ethanesulfonyl chloride, 2,2,2-trifluoroethanesulfonyl chloride, nonafluorobutanesulfonyl chloride, α

-toluenesulfonyl chloride and p-toluenesulfonyl chloride.

10. A method according to claim 9, wherein R′

SO₂X is selected from methanesulfonyl chloride.

11. A method according to any of claims 1-10, wherein the ratio between compound I and R′

SO₂X is in the range of 1;

2 to 1;

10.

12. A method according to claim 11, wherein the ratio between compound I and R′

SO₂X is in the range of 1;

2-1;

5.

13. A method according to claim 12, wherein the ratio between compound I and R′

SO₂X is in the range of 1;

2-1;

4.

14. A method according to claim 13. wherein the ratio between compound I and R′

SO₂X is in the range of 1;

2.5-1;

3.5.

15. A method according to any of claims 1-9, wherein compound I is subsequently treated with two different sulfonyl halides, R^IIISO₂X and R^IVSO₂X, wherein R^III and R^IV are independently selected from the group of substituents defined for R′

provided that R^III and R^IV do not represent the same group, and X is a halogen.

16. A method according to claim 15, wherein compound I is first treated with R^IIISO₂X in the ratio 1:

1-1;

1.5 to afford compound II, wherein R₄ is R^IIISO₂O— and

R₅ is hydroxyl and subsequently, the formed compound II is treated with R^IVSO₂X in the ratio 1;

1-1;

2.5, to afford compound II wherein R₄ is R^IIISO₂O— and

R₅ is R^IVSO₂O—

.

17. A method according to claims 1-16, wherein the treatment of compound I with the sulfonyl halide is performed in the presence of a base, such as pyridine, 4-dimethylaminopyridine, triethylamine, and sodium hydride.

18. A method according to claim 17, wherein the treatment of compound I with the sulfonyl halide is performed in the presence of pyridine or 4-dimethylamino-pyridine.

19. A method according to claim 18, wherein the treatment of compound I with the sulfonyl halide is performed in the presence of pyridine.

20. A method according to any of claims 1-19, wherein the treatment of compound I with the sulfonyl halide is performed in the presence of a solvent selected from pyridine, tetrahydrofuran, toluene, xylene, benzene, ether, ethylacetate, acetonitrile, triethylamine, N,N-dimethylformamide, dimethylsulfoxide, dichloromethane, and 1,2-dichloroethane.

21. A method according to any of claims 17-20, wherein the base and the solvent is constituted by the same substance.

22. A method according to any of claims 1-21, wherein the treatment of compound I with sulfonyl halide is performed at −

30°

C. to 40°

C.

23. A method according to claim 22, wherein the treatment of compound I with sulfonyl halide is performed at −

5°

C. to 30°

C.

24. A method according to claim 23, wherein treatment of compound I with sulfonyl halide is performed at preferably 0°

C. to 25°

C.

25. A method according to any of claims 1-24, wherein R₁ is benzyl.

26. A method according to any of claims 1-25, wherein R₂ and R₃ are selected from methyl, ethyl, propyl, iso-propyl, butyl, phenyl, benzyl, phenylethyl, or R₂ and R₃ together designate 1,5-pentylene.

27. A method according to any of claims 1-26, wherein R₂ and R₃ both represent methyl.

28. A method according to any of claims 1-27, wherein R₁ represents benzyl and R₂ and R₃ both represent methyl.

29. A compound of the general formula II:

30. A compound according to claim 29, wherein R₁ is selected from benzyl, o-, m-, and p-methylbenzyl, 2-chlorobenzyl, tetrahydropyranyl, benzoyl and phenyl.

31. A compound according to claim 30, wherein R₁ represents benzyl.

32. A compound according to any of claims 29-31, wherein each of the substituents R₂ and R₃ are independently selected from hydrogen, methyl, trifluoromethyl, ethyl, propyl, iso-propyl, butyl, t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, phenyl, benzyl, phenylethyl, o-, m-, and p-methylbenzyl, 2-chlorobenzyl, or R₂ and R₃ together are selected from 1,3-propylene, 1,4-butylene, 1,5-pentylene.

33. A compound according to any of claims 29-32, wherein each of the substituents R₂ and R₃ are independently selected from hydrogen, methyl, phenyl, benzyl, and phenylethyl.

34. A compound according to any of claims 29-33, wherein each of the substituents R₂ and R₃ are methyl.

35. A compound according to any of claims 29-34, wherein each of the substituents R₄ and R₅ are selected from methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, propanesulfonyl, iso-propanesulfonyl, butanesulfonyl, nonafluorobutanesulfonyl, pentanesulfonyl, cyclopentanesulfonyl, hexanesulfonyl, cyclohexanesulfonyl, α

-toluenesulfonyl, 2-chloro-α

-toluenesulfonyl, o-, m-, p-toluenesulfonyl, benzenesulfonyl, o-, m-, p-bromobenzenesulfonyl, and o-, m-, p-nitrobenzenesulfonyl.

36. A compound according claim 35, wherein each of the substituents R₄ and R₅ are methanesulfonyl, trifluoromethanesulfonyl, o-, m-, p-toluenesulfonyl and o-, m-, p-bromobenzenesulfonyl, more preferably methanesulfonyl, and o-, m-, p-toluenesulfonyl,

37. A compound according claim 36, wherein both of the substituents R₄ and R₅ are methanesulfonyl.

51. The use of a compound of the formula II, as defined in any of the claims 29-37, for the preparation of a [2.2.1]bicyclo nucleosides and derivatives thereof.

38. A compound of the general formula III:

39. A compound according to claim 38, wherein R₁ is selected from benzyl, o-, m-, and p-methylbenzyl, 2-chlorobenzyl, tetrahydropyran-2-yl, benzoyl, phenyl,

40. A compound according to claim 39, wherein R₁ is benzyl.

41. A compound according to any of claims 38-40, wherein each of the substituents R₄ and R₅ are selected from methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, propanesulfonyl, iso-propanesulfonyl, butanesulfonyl, nonafluorobutanesulfonyl, pentanesulfonyl, cyclopentanesulfonyl, hexanesulfonyl, cyclohexanesulfonyl, α

-toluenesulfonyl, 2-chloro-α

-toluenesulfonyl, o-, m-, p-toluenesulfonyl, benzenesulfonyl. o-, m-. p-bromobenzenesulfonyl, and o-, m-, p-nitrobenzenesulfonyl.

42. A compound according to claim 41, wherein each of the substituents R₄ and R₅ are selected from methanesulfonyl, trifluoromethanesulfonyl, and o-, m-, p-toluenesulfonyl, more preferably methanesulfonyl, and o-. m-, p-toluenesulfonyl.

43. A compound according to claim 42, wherein both of the substituents R₄ and R₅ are methanesulfonyl.

44. A compound according to any of claims 38-43, wherein R₆ represents acetyl, benzoyl, m-trifluoromethylbenzoyl and benzyl.

45. A compound according to any of claims 38-44, wherein R₇ represents acetyloxy, methoxy, ethoxy, chloride, fluroride, bromide, iodide and —

SC₆H₅.

46. A compound according to any of claims 38-45, wherein R₁ represents benzyl and R₄ and R₅ are both selected from methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, butanesulfonyl, nonafluorobutanesulfonyl, α

-toluenesulfonyl, p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl, and p-nitrobenzenesulfonyl.

47. A compound according to claim 46, wherein R₄ and R₅ both are selected from methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl and p-bromobenzenesulfonyl.

48. A compound according to claim 47, wherein R₄ and R₅ both are selected from methanesulfonyl, and p-toluenesulfonyl.

49. A compound according to claim 48, wherein R₄ and R₅ both represent methanesulfonyl.

50. A compound according to claim 48, wherein R₁ represents benzyl, R₄ and R₅ represent methanesulfonyl, R₆ represents acetyl, and R₇ represents acetyloxy.

52. The use of a compound of the formula III, as defined in any of the claims 38-50, for the preparation of a [2.2.1]bicyclo nucleosides and derivatives thereof.