Claims
- 1. A method for the synthesis of purine LNA analogues of the general formula I
- 2. A method according to claim 1, wherein the nucleophilic reagent is selected from optionally substituted hydroxy(C1-6-alkane), optionally substituted phenol, optionally substituted hydroxy(C1-6-alkyl)benzene, NH3, optionally substituted amino(C1-6-alkane), optionally substituted aniline, optionally substituted amino(C1-6-alkyl)benzene, optionally substituted thio(C1-6-alkane), optionally substituted benzenethiol, optionally substituted thio(C1-6-alkyl)benzene, M—K—OH, M—K—NH2 and M—K—SH.
- 3. A method according to claim 2, wherein the nucleophilic reagent is 3-hydroxy-propionitrile, NH3, 3-mercaptopropionitrile, benzyl alcohol, 2-hydroxy-ethylbenzene, 2-hydroxy-1-nitroethane and benzylamine.
- 4. A method according to claim 1, wherein the molar ratio between compound II and the nucleophilic reagent is in the range of 1:2 to 1:10,
- 5. A method according to claim 4, wherein the molar ratio between compound II and the nucleophilic reagent is in the range of 1:2 to 1:8.
- 6. A method according to claim 5, wherein the molar ratio between compound II and the nucleophilic reagent is in the range of 1:2 to 1:6.
- 7. A method according to claim 1, wherein the treatment of compound II with the nucleophilic reagent is performed in the presence of a non-nucleophilic strong base.
- 8. A method according to claim 7, wherein the treatment of compound II with the nucleophilic reagent is performed in the presence of NaH or LiH.
- 9. A method according to claim 1, wherein the treatment of compound II with the nucleophilic reagent is performed in the presence of a solvent selected from pyridine, tetrahydrofuran, toluene, xylene, benzene, diethyl ether, acetonitrile, triethylamine, N,N-dimethylformamide, dimethylsulfoxide, dichloromethane and 1,2-dichloroethane, preferably tetrahydrofuran.
- 10. A method according to claim 1, wherein the treatment of compound II with the nucleophilic reagent is performed at −30° C. to 100° C.
- 11. A method according to claim 1, wherein A1, A2, A3, A4 and A5 all represent oxygen.
- 12. A method according to claim 1, wherein R6 is selected from benzyl, ortho-, meta-, para-methylbenzyl, 2-chlorobenzyl, 4-phenylbenzyl, tetrahydropyran-2-yl, benzoyl and phenyl.
- 13. A method according to claim 12, wherein R6 is benzyl.
- 14. A method according to claim 1, wherein each of the substituents R5 and R7 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, ortho-, meta-, para-toluenesulfonyl, benzenesulfonyl, ortho-, meta-, para-bromobenzenesulfonyl, ortho-, meta-, para-nitrobenzenesulfonyl, di-tert-butylsilylene, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tert-butylmethoxyphenylsilyl and tert-butoxydiphenylsilyl.
- 15. A method according claim 14, wherein each of the substituents R5 and R7 are selected from methanesulfonyl, trifluoromethanesulfonyl, para-toluenesulfonyl and para-bromobenzenesulfonyl.
- 16. A method according claim 15, wherein both of the substituents R5 and R7 are methanesulfonyl.
- 17. A method according to claim 1, wherein R8 is selected from acetyl, benzoyl and m-trifluoromethylbenzoyl.
- 18. A method according to claim 17, wherein R8 represents acetyl.
- 19. A method according to claim 1, wherein W represents OH, SH or NH2.
- 20. A method according to claim 19, wherein W represents NH2.
- 21. A method according to claim 1, wherein X represents chloro.
- 22. A method according to claim 1, wherein A1, A2, A3, A4 and A5 all represent oxygen, X is chloro, W is NH2, both of the substituents R5 and R7 are methanesulfonyl, R6 represents benzyl, R8 represent acetyl and n is 1.
- 23. A method according to claim 1, wherein the compound of the general formula II is prepared by coupling of a compound of the general formula III:
- 24. A method according to claim 23, wherein the glycosylation reaction is performed in the presence of a Lewis acid.
- 25. A method according to claim 24, wherein the Lewis acid is trimethylsilyl trifluoro-methanesulfonate.
- 26. A method according to claim 23, wherein the glycosylation reaction is performed in the presence of silylating agent.
- 27. A method according to claim 26, wherein the silylating agent is N,O-bis(trimethylsilyl)acetamide.
- 28. A method according to claim 23, wherein R14 is selected from acetyloxy, methoxy, ethoxy, chloride, fluoride, bromide, iodide, and SC6H5.
- 29. A method according to claim 28, wherein R14 is selected from acetyloxy and methoxy.
- 30. A compound the general formula I
- 31. A compound according to claim 30, wherein A1, A2, A3, A4 and A5 all represent oxygen.
- 32. A compound according to the claim 30, wherein R6 is selected from benzyl, ortho-, meta-, para-methylbenzyl, 2-chlorobenzyl, 4-phenylbenzyl, tetrahydropyran-2-yl, benzoyl and phenyl.
- 33. A compound according to claim 32, wherein R6 is benzyl.
- 34. A compound according to claim 30, wherein R5 is selected from methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, 2,2,2-trifluoroethanesulfonyl, propanesulfonyl, iso-propanesulfonyl, butanesulfonyl, nonafluorobutanesulfonyl, pentanesulfonyl, cyclopentanesulfonyl, hexanesulfonyl, cyclohexanesulfonyl, α-toluenesulfonyl, 2-chloro-α-toluenesulfonyl, ortho-, meta-, para-toluenesulfonyl, benzenesulfonyl, ortho-, meta-, para-bromobenzenesulfonyl, and ortho-, meta-, para-nitrobenzenesulfonyl.
- 35. A compound according claim 34, wherein R5 is selected from methanesulfonyl, trifluoromethanesulfonyl and ortho-, meta-, para-toluenesulfonyl, preferably methanesulfonyl and ortho-, meta-, para-toluenesulfonyl.
- 36. A compound according claim 35, wherein R5 is methanesulfonyl.
- 37. A compound according to claim 30, wherein W represents OH, SH or NH2.
- 38. A compound according to claim 37, wherein W represents NH2.
- 39. A compound according to claim 38, wherein A1, A2, A3 and A4 all represent oxygen, W is NH2, R5 is methanesulfonyl, R6 represents benzyl and n is 1.
- 40. A compound of the general formula II:
- 41. A compound according to claim 40, wherein A1, A2, A3 and A4 all represent oxygen.
- 42. A compound according to the claim 40, wherein R6 is selected from benzyl, ortho-, meta-, and para-methylbenzyl, 2-chlorobenzyl, 4-phenylbenzyl, tetrahydropyran-2-yl, benzoyl and phenyl.
- 43. A compound according to claim 42, wherein R6 is benzyl.
- 44. A compound according to claim 40, wherein each of the substituents R5 and R7 independently 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, ortho-, meta-, para-toluenesulfonyl, benzenesulfonyl, ortho-, meta-, para-bromo-benzenesulfonyl and ortho-, meta-, para-nitrobenzenesulfonyl.
- 45. A compound according claim 44, wherein each of the substituents R5 and R7 are methanesulfonyl, trifluoromethanesulfonyl and ortho-, meta-, para-toluenesulfonyl, preferably methanesulfonyl and ortho-, meta-, para-toluenesulfonyl.
- 46. A compound according claim 45, wherein both of the substituents R5 and R7 are methanesulfonyl.
- 47. A compound according to claim 40, wherein R8 represents acetyl, benzoyl and m-trifluoromethylbenzoyl.
- 48. A compound according to claim 47, wherein R8 represents acetyl.
- 49. A compound according to any of the claims 40-48, wherein W represents OH, SH or NH2.
- 50. A compound according to claim 49, wherein W represents NH2.
- 51. A compound according to claim 40, wherein X represent chloro.
- 52. A compound according to claim 40, wherein A1, A2, A3, A4 and A5 all represent oxygen, X is chloro, W is NH2, both of the substituents R5 and R7 are methanesulfonyl, R8 represents acetyl and n is 1.
Priority Claims (1)
Number |
Date |
Country |
Kind |
PA 2000 01473 |
Oct 2000 |
DK |
|
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S. Provisional Patent Application No. 60/239,540 filed on Oct. 10, 2000, the disclosure of which is incorporated herein by reference.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60239540 |
Oct 2000 |
US |