Synthesis of [;2.2.1];bicyclo nucleosides

• US 6,734,291 B2
• Filed: 12/16/2002
• Issued: 05/11/2004
• Est. Priority Date: 03/24/1999
• Status: Expired due to Term

• Current Assignee: Qiagen GmbH (Qiagen NV)
• Original Assignee: Exiqon A/S (Qiagen NV)
• Inventors: Fensholdt, Jef, Pfundheller, Henrik M., Kochkine, Alexei
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Crane, Lawrence E
• Application Number:
  US10/233,177
• Publication Number:
  US 20030092905A1
• Time in Patent Office: 512 Days
• Field of Search: 536/4.1, 536/18.6
• US Class Current: 536/4.1
• 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 compound of the formula II:

wherein R₁ is selected from optionally substituted aryl(C_1-6-alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl;

each of the substituents R₂ and R₃ is independently selected from hydrogen, optionally substituted C_1-6alkyl, optionally substituted aryl, and optionally substituted aryl(C_1-6-alkyl), or R₂ and R₃ together designate C_3-7-alkylene, with the proviso that R₂ and R₃ are not both hydrogen;

R₄ is R^IIISO₂O—

wherein R^III is selected from optionally substituted alkyl and optionally substituted aryl;

R₅ is R^IVSO₂O—

wherein R^IV is selected from optionally substituted alkyl and optionally substituted aryl; and

provided that R₄ and R₅ are different;

said method comprising the following step;

treatment of a compound of the formula I;

wherein R₁ is selected from optionally substituted aryl(C_1-6-alkyl), optionally substituted tetrahydropyran-2-yl, optionally substituted arylcarbonyl and optionally substituted aryl;

each of the substituents R₂ and R₃ is independently selected from hydrogen, optionally substituted C_1-6-alkyl, optionally substituted aryl, and optionally substituted aryl(C_1-6-alkyl), or R₂ and R₃ together designate C_3-7-alkylene, with the proviso that R₂ and R₃ are not both hydrogen; and

wherein compound I is subsequently treated with two different sulfonyl halides, R^IIISO₂X and R^IVSO₂X, wherein R^III and R^IV are as defined above, and X is a halogen.

2. A method according to claim 1, wherein compound I is first treated with R^IIISO₂X in a ratio of 1:

1-1;

1.5 to provide a compound of the formula;

wherein R₄ is R^IIISO₂O— and

subsequently, the formed compound is treated with R^IVSO₂X in a ratio of 1;

1-1;

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

R₅ is R^IVSO₂O—

.

3. A method according to claim 1, wherein the treatment of compound I with the two sulfonyl halides is performed in the presence of a base selected from the group consisting of pyridine, 4-dimethylaminopyridine, triethylamine, and sodium hydride.

4. A method according to claim 1, wherein the treatment of compound I with the two sulfonyl halides is performed in the presence of pyridine or 4-dimethylaminopyridine.

5. A method according to claim 1, wherein the treatment of compound I with the two sulfonyl halides is performed in the presence of pyridine.

6. A method according to claim 1, wherein the treatment of compound I with the two sulfonyl halides 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.

7. A method according to any one of claims 3-6, wherein the base and the solvent is the same substance.

8. A method according to claim 1, wherein the treatment of compound I with the two sulfonyl halides is performed at −

30°

C. to 40°

C.

9. A method according to claim 1, wherein the treatment of compound I with the two sulfonyl halides is performed at −

5°

C. to 30°

C.

10. A method according to claim 1, wherein the treatment of compound I with the two sulfonyl halides is performed at 0°

C. to 25°

C.

11. A method according to claim 1, wherein R₁ is selected from the group consisting of benzyl, ortho-, meta-, and para-methylbenzyl, 2-chlorobenzyl, 4-phenylbenzyl, tetrahydropyran-2-yl, benzoyl and phenyl.

12. A method according to claim 1, 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, ortho-, meta-, or para-methylbenzyl, or 2-chlorobenzyl, or R₂ and R₃ together designate 1,5-pentylene.

13. A method according to claim 1, wherein R′

is selected from the group consisting of methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, propyl, iso-propyl, butyl, nonafluorobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, ortho-, meta- and para-methylbenzyl, 2-chlorobenzyl, phenyl, ortho-, meta-, and para-bromophenyl, and para-nitrophenyl, and X is a halogen.

14. A method according to claim 1, wherein R^IIISO₂X and R^IVSO₂X are each selected from the group consisting of methanesulfonyl chloride, trifluoromethanesulfonyl chloride, ethanesulfonyl chloride, 2,2,2-trifluroethanesulfonyl chloride, nonafluorobutanesulfonyl chloride, α

-toluenesulfonyl chloride and para-toluenesulfonyl chloride.

15. A method according to claim 1, wherein either R^IIISO₂X or R^IVSO₂X is methanesulfonyl chloride.