Purine nucleoside modifications by palladium catalyzed methods and compounds produced

• US 6,355,787 B1
• Filed: 01/31/2000
• Issued: 03/12/2002
• Est. Priority Date: 09/25/1998
• Status: Expired due to Term

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Tu, Chi, Beckvermit, Jeffrey T.
• Primary Examiner(s): Gitomer, Ralph
• Assistant Examiner(s): CRANE, LAWRENCE E
• Application Number:
  US09/495,429
• Time in Patent Office: 771 Days
• Field of Search: 536/23.1, 536/27.11, 536/27.6, 536/27.61, 536/27.62, 536/27.63, 536/27.81, 544/264
• US Class Current: 536/23.1
• CPC Class Codes: C07H 19/06 Pyrimidine radicals

Abstract

This invention discloses a method for the preparation of 2′-modified nucleosides, using a palladium catalyst and an alkene functionalized with a heteroatom. Included in the invention are the novel pyrimidines and purines that can be prepared according to the method of the invention and oligonucleotides containing said modified pyrimidines and purines.

Claims

1. A method for the preparation of a purine base, purine nucleoside or purine nucleotide modified at the 2-, 6- or 8-position of the purine ring comprising the steps of:

reacting a purine starting material containing a leaving group attached to the 2-, 6- or 8-position of said purine starting material with a functionalized alkene having the formula;

wherein

Y is selected from the group consisting of —

CHROH, —

C(O)R, —

COOR, —

C(O)NRR′

, —

CN, a substituted or unsubstituted aryl group or heterocylic group, selected from the group consisting of phenyl, 2-,3- or 4-hydroxyphenyl, 2-, 3- or 4-pyridyl and 1H-tetrazol-5-yl;

R and R′

are independently selected from the group consisting of H, substituted or unsubstituted alkyl, alkenyl and aryl; and

n is an integer from 0-15

in the presence of a palladium catalyst of the general formula PdL₃ or PdL₄, wherein L is a ligand of palladium; and

isolating said modified nucleoside.

2. The method of claim 1 wherein said purine is selected from the group consisting of an adenine and a guanine.

3. The method of claim 2 wherein said purine is selected from the group consisting of 8-halo-adenine and 8-halo-guanine.

4. The method of claim 2 wherein said purine is selected from the group consisting of 8-iodo-adenine, 8-bromo-adenine, 8-iodo-guanine, and 8-bromo-guanine.

5. The method of claim 1 wherein said functionalized alkene is selected from the group consisting of:

6. The method of claim 1 wherein said palladium catalyst is of the formula PdL₃ or PdL₄, wherein L is selected from the group consisting of PPh₃, (o-tol)₃P, tris(dibenzylideneacetone)dipalladium (dba), P(m-NaSO₃Ph)₃,

7. The method of claim 1 wherein said palladium catalyst is Pd₂(dba)₃.

8. The method of claim 1 wherein said leaving group is selected from the group consisting of a halide, acetate, trifluoroacetate, tosylate, methylsulfonate, and trifluoromethyl sulfonate.

9. The method of claim 1 wherein said leaving group is selected from the group consisting of I, Cl and Br.

10. The method of claim 1 which further comprises a solvent selected from the group consisting of tetrahydrofuran (THF), acetonitrile, dioxane, acetone, ethyl acetate, benzene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoramide, and hexamethylphosphoroustriamide.

11. A compound selected from the group consisting of:

wherein

Y is selected from the group consisting of —

C(O)R, —

COOR, —

C(O)NRR′

, —

CN, a substituted or unsubstituted aryl group or heterocyclic group, selected from the group consisting of phenyl, 2- , 3- or 4-hydroxyphenyl, 2-, 3- or 4-pyridyl and 1H-tetrazol-5-yl;

Z is selected from the group consisting of H, ribosyl, deoxyribosyl and dideoxyribosyl;

R and R′

are independently selected from the group consisting of H, substituted or unsubstituted alkyl, alkenyl and aryl; and

n is an integer from 0-15.

12. A compound of claim 11 where in Y is selected from the group consisting of —

C(O)R, —

COOR, C(O)NH₂ and C(O)NHR.

13. An oligonucleotide comprising a nucleoside as defined in claim 11.

14. The oligonucleotide of claim 13 wherein said oligonucleotide is a ribonucleic acid.

15. The oligonucleotide of claim 13 wherein said oligonucleotide is a deoxyribonucleic acid.