Nucleoside modifications by palladium catalyzed methods

• US 6,020,483 A
• Filed: 09/25/1998
• Issued: 02/01/2000
• Est. Priority Date: 09/25/1998
• Status: Expired due to Term

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: NeXstar Pharmaceuticals, Inc. (Gilead Sciences Inc.)
• Inventors: Tu, Chi, Beckvermit, Jeffrey T.
• Primary Examiner(s): Crane, L. Eric
• Application Number:
  US09/160,747
• Time in Patent Office: 494 Days
• Field of Search: 536/22.11, 536/27.14, 536/27.2, 536/27.3, 536/27.4, 536/27.5, 536/27.6, 536/27.61, 536/27.62, 536/27.63, 536/27.7, 536/27.8, 536/27.81, 536/28.2 , 536/28.3, 536/28.4, 536/28.5, 536/28.51, 536/28.52, 536/28.53, 536/28.54, 536/28.55
• US Class Current: 536/27.11
• 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 pyrimidine nucleoside modified at the 5- or 6-position of the pyrimidine ring comprising the steps of:

reacting a pyrimidine starting material containing a leaving group attached to the 5- or 6-position of said pyrimidine starting material with a functionalized alkene having the formula;

##STR40## wherein Y is --CHROH;

R is independently selected from the group consisting of H, 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 to produce a pyrimidine nucleoside having the following formula;

##STR41## and isolating said modified nucleoside.

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

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

4. The method of claim 1 wherein said pyrimidine starting material is a pyrimidine derivative selected from the group consisting of a uridine derivative and a cytidine derivative.

5. The method of claim 4 wherein said pyrimidine derivative is selected from the group consisting of 5-chloro-uridine, 5-chloro-cytidine, 5-iodo-uridine, 5-iodo-cytidine, 5-bromo-uridine, 5-bromo-cytidine, 6-chloro-uridine, 6-chloro-cytidine, 6-iodo-uridine, 6-iodo-cytidine, 6-bromo-uridine and 6-bromo-cytidine.

6. 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.

7. The method of claim 4 wherein said pyrimidine derivative is selected from the group consisting of:

##STR42## wherein X is selected from the group consisting of I, Cl and Br.

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

##STR45##

11. 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)₃ P, tris(dibenzylideneacetone)dipalladium (dba), P(m-NaSO₃ Ph)₃,

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

13. A pyrimidine nucleoside modified at the 5- or 6-position of the pyrimidine ring prepared according to the method of claim 1.

8. A method for the preparation of a pyrimidine nucleoside modified at the 5- or 6-position of the pyrimidine ring comprising the steps of:

reacting a pyrimidine starting material containing a leaving group attached to the 5- or 6-position of said pyrimidine starting material with a functionalized alkene having the formula;

##STR43## wherein Y is selected from the group consisting of --C(O)R, --COOR, --C(O)NRR'"'"', --CN, 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, alkyl, alkenyl and aryl; and

n is an integer from 1-15 in the presence of a palladium catalyst of the general formula PdL₃ or PdL₄, wherein L is a ligand of palladium to produce a pyrimidine nucleoside having the following formula;

##STR44## and isolating said modified nucleoside.

9. The method of claim 8 wherein Y is selected from the group consisting of --CH₂ OH, --CHROH, --C(O)R, --COOR, --C(O)NH₂ and --C(O)NHR.

19. A pyrimidine nucleoside modified at the 5- or 6-position of the pyrimidine ring prepared according to the method of claim 8.

20. The method of claim 8 wherein said functionalized alkene is:

##STR46##

14. A compound selected from the group consisting of:

wherein Y is selected from the group consisting of --CHROH, --C(O)R, --COOR, --C(O)NRR'"'"', --CN, phenyl,1-, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-pyridyl and 1H-tetrazol-5-yl;

Z is selected from the group consisting of H, ribose, deoxyribose and dideoxyribose and derivatives thereof;

R and R'"'"' are independently selected from the group consisting of H, alkyl, alkenyl or aryl; and

n is an integer from 0-15.

15. A compound of claim 14 where in Y is selected from the group consisting of --C(O)R, --COOR, C(O)NH₂ and C(O)NHR.

16. An oligonucleotide comprising a nucleoside as defined in claim 14.

17. The oligonucleotide of claim 15 wherein said oligonucleotide is a ribonucleic acid.

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