Purine nucleoside modifications by palladium catalyzed methods

• US 5,580,972 A
• Filed: 12/01/1994
• Issued: 12/03/1996
• Est. Priority Date: 06/14/1993
• Status: Expired due to Term

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: NeXstar Pharmaceuticals, Inc. (Gilead Sciences Inc.)
• Inventors: Eaton, Bruce, Tu, Chi
• Primary Examiner(s): Wilson, James O.
• Application Number:
  US08/347,600
• Time in Patent Office: 733 Days
• Field of Search: 536/26.7, 536/26.71, 536/26.72, 536/27.14, 536/27.6, 536/27.81, 536/23.1, 536/27.14, 536/27.21, 536/27.8, 514/45, 514/46, 514/47, 514/48, 514/43
• US Class Current: 536/27.21
• CPC Class Codes: B01J 2231/4255 Stille-type, i.e. RY + R'3SnR'', in which R is alkenyl, aryl, R' is alkyl and R'' is alkenyl or aryl
• CPC Class Codes: B01J 2531/824 Palladium
• CPC Class Codes: B01J 31/2404 Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

This invention discloses an improved method for the preparation modified purine nucleosides at the 2-, 6-, or 8-position of the purine ring, using a palladium catalyst.

Claims

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

a) reacting a purine starting material containing a halogen leaving group attached to the 2-, 6-, or 8-positions of said purine starting material with an organotin compound of the formula R² SnR¹₃, wherein R² displaces the leaving group from the purine starting material, wherein R¹ is a C1 to C15 alkyl, and R² is selected from the group consisting of a C1 to C15 alkyl and a substituted or unsubstituted C1 to C15 alkenyl or C6 to C12 aryl, in the presence of a palladium catalyst PdL₃, wherein L is a ligand of palladium, and

b) isolating and purifying said purine nucleoside.

2. The method of claim 1 wherein said leaving group is attached to the 8-position of the purine ring.

3. The method of claim 1 wherein said purine starting material is an adenine.

4. The method of claim 3 wherein said adenine is 8-halo-adenine.

5. The method of claim 4 wherein said 8-halo-adenine is 8-bromo-adenine.

6. The method of claim 1 wherein said purine starting material is a guanine.

7. The method of claim 6 wherein said guanine is 8-halo-guanine.

8. The method of claim 7 wherein said 8-halo-guanine is 8-bromo-guanine.

9. The method of claim 1 wherein

R¹ is selected from the group consisting of methyl, ethyl, butyl, and propyl, and

R² is selected from the group consisting of substituted or unsubstituted vinyl and phenyl.

10. The method of claim 9 wherein R² SnR¹₃ has a structure selected from the group consisting of:

##STR15## wherein Y₁, Y₂ and Y₃ are independently selected from the group consisting of hydrogen, alcohols, ethers, ketones, aldehydes, esters, amides, amines, C1 to C15 alkanes, C1 to C15 alkenes, C1 to C15 alkynes, sulfides, and disulfides.

11. The method of claim 1 wherein said catalyst is Pd(P(C₆ H₅)₃)₃.

12. The method of claim 1 wherein the catalyst further comprises a reducing reagent selected from the group consisting of CuI, CuBr and CuCl.

13. The method of claim 1 wherein the preparation of said purine nucleoside modified in the 2-, 6-, or 8- positions is performed in a solvent selected from the group consisting of THF, acetonitrile, dioxane, acetone, ethyl acetate, benzene, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, hexamethylphosphoramide or hexamethylphosphoroustriamide.

14. The method of claim 13 wherein said palladium catalyst is added to the reaction mixture in a solvent selected from the group consisting of THF, acetonitrile, dioxane, acetone, ethyl acetate, benzene, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, hexamethylphosphoramide or hexamethylphosphoroustriamide.