Palladium catalyzed nucleoside modifications methods using nucleophiles and carbon monoxide

• US 5,719,273 A
• Filed: 06/02/1995
• Issued: 02/17/1998
• Est. Priority Date: 06/14/1993
• Status: Expired due to Term

• Current Assignee: EP Technology (Boston Scientific Corporation), Medallion Biomedical, LLC
• Original Assignee: NeXstar Pharmaceuticals, Inc. (Gilead Sciences Inc.)
• Inventors: Dewey, Torin M., Eaton, Bruce, Tu, Chi
• Primary Examiner(s): Wilson, James O.
• Application Number:
  US08/458,421
• Time in Patent Office: 991 Days
• Field of Search: 536/28.1, 536/28.4, 536/28.5, 536/28.51, 536/28.52, 536/28.53, 536/28.54, 536/27.6, 536/27.61, 536/27.62, 536/27.8, 536/27.81
• US Class Current: 536/27.6
• 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 a method for the preparation modified nucleosides using a palladium catalyst, a nucleophile and carbon monoxide.

Claims

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

a) preparing a solution of a palladium catalyst, wherein said palladium catalyst is selected from the group consisting of PdL₃ or PdL₄, wherein L is a ligand of palladium;

b) reacting a purine starting material containing a halogen leaving group attached to the 2-, 6- or 8-position of said purine starting material with a nucleophile and carbon monoxide in the presence of the palladium catalyst; and

c) 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 selected from the group consisting of 8-iodo-adenine and 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 selected from the group consisting of 8-iodo-guanine and 8-bromo-guanine.

9. The method of claim 1 wherein said nucleophile is selected from the group consisting of a primary amine, secondary amine and alcohol.

10. The method of claim 9 wherein said nucleophile has the formula RYH, wherein,

Y is selected from the group consisting of O, NH and NR'"'"';

and

R and R'"'"' are independently selected from the group consisting of a C1-C20 alkyl, C2-C20 alkenyl, C6-C20 aryl, or an amino acid, wherein R and R'"'"' are optionally part of a cyclic structure.

11. The method of claim 10 wherein R and R'"'"' are substituted with a functional group independently selected from the group consisting of an amide, ester, nitrile, nitro, urea halide, cyanate, alcohol, amine, ether, thiol and aryl.

12. The method of claim 10 wherein,

Y is selected from the group consisting of O, and NH;

R is (CH_z)_m (CH₃)_n, wherein z is 0, 1 or 2;

m is 0-19;

n is 0, 1, 2 or 3; and

wherein one or more of the H are optionally replaced with ═

O, --OH, ═

NH, NH₂, N⁺ Me₃ Cl^-, ##STR28##

13. The method of claim 10 wherein said nucleophile is selected from the group consisting of:

##STR29##

14. 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 P(C₆ H₅)₃, (o-tol)₃ P, CH₃ CN, DMSO, N,N-dimethylformamide (DMF), ##STR30##

15. The method of claim 14 wherein said palladium catalyst is Pd(P(C₆ H₅)₃)₄.

16. The method of claim 1 wherein the preparation of said purine nucleoside modified at the 2-, 6- or 8- position of the purine ring 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, and hexamethylphosphoroustriamide.

17. Purine nucleosides modified at the 2-, 6- or 8- position of the purine ring prepared according to the method of claim 1.

40. The modified nucleoside of claim 17 wherein said purine is selected from the group consisting of an adenine and a guanine.

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

a) preparing a solution of a palladium catalyst, wherein said palladium catalyst is selected from the group consisting of PdL₃ or PdL₄, wherein L is a ligand of palladium;

b) reacting a pyrimidine starting material containing a halogen leaving group attached to the 5- or 6- position of said pyrimidine starting material with a nucleophile and carbon monoxide in the presence the palladium catalyst; and

c) isolating and purifying said pyrimidine nucleoside.

19. The method of claim 18 wherein said leaving group is attached to the 5- position of the pyrimidine ring.

20. The method of claim 18 wherein said pyrimidine starting material is a cytidine.

21. The method of claim 20 wherein said cytidine is 5-halo-cytidine.

22. The method of claim 21 wherein said 5-halo-cytidine is selected from the group consisting of 8-iodo-cytidine and 8-bromo-cytidine.

23. The method of claim 18 wherein said pyrimidine starting material is a uridine.

24. The method of claim 23 wherein said uridine is 5-halo-uridine.

25. The method of claim 24 wherein said 5-halo-uridine is selected from the group consisting of 5-iodo-uridine and 8-bromo-uridine.

26. The method of claim 18 wherein said pyrimidine starting material is a 5'"'"'-protected 5-iodo-uridine selected from the group consisting of

5'"'"'-DMT-5-iodo-2'"'"',3'"'"'-isopropylideneuridine and

5'"'"'-TBDMS-5-iodo-2'"'"',3'"'"'-isopropylideneuridine.

27. The method of claim 18 wherein said nucleophile is selected from the group consisting of an amine and an alcohol.

28. The method of claim 27 wherein said nucleophile has the formula RYH, wherein,

Y is selected from the group consisting of O, NH and NR'"'"';

and

R and R'"'"' are independently selected from the group consisting of a C1-C20 alkyl, C2-C20 alkenyl, C6-C20 aryl and an amino acid, wherein R and R'"'"' are optionally part of a cyclic structure.

29. The method of claim 28 wherein R and R'"'"' are substituted with a functional group independently selected from the group consisting of an amide, ester, nitrile, nitro, urea halide, cyanate, alcohol, amine, ether, thiol and aryl.

30. The method of claim 28 wherein,

Y is selected from the group consisting of O, and NH;

R is (CH_z)_m (CH₃)_n, wherein z is 0, 1 or 2;

m is 0-19;

n is 0, 1, 2 or 3; and

wherein one or more of the H are optionally replaced with ═

O, --OH, ═

NH, NH₂, N⁺ Me₃ Cl^-, ##STR31## or an amino acid.

31. The method of claim 28 wherein said nucleophile is selected from the group consisting of:

##STR32##

32. The method of claim 18 wherein said palladium catalyst is of the formula PdL₃ or PdL₄, wherein L is selected from the group consisting of P(C₆ H₅)₃, (o-tol), P, CH₃ CN, DMSO, N,N-dimethylformamide (DMF), ##STR33##

33. The method of claim 32 wherein said palladium catalyst is Pd(P(C₆ H₅)₃)₄.

34. The method of claim 18 wherein the preparation of said pyrimidine nucleoside modified at the 5- or 6- position of the pyrimidine ring 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, and hexamethylphosphoroustriamide.

35. Pyrimidine nucleosides modified at the 6-position of the pyrimidine ring prepared according to the method of claim 18.

41. The modified nucleoside of claim 35 wherein said pyrimidine is selected from the group consisting of a uridine and a cytidine.

36. A compound selected from the group consisting of:

##STR34## wherein, Y is selected from the group consisting of O, NH and NR¹ ; and

R and R'"'"' are independently selected from the group consisting of a C1-C20 alkyl, C2-C20 alkenyl, aryl, and an amino acid, wherein R and R'"'"' are optionally part of a cyclic structure selected from an aromatic, aliphatic, or heterocyclic; and

Z is selected from the group consisting of a ribose, deoxyribose, and dideoxyribose.

37. The method of claim 36 wherein R and R'"'"' are substituted with a functional group independently selected from the group consisting of an amide, ester, nitrile, nitro, urea halide, cyanate, alcohol, amine, ether, thiol and aryl.

38. A compound of claim 36 wherein,

Y is selected from the group consisting of O and NH;

R is (CH_z)_m (CH₃)_n, wherein z is 0, 1 or 2;

m is 0-19;

n is 1, 2 or 3; and

wherein one or more of the H are optionally replaced with ═

O, --OH, ═

NH, NH₂, N⁺ Me₃ Cl^-, ##STR35## or an amino acid.

39. A compound selected from the group consisting of:

##STR36##

42. A compound selected from the group consisting of:

##STR37## wherein, Y is selected from the group consisting of SR'"'"', NHR'"'"' and NR'"'"'R";

R'"'"' and R" are independently selected from the group consisting a C1-C20 alkyl, C2-20 alkenyl, aryl, natural amino acids and unnatural amino acids, wherein R'"'"' and R" can optionally be part of a cyclic structure which can be aromatic, aliphatic, or heterocyclic; and

Z is selected from the group consisting of a ribose, deoxyribose and dideoxyribose.

43. A compound of claim 42 wherein,

Y is selected from the group consisting of SR'"'"', and NHR'"'"';

R'"'"' is (CH_z)_m (CH₃)_n, wherein z is 0, 1, or 2;

m is 0-19;

n is 1, 2, or 3; and

wherein one or more of the H atom(s) are optionally replaced with ═

O, --OH, ═

NH, NH₂, +NMe₃ Cl, or an amino acid.