SYNTHESIS OF PURINE NUCLEOSIDES

• US 20100279973A1
• Filed: 12/23/2009
• Published: 11/04/2010
• Est. Priority Date: 12/23/2008
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Inventors: ROSS, BRUCE, DU, JINFA, CHUN, BYOUNG-KWON, SOFIA, MICHAEL JOSEPH, NAGARATHNAM, DHANAPALAN, CHANG, WONSUK, ZHANG, HAI-REN, PAMULAPATI, GANAPATI REDDY, RACHAKONDA, SUGUNA
• Granted Patent: US 8,716,263 B2
• Time in Patent Office: Days
• US Class Current: 514/48
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 1/00 Processes for the preparation of sugar derivatives
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical
• CPC Class Codes: C07H 19/167 with ribosyl as the saccharide radical
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/213 containing cyclic phosphate
• CPC Class Codes: C07H 5/02 to halogen
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A process for preparing phosphoramidate prodrugs or cyclic phosphate prodrugs of nucleoside derivatives, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof.

Claims

1. A compound I or salt thereof or compound II or salt thereof:

2. The compound I or salt thereof of claim 1, wherein R¹ is Ph, R² is H, R^3a is H, R^3b is CH₃, R⁵ is H, R⁶ is CH₃, R⁹ is NH₂, X is F, Y is OH, and Z is N, as shown in the following structure:

3. The compound I or salt thereof of claim 2, wherein R⁴ is Me, Et, ⁱPr, ^cPr, ^cBu, or ^cPn and R⁸ is OMe, OEt, OⁱPr, O^cPr, O^cBu, or O^cPn.

4. A composition comprising the compound or salt thereof of claim 3.

5. A pharmaceutical composition comprising the compound or salt thereof of claim 3.

6. A method of treating a condition caused by a viral agent, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound or salt thereof of claim 3.

7. Use of the compound or salt thereof of claim 3 in the manufacture of a medicament for the treatment of a condition caused by a viral agent.

8. The compound II or salt thereof of claim 1, wherein R⁵ is H, R⁶ is CH₃, R⁹ is NH₂, X is F, and Z is N, as shown in the following structure:

9. The compound or salt thereof of claim 8, wherein R⁴ is Me, Et, ⁱPr, ^cPr, ^cBu, or ^cPn and R⁸ is OMe, OEt, OⁱPr, O^cPr, O^cBu, or O^cPn.

10. A composition comprising the compound or salt thereof of claim 9.

11. A pharmaceutical composition comprising the phosphoramidate nucleoside or salt thereof of claim 9.

12. A method of treating a condition caused by a viral agent, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound or salt thereof of claim 9.

13. Use of the compound or salt thereof of claim 9 in the manufacture of a medicament for the treatment of a condition caused by a viral agent.

14. A process for preparing the compound I or salt thereof or the compound II or salt thereof of claim 1, wherein said process comprises:

(a) stereoselective reduction of a protected ribonolactone III using a hydride reducing agent

15. A process for preparing the compound I or salt thereof or the compound II or salt thereof of claim 1, said process comprising stereoselective reduction of a protected ribonolactone III using a hydride reducing agent to provide a mixture comprising a beta-lactol derivative IV and an alpha-lactol derivative of the structure IV-α

;

18. A compound VI or salt thereof

19. The compound VI or salt thereof of claim 18, wherein R⁵ is H, R⁶ is CH₃, R⁹ is NH₂, R¹¹ is 4-chloro-benzoyl, X is F, X″

is Cl, and Z is N.

20. A process for preparing compound VI of claim 18, wherein said process comprises:

(a) stereoselective reduction of a protected ribonolactone III using a hydride reducing agent to provide a beta-lactol derivative IV;

16. A compound IV

17. A compound V

21. A compound VII or salt thereof

22. A compound VIII or salt thereof

23. A compound or salt thereof represented by the following structure:

24. Crystalline R_P-17.

25. Crystalline R_P-17 having an XRD 2θ

-reflections)(°

) at about 12.2.

26. Orthorhombic crystalline R_P-17.

27. Crystalline R_P-17 having an FT-IR peak at about 999 cm⁻

1.