Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives

• US 7,601,820 B2
• Filed: 02/13/2006
• Issued: 10/13/2009
• Est. Priority Date: 07/21/2004
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Inventors: Du, Jinfa, Wang, Peiyuan, Chun, Byoung-Kwon, Stec, Wojciech, Shi, Junxing
• Primary Examiner(s): McIntosh, III; Traviss C
• Application Number:
  US11/353,597
• Publication Number:
  US 20060199783A1
• Time in Patent Office: 1,338 Days
• Field of Search: None
• US Class Current: 536/1.11
• CPC Class Codes: C07D 307/33 in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 307/62 Three oxygen atoms, e.g. ascorbic acid
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07H 19/12 Triazine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

The present invention provides (i) a process for preparing a 2-deoxy-2-fluoro-2-methyl-D-ribonolactone derivative, (ii) conversion of the lactone to nucleosides with potent anti-HCV activity, and their analogues, and (iii) a method to prepare the anti-HCV nucleosides containing the 2-deoxy-2-fluoro-2-C-methyl-β-D-ribofuranosyl nucleosides from a preformed, preferably naturally-occurring, nucleoside.

Claims

1. A compound of the following formula:

2. A compound of claim 1, wherein R³ and R⁵ are each independently H, CH₃, acetyl, benzoyl, pivaloyl, 4-nitrobenzoyl, 3-nitrobenzoyl, 2-nitrobenzoyl, 4-chlorobenzoyl, 3-chlorobenzoyl, 2-chlorobenzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 2-methylbenzoyl, 4-phenylbenzoyl, benzyl, 4-methoxybenzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, THP, MOM, or MEM.

3. A compound of claim 1, wherein R³ and R⁵ are each independently H, CH₃, acetyl, benzoyl, benzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, THP, MOM, or MEM.

4. A compound of claim 1, wherein R³ and R⁵ are each independently H, CH₃, acetyl, benzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, or THP.

5. A compound of claim 1, wherein R³ and R⁵ are each independently H, CH₃, acetyl, benzyl, trityl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, or TIPDS.

6. A compound of claim 1, wherein R³ and R⁵ are each independently H, CH₃, acetyl, benzyl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, or TIPDS.

7. A compound of claim 1, wherein R³ and R⁵ are each independently H, CH₃, acetyl, or benzyl.

8. A compound of claim 1, wherein R³ and R⁵ are each independently H, CH₃, or acetyl.

9. A compound of claim 1, wherein R³ and R⁵ are each independently H or CH₃.

10. A compound of claim 1, wherein R³ and R⁵ are H.

11. A compound of claim 1, wherein R³ and R⁵ are CH₃.

12. A compound of claim 1, wherein R³ and R⁵ are acetyl.

13. A compound of claim 1, wherein R³ and R⁵ are benzyl.

14. A compound of claim 1, wherein R³ and R⁵ are acyl.

15. A compound of claim 1, wherein R³ and R⁵ are linked through —

SiR₂—

O—

SiR₂—

or —

SiR₂—

, and

wherein R is selected from among methyl, ethyl, n-propyl, and i-propyl.

16. A process for the preparation of the compound of claim 1 wherein R⁵ is H and R³ is Bz, comprising the steps of:

(a) reacting a compound of the formula, 39,

17. The process of claim 16, wherein the solvent of step (a) is selected from the group consisting of diethyl ether and tetrahydrofuran.

18. The process of claim 16, wherein the oxidizing agent of step (b) is selected from the group consisting of:

an activated dimethylsulfoxide, a chromatic agent, a Dess-Martin periodione, and tetrapropylammonium perruthenate.