Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives

• US 8,492,539 B2
• Filed: 09/13/2005
• Issued: 07/23/2013
• Est. Priority Date: 09/14/2004
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Chun, Byoung-Kwon, Wang, Peiyuan, Du, Jinfa, Rachakonda, Suguna
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US11/225,425
• Publication Number:
  US 20060122146A1
• Time in Patent Office: 2,870 Days
• Field of Search: None
• US Class Current: 536/124
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07D 307/20 Oxygen atoms
• CPC Class Codes: C07D 307/33 in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 317/00 Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
• CPC Class Codes: C07D 317/30 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 407/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 411/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07H 15/203 Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
• CPC Class Codes: C07H 19/06 Pyrimidine radicals

Abstract

The present invention provides (i) processes for preparing a 2′-deoxy-2′-fluoro-2′-methyl-D-ribonolactone derivatives, (ii) conversion of intermediate lactones to nucleosides with potent anti-HCV activity, and their analogues, and (iii) methods 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 general formula, 49B:

2. A process for the preparation of a compound of formula 49B:

3. The process of claim 2, wherein the acid from either step (a) or step (b) is selected from one or more of the group consisting of HCl, H₂PO₃, H₂SO₄, TsOH, CH₃CO₂H, CF₃CO₂H and HCO₂H.

4. The process of claim 2, wherein the solvent from step (a) is selected from one or more of the group consisting of MeOH, EtOH, i-PrOH, CH₃CN, THF and water.

5. The process of claim 2, wherein compound 53B from step (c) is protected with:

6. The process of claim 5, wherein the base is selected from one or more of the group consisting of imidazole, pyridine, 4-(dimethylamino)pyridine, triethyllamine, diisopropylethylamine, and 1,4-diazabicyclo[2,2,2]octane.

7. The process of claim 5, wherein the solvent is selected from one or more of the group consisting of pyridine, dichloromethane, chloroform, and 1,2-dichloroethane, and tetrahydrofuran.