PREPARATION OF ALKYL-SUBSTITUTED 2-DEOXY-2-FLUORO-D-RIBOFURANOSYL PYRIMIDINES AND PURINES AND THEIR DERIVATIVES

• US 20100234585A1
• Filed: 05/25/2010
• Published: 09/16/2010
• 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
• Granted Patent: US 8,481,713 B2
• Time in Patent Office: Days
• US Class Current: 536/28.500
• 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

1-19. -19. (canceled)

20. A method for the preparation of a 2′

-deoxy-2′

-fluoro-2′

-C-methyl-β

-D-ribofuranosyl nucleoside of the following formula;

comprising the following steps;

(a) reacting a nucleoside intermediate of the following formula;

wherein R³ and R⁵ are each independently tetrahydropyranyl, methyl, ethyl, benzyl, benzoyl, p-methoxybenzyl, benzyloxymethyl, phenoxymethyl, methoxymethyl, ethoxymethyl, mesyl, tosyl, trifluoroacetyl, or trichloroacetyl with diethylaminosulfur trifluoride or bis(2-methoxyethyl)aminosulfur trifluoride to yield a fluorinated intermediate of the following formula;

(b) deprotecting the R³ and R⁵ groups of the product of step (a) by treatment with a boron trihalide to yield an intermediate of the following formula;

(c) saponifying the product of step (b) to yield the desired nucleoside.

21. The method of claim 20, wherein the boron trihalide of step (b) is selected from boron trifluoride, boron trichloride, boron tribromide or boron triiodide.

22. The method of claim 20, wherein the saponification of step (c) is done with a metal alcoholate in alcohol.

23. The method of claim 22, wherein the metal alcoholate in alcohol is sodium methoxide in methanol.