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

• US 20060199783A1
• Filed: 02/13/2006
• Published: 09/07/2006
• 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 7,601,820 B2
• Time in Patent Office: Days
• US Class Current: 514/45
• 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-o-D-ribofuranosyl nucleosides from a preformed, preferably naturally-occurring, nucleoside.

Claims

1. A 3,5-di-O-protected-2-deoxy-2-fluoro-2-C-methyl-D-ribono-γ

-lactone of the following general 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 process for the preparation of the lactone of claim 1, comprising the steps of:

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

with an alkyl-2-bromopropionate in the presence of activated zinc in a suitable solvent;

(b) adding an oxidizing agent to provide a ketone;

(c) fluorinating the product of step (b) to produce a fluorinated ketone;

(d) reducing the fluorinated ketone of step (c);

(e) benzylating the product of step (d) to yield the desired lactone.

4. The process of claim 3, wherein the solvent of step (a) is selected from the group consisting of diethyl ether and tetrahydrofuran.

5. The process of claim 3, wherein the oxidizing agent of step (b) is selected from the group consisting of:

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

14. A process for the preparation of the lactone of claim 1, comprising the steps of:

(a) reacting a compound of the formula 39 with (1-alkoxycarbonylethylidene)triphenylphosphorane under Wittig conditions in a suitable solvent;

(b) asymmetric dihydroxylation of the Wittig reaction product 41 to provide a diol 42;

(c) treatment of the compound 42 with concentrated HCl in ethanol;

(d) selective 0-protection of primary and secondary OH groups yielding 3,5-di-O-protected derivative 47;

(e) fluorination of compound 47 provides the desired lactone 49.

15. A process for the preparation of the lactone of claim 1, comprising the steps of:

(a) selective O-protection of secondary OH group of compound 42 yield mono-O-protected derivative 43;

6. A process for the preparation of a lactone intermediate, 46,

7. A process of preparing a 2′

-deoxy-2′

-fluoro-2′

-C-methyl-β

-D-ribofuranosyl nucleoside of the following formula;

8. The process of claim 7, wherein the silylated base of step (b) is silylated N⁴-benzoylcytosine.

9. The process of claim 7, wherein the deprotection of the nucleoside of step (b), 86, is deprotected with a metal alcoholate in alcohol.

10. The process of claim 9, wherein the metal alcoholate in alcohol is NaOMe/MeOH or methanolic ammonia.

11. A process for the preparation of a 2′

-deoxy-2′

-fluoro-2′

-C-methyl-β

-D-ribofuranosyl nucleoside of formula 63

12. A process for the preparation of a 2′

-deoxy-2′

-fluoro-2′

-C-methyl-β

-D-ribofuranosyl nucleoside of formula 14

13. A process for the preparation of a 2′

-deoxy-2′

-fluoro-2′

-C-methyl-β

-D-ribofuranosyl nucleoside of formula 14,

16. A 2-alkyl-4,5-di-O-protected-2,3-dihydroxy-pentanoic-acid ester of the following general formula:

17. An ester according to claim 16, wherein acyl is acetyl, benzoyl, pivaloyl, 2,3,4-nitro, chloro or methyl benzoyl, or 4-phenylbenzoyl.

18. A process for the preparation of the diol of the formula,