Process for the preparation of a fluorolacton derivative

• US 9,624,183 B2
• Filed: 07/14/2015
• Issued: 04/18/2017
• Est. Priority Date: 01/14/2013
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Zheng, Jianbing, Chen, Rongmin, Li, Yuanqiang, Zhao, Jianqiang, Zhu, Guoliang
• Primary Examiner(s): SAEED, KAMAL A
• Application Number:
  US14/798,879
• Publication Number:
  US 20150315165A1
• Time in Patent Office: 644 Days
• Field of Search: None
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07D 263/26 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 307/33 in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A novel process for the preparation of a fluorolactone derivative of the formula

• • and of its acylated derivative of formula

• • wherein R¹ stands for a hydroxy protecting group is described.

The acylated fluorolactones of formula V, particularly the benzoyl derivative with R¹=benzyl are important precursors for the synthesis of prodrug compounds which have the potential to be potent inhibitors of the Hepatitis C Virus (HCV) NS5B polymerase.

Claims

1. Process for the preparation of a fluorolactone derivative of the formula

2. Process of claim 1, wherein the chiral moiety A in the fluoropropionate derivative of formula III is A3.

3. Process of claim 1, wherein the fluorolactone derivative has the formula

4. Process of claim 3, wherein the chiral moiety A in the fluoropropionate derivative of formula III is A3a.

5. Process of claim 1, wherein the fluorolactone derivative of formula I is acylated to form the acylated fluorolactone of formula

6. Process of claim 5, wherein the acylated fluorolactone has the formula

7. Process of claim 5, wherein the hydroxy protecting group R¹ stands for benzyl.

8. Process of claim 1, wherein the chiral moieties A can be recovered in the form of the respective chiral amines A-H of the formulae

9. Process of claim 1, wherein the reaction in step a) is performed in the presence of a catalyst selected from dibutylboron trifluormethanesulfonate, titanium chloride, titanium(IV) trichloride isopropoxide, titanium isopropoxide, magnesium chloride, magnesium triflate or zinc chloride.

10. Process of claim 9, wherein the catalyst is dibutylboron trifluormethanesulfonate.

11. Process of claim 1, wherein the reaction in step a) is performed in the presence of a base and an organic solvent at reaction temperatures between −

78°

C. and 50°

C.

12. Process of claim 1, wherein the hydrolysis in step b) is performed with an oxidizing agent in the presence of an alkali hydroxide base.

13. Process of claim 12, wherein the hydrolysis in step b) is performed with hydrogen peroxide as oxidizing agent and lithium hydroxide as alkali hydroxide base.

14. Process of claim 1, wherein the hydrolysis in step b) is performed at reaction temperatures between −

30°

C. and 50°

C.

15. Process of claim 5, wherein the acylation is performed in the presence of a tertiary amine at reaction temperatures between −

20°

C. and 80°

C.

16. Process of claim 15 wherein the acylating agent is benzoyl chloride.