Process for the preparation of a fluorolacton derivative

Patent metadata

Field	Value
Publication number	US-9624183-B2
Application number	US-201514798879-A
Country	US
Kind code	B2
Filing date	Jul 14, 2015
Priority date	Jan 14, 2013
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

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

and of its acylated derivative of formula

wherein R 1 stands for a hydroxy protecting group is described.

The acylated fluorolactones of formula V, particularly the benzoyl derivative with R 1 =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.

First claim

The invention claimed is:

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

comprising the steps
a) reacting the aldehyde of the formula

with a fluoropropionate derivative of formula

wherein A is selected from the chiral moieties

and Ph stands for phenyl to form an aldol adduct of the formula

wherein A is as above; and
b) subjecting to hydrolysis the aldol adduct of formula IV to give the fluorolactone derivative of the formula I.

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

and A is selected from the chiral moieties

and Ph is phenyl.

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

wherein R 1 stands for a hydroxy protecting group.

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

wherein R 1 stands for a hydroxy protecting group.

7. Process of claim 5 , wherein the hydroxy protecting group R 1 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.

Assignees

• Gilead Pharmasset Llc

Inventors

• Chen Rongmin
• Li Yuanqiang
• Zhao Jianqiang
• Zheng Jianbing
• Zhu Guoliang

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D307/33 Primary

  in position 2, the oxygen atom being in its keto or unsubstituted enol form · CPC title

• C07D263/26 Primary

  with hetero atoms or acyl radicals directly attached to the ring nitrogen atom · CPC title

• A61P31/14

  for RNA viruses · CPC title