Process for the preparation of Z-5-carboxymethylene-1,3-dioxolan-4-ones

• US 20060047129A1
• Filed: 08/22/2005
• Published: 03/02/2006
• Est. Priority Date: 09/01/2004
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Nugent, William A., Delaney, Edward J., Zhu, Keming, Simpson, James H.
• Granted Patent: US 7,507,838 B2
• Time in Patent Office: Days
• US Class Current: 549/296
• CPC Class Codes: C07D 317/34 Oxygen atoms

Abstract

A process for preparing Z-5-carboxymethylene-1,3-dioxolan-4-ones is provided which includes the steps of reacting a bis-ketal or bis-acetal of tartaric acid with a potassium containing base to form the carboxymethylene-1,3-dioxolan-4-one. A process for preparing HIV integrase inhibitors employing the carboxymethylene-1,3-dioxolan-4-one inhibitor is also provided.

Claims

1. A process for preparing a Z-5-carboxymethylene-1,3-dioxolan-4-one of the structure

2. The process as defined in claim 1 wherein R₁ and R₂ are the same or different and are lower alkyl.

3. The process as defined in claim 1 wherein R₁ and R₂ are each CH₃.

4. The process as defined in claim 1 wherein the bis-ketal or bis-acetal of tartaric acid is contacted with the potassium base in an organic solvent.

5. The process as defined in claim 1 wherein the potassium-containing base is a potassium alkoxide or a potassium dialkylamide in which the conjugate acid has a pK_a higher than about 16.

6. The process as defined in claim 5 wherein the potassium containing base is potassium tert-butoxide, potassium tert-amyloxide, potassium hexamethyldisilamide or potassium diisopropylamide.

7. The process as defined in claim 1 wherein the potassium containing base is generated in situ by the action of potassium hydride on a conjugate acid with a pK_a higher than about 16 which is an alcohol or a dialkylamine.

8. The process as defined in claim 4 wherein the solvent is 1,2-dimethoxyethane, tert-butyl alcohol, tert-amyl alcohol, dimethylformamide or tetrahydrofuran.

9. The process as defined in claim 1 wherein the reaction between the bis-ketal or bis-acetal of tartaric acid and the potassium containing base is carried out at a temperature within the range from about −

80°

C. to about +25°

C.

10. The process as defined in claim 9 wherein the reaction is carried out at a temperature within the range from about −

60°

C. to about −

20°

C.

11. The process as defined in claim 1 wherein the bis-acetal of tartaric acid is prepared by reacting L-tartaric acid, acetone, 2,2-dimethoxypropane and boron trifluoride diethyletherate to form tartaric acid bis(acetonide).

13. A process for preparing a compound of the structure

14. The process as defined in claim 1 wherein R₁ and R₂ are each lower alkyl.

15. The process as defined in claim 1 wherein R₁ and R₂ are each CH₃.

17. Z-5-carboxymethylene-1,3-dioxolan-4-one prepared by the process as defined in claim 1.

12. A process for preparing Z-2,2-dimethyl-5-carboxymethylene-1,3-dioxolan-4-one having the structure

18. Z-2,2-dimethyl-5-carboxymethylene-1,3-dioxolan-4-one prepared by the process as defined in claim 12.

16. A process for preparing