Process for the preparation of 5-carboxyphthalide

• US 20030009038A1
• Filed: 08/23/2002
• Published: 01/09/2003
• Est. Priority Date: 01/18/2000
• Status: Active Grant

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: Infosint SA
• Inventors: Casazza, Umberto, DallʼAsta, Leone, Cotticelli, Giovanni
• Granted Patent: US 6,703,516 B2
• Time in Patent Office: Days
• US Class Current: 549/307
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: C07D 307/83 Oxygen atoms
• CPC Class Codes: C07D 307/88 with one oxygen atom directly attached in position 1 or 3

Abstract

There is described a process for the preparation of 5-carboxy phthalide, which comprises adding terephthalic acid to fuming sulfuric acid containing at least 20% of SO₃, then adding formaldehyde to the mixture, heating the mixture at a temperature of 120-145° C. and isolating 5-carboxyphthalide from the reaction mixture.

Claims

1. A process for the preparation of 5-carboxyphthalide of formula A

2. A process according to claim 1, in which formaldehyde is used in form of its precursor 1,3,5-trioxane of formula II

3. A process according to claim 1, in which formaldehyde is used in form of its precursor paraformaldehyde.

4. A process according to claim 2, in which the 1,3,5-trioxane of formula II is used in an amount corresponding to 2.5-3.2 mol of formaldehyde/mol of the starting terephthalic acid.

5. A process according to claim 4, in which said 1,3,5-trioxane is added at a temperature of 30-35°

C.

6. A process according to claim 1, in which the fuming sulfuric acid contains 22-33% of SO₃.

7. A process according to claim 6, in which the fuming sulfuric acid is used in an amount of 3-6 liters/Kg of terephthalic acid.

8. A process according to claim 7, in which fuming sulfuric acid is used in an amount of about 3 liters/Kg of terephthalic acid.

9. A process according to claim 1, in which 5-carboxyphthalide is isolated by neutralization of the reaction mixture with a base.

10. A process according to claim 1, in which 5-carboxyphthalide is isolated by diluting the reaction mixture with glacial acetic acid, then adding water and neutralizing with a base.

11. A process according to claim 9 or 10, in which said base is an alkaline metal base.

12. A process according to claim 11, in which said alkaline metal base is sodium hydroxide, carbonate or bicarbonate.

13. A process according to claim 1, in which, at the end of the reaction, the 5-carboxyphthalide is isolated by the formation of a solution containing a salt thereof which is neutralized with an acid.

14. A process according to claim 13, in which said salt is the sodium salt.

15. A process according to claim 13, in which the salt is formed by adding the base to a pH of about 8.

16. A process according to claim 13, in which said acid is hydrochloric acid.

17. A process according to claim 1, in which 5-carboxyphthalide is isolated by treatment of the reaction mixture with water.

18. A process according to claim 17, in which the addition of water is made at 0-5°

C. and the exothermia is controlled by keeping the temperature at about 20-25°

C.

19. A process according to claim 1, in which the mixture is heated at 130-135°

C.

20. A process according to claim 1, in which formaldehyde is added to fuming sulfuric acid after the addition of terephthalic acid.

21. A process for the synthesis of citalopram, in which a process for the synthesis of 5-carboxyphthalide according to claim 1 is contained.