Process for the preparation of 5-carboxyphthalide

• US 6,703,516 B2
• Filed: 08/23/2002
• Issued: 03/09/2004
• Est. Priority Date: 01/18/2000
• Status: Expired due to Fees

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: Infosint SA
• Inventors: Cotticelli, Giovanni, Casazza, Umberto, DallʼAsta, Leone
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US10/227,038
• Publication Number:
  US 20030009038A1
• Time in Patent Office: 564 Days
• Field of Search: 549/305, 549/307, 549/462
• US Class Current: 549/462
• 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 producing citalopram comprising a process for producing 5-carboxyphthalide which comprises adding 1,3,5-trioxane and terephthalic acid to fuming sulfuric acid having an SO₃ content of at least 20% and heating the mixture to a temperature of 120 to 145°

C.

2. A process according to claim 1, wherein the fuming sulfuric acid has an SO₃ content of at least 22-23%.

3. A process according to claim 2, wherein the fuming sulfuric acid has an SO₃ content of at least 25-30%.

4. A process according to claim 1, wherein the mixture is heated to a temperature of 130 to 135°

C.

5. A process according to claim 1, 2, 3 or 4 in which the process for producing 5-carboxyphthalide is carried out in a non-pressurized reactor.

6. A process according to claim 1, wherein the 5-carboxyphthalide is isolated by neutralization of the mixture with a base.

7. A process according to claim 1, wherein the mixture is diluted with glacial acetic acid prior to neutralization with a base.

8. A process according to claim 7, wherein the 5-carboxyphthalide is isolated by diluting the mixture with glacial acetic acid, then adding water and neutralizing with base.

9. A process according to claim 6, 7 or 8 wherein the base is an alkaline metal base.

10. A process according to claim 6, 7 or 8 wherein the base is sodium hydroxide, carbonate or bicarbonate.

11. A process according to claim 6, 7 or 8 wherein the base is sodium hydroxide.

12. A process according to claim 1, wherein 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.

13. A process according to claim 12, wherein the salt is a sodium salt.

14. A process according to claim 12, wherein the salt is formed by adding the base to a pH of about 8.

15. A process according to claim 12, wherein the acid is hydrochloric acid.

16. A process according to claim 1, wherein the 5-carboxyphthalide is isolated by treatment of the mixture with water.

17. A process according to claim 16, wherein the water is added at 0-5°

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

C.

18. A process according to claim 1, wherein the 1,3,5-trioxane is added to the fuming sulfuric acid after the terephthalic acid.

19. Citalopram which has been produced by a process according to claim 1.

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

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

C.

22. A process for the synthesis of citalopram, comprising a process for the synthesis of 5-carboxyphthalide that comprises adding 1,3,5-trioxane and terephthalic acid to fuming sulfuric acid having an SO₃ content of at least 20% and heating the mixture to 120°

C., and allowing the temperature of the mixture to increase by spontaneous exothermia up to 130-135°

C.

23. A process according to claim 22, in which the temperature of the mixture is increased to 130 to 145°

C. if spontaneous exothermia sufficient to bring the reaction to a temperature in the range of 130-135°

C. does not occur.

24. A process according to claim 22, wherein the fuming sulfuric acid has an SO₃ content of at least 22-33%.

25. A process according to claim 22, wherein the fuming sulfuric acid has an SO₃ content of at least 25-30%.

26. A process according to claim 22, wherein the mixture is heated to a temperature of 130 to 135°

C.

27. A process according to claim 22, 23, 24, 25, or 26 in which the process for producing 5-carboxyphthalide is carried out in a non-pressurized reactor.

28. A process according to claim 22, wherein the 5-carboxyphthalide is isolated by neutralization of the mixture with a base.

29. A process according to claim 28, wherein the mixture is diluted with glacial acetic acid prior to neutralization with a base.

30. A process according to claim 29, wherein the 5-carboxyphthalide is isolated by diluting the mixture with glacial acetic acid, then adding water and neutralizing with base.

31. A process according to claim 28, 29 or 30 wherein the base is an alkaline metal base.

32. A process according to claim 28, 29 or 30 wherein the base is sodium hydroxide, carbonate or bicarbonate.

33. A process according to claim 28, 29 or 30 wherein the base is sodium hydroxide.

34. A process according to claim 22, wherein 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.

35. A process according to claim 34, wherein the salt is a sodium salt.

36. A process according to claim 34, wherein the salt is formed by adding the base to a pH of about 8.

37. A process according to claim 34, wherein the acid is hydrochloric acid.

38. A process according to claim 22, wherein the 5-carboxyphthalide is isolated by treatment of the mixture with water.

39. A process according to claim 38, wherein the water is added at 0-5°

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

C.

40. A process according to claim 22, wherein the 1,3,5-trioxane is added to the fuming sulfuric acid after the terephthalic acid.

41. Citalopram which has been produced by a process according to claim 22.

42. A process according to claim 22, in which the 1,3,5-trioxane is used in an amount corresponding to 2.5-3.2 mol of formaldehyde/mol of the starting terephthalic acid.

43. A process according to claim 22, in which said 1,3,5trioxane is added at a temperature of 30-35°

C.

44. A process for the synthesis of 5-carboxyphtalide which comprises adding 1,3,5-trioxane and terephthalic acid to fuming sulfuric acid containing at least 20% of SO₃, heating the mixture at 130-135 °

C. and isolating the 5-carboxyphthalide thus obtained.

45. A process according to claim 44, wherein the fuming sulfuric acid has an SO₃ content of at least 22-33%.

46. A process according to claim 45, wherein the fuming sulfuric acid has an SO₃ content of at least 25-30%.

47. A process according to claim 44, 45, or 46 in which the process for the synthesis of 5-carboxyphthalide is carried out in a non-pressurized reactor.

48. A process according to claim 44, wherein the 5-carboxyphthalide is isolated by neutralization of the mixture with a base.

49. A process according to claim 48, wherein the mixture is diluted with glacial acetic acid prior to neutralization with a base.

50. A process according to claim 49, wherein the 5-carboxyphthalide is isolated by diluting the mixture with glacial acetic acid, then adding water and neutralizing with base.

51. A process according to claim 48, 49 or 50 wherein the base is an alkaline metal base.

52. A process according to claim 48, 49 or 50 wherein the base is sodium hydroxide, carbonate or bicarbonate.

53. A process according to claim 48, 49 or 50 wherein the base is sodium hydroxide.

54. A process according to claim 44, wherein 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.

55. A process according to claim 54, wherein the salt is a sodium salt.

56. A process according to claim 54, wherein the salt is formed by adding the base to a pH of about 8.

57. A process according to claim 54, wherein the acid is hydrochloric acid.

58. A process according to claim 44, wherein the 5-carboxyphthalide is isolated by treatment of the mixture with water.

59. A process according to claim 58, wherein the water is added at 0-5°

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

C.

60. A process according to claim 44, wherein the 1,3,5-trioxane is added to the fuming sulfuric acid after the terephthalic acid.

61. Citalopram which has been produced by a process comprising the process for the synthesis of 5-carboxyphtalide according to claim 44.

62. A process according to claim 44, in which the 1,3,5-trioxane is used in an amount corresponding to 2.5 -3.2 mol of formaldehyde/mol of the starting terephthalic acid.

63. A process according to claim 44, in which said 1,3,5-trioxane is added at a temperature of 30-35°

C.

64. A process for producing citalopram comprising a process for producing 5-carboxyphthalide which comprises adding 1,3,5-trioxane and terephthalic acid to fuming sulfuric acid having an SO₃ content of at least 20% and heating the mixture to a temperature of 120 to 145°

C., wherein the 5-carboxyphthalide is isolated by diluting the mixture with glacial acetic acid, the adding water and neutralizing with an alkaline metal base, in which the process for producing the 5-carboxyphthalide is carried out in a non-pressurized reactor.

65. A process according to claim 64, wherein the alkaline metal base is selected from the group consisting of sodium hydroxide, carbonate or bicarbonate.

66. A process for producing citalopram comprising a process for producing 5-carboxyphthalide which comprises adding 1,3,5-trioxane and terephthalic acid to fuming sulfuric acid having an SO₃ content of at least 25-30% and heating the mixture to a temperature of 130 to 135°

C., wherein the 5-carboxyphthalide is isolated by diluting the mixture with glacial acetic acid, then adding water and neutralizing with an alkaline metal base, in which the process for producing the 5-carboxyphthalide is carried out in a non-pressurized reactor.

67. A process according to claim 66, wherein the alkaline metal base is selected from the group consisting of sodium hydroxide, carbonate or bicarbonate.