Synthesis of antidiabetic rosigltazone derivatives

• US 20070191611A1
• Filed: 05/03/2005
• Published: 08/16/2007
• Est. Priority Date: 05/05/2004
• Status: Active Grant

• Current Assignee: Cipla (EU) Limited (Cipla Limited)
• Original Assignee: Cipla (EU) Limited (Cipla Limited)
• Inventors: Kankan, Rajendra, Rao, Dharmaraj
• Granted Patent: US 7,598,387 B2
• Time in Patent Office: Days
• US Class Current: 546/269.7
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

A process of preparing rosiglitazone, or a pharmaceutically acceptable salt thereof, which process employs an intermediate metabisulphite complex of 4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy] benzaldehyde, which metabisulphite complex is represented by following formula (III); where X represents an alkali metal. The present invention further provides rosiglitazone, or a pharmaceutically acceptable salt thereof, prepared by the above process.

Claims

1. A process of preparing rosiglitazone of formula (I), or a pharmaceutically acceptable salt thereof,

2. A process according to claim 1, wherein X is sodium or potassium.

3. A process according to claim 2, wherein X is sodium.

4. A process according to claim 1, wherein said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione in toluene in the presence of a catalytic amount of piperidine and acetic acid.

5. A process according to claim 1, wherein said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione in a C_1-4 alcohol or in a mixture of water and a C_1-4 alcohol.

6. A process according to claim 5, wherein said C_1-4 alcohol is ethanol.

7. A process according to claim 5, wherein said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione at a temperature in the range of about 40°

C. to about reflux temperature.

8. A process according to claim 7, wherein said temperature is about 80°

C.

9. A process according to claim 5, wherein said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione in the presence of an alkali or alkaline earth metal hydroxide, alkoxide or carboxylate.

10. A process according to claim 1, wherein said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione so as to yield a benzylidene intermediate of formula (II):

11. A process according to claim 1, wherein said metabisulphite complex of formula (III) is prepared from 4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy] benzaldehyde of formula (IV):

12. A process according to claim 11, wherein said alkali metal metabisulphite salt is sodium or potassium metabisulphite.

13. A process according to claim 12, wherein said alkali metal metabisulphite salt is sodium metabisulphite.

14. A process according to claim 11, wherein said intermediate benzaldehyde compound of formula (IV) is reacted with said alkali metal metabisulphite salt in an aqueous solution comprising C_1-4 alcohols.

15. A process according to claim 11, wherein said intermediate benzaldehyde compound of formula (IV) is reacted with said alkali metal metabisulphite salt at a temperature in the range of −

10°

C. to reflux.

16. A process according to claim 11, wherein said intermediate benzaldehyde compound of formula (IV) is prepared from an intermediate compound of formula (V):

17. A process according to claim 16, wherein Hal represents fluoro.

18. A process according to claim 16, wherein said polar aprotic solvent is DMF.

22. A process according to claim 10, wherein said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione in toluene in the presence of a catalytic amount of piperidine and acetic acid.

23. A process according to claim 10, wherein said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione in a C_1-4 alcohol or in a mixture of water and a C_1-4 alcohol.

24. A process according to claim 23, wherein said C_1-4 alcohol is ethanol.

25. A process according to claim 23, wherein said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione at a temperature in the range of about 40°

C. to about reflux temperature.

26. A process according to claim 25, wherein said temperature is about 80°

C.

27. A process according to claim 23, wherein said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione in the presence of an alkali or alkaline earth metal hydroxide, alkoxide or carboxylate.

36. A process according to claim 1, represented by the following reaction scheme:

37. A process according to claim 36, wherein for intermediate process step (a) Hal represents fluoro.

38. A process according to claim 36, wherein for intermediate process step (a) said polar aprotic solvent is DMF.

39. A process according to claim 36, wherein for intermediate process step (b) X is sodium or potassium and said alkali metal metabisulphite salt is sodium or potassium metabisulphite.

40. A process according to claim 39, wherein for intermediate process step (b) X is sodium and said alkali metal metabisulphite salt is sodium metabisulphite.

41. A process according to claim 36, wherein for intermediate process step (b) said intermediate benzaldehyde compound of formula (IV) is reacted with said alkali metal metabisulphite salt in an aqueous solution comprising C_1-4 alcohols.

42. A process according to claim 36, wherein for intermediate process step (b) said intermediate benzaldehyde compound of formula (IV) is reacted with said alkali metal metabisulphite salt at a temperature in the range of −

10°

C. to reflux.

43. A process according to claim 36, wherein for intermediate process step (c) said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione in toluene in the presence of a catalytic amount of piperidine and acetic acid.

44. A process according to claim 36, wherein for intermediate process step (c) said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione in a C_1-4 alcohol or in a mixture of water and a C_1-4 alcohol.

45. A process according to claim 44, wherein for intermediate process step (c) said C_1-4 alcohol is ethanol.

46. A process according to claim 44, wherein for intermediate process step (c) said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione at a temperature in the range of about 40°

C. to about reflux temperature.

47. A process according to claim 46, wherein said temperature is about 80°

C.

48. A process according to claim 44, wherein for intermediate process step (c) said metabisulphite complex of formula (III) is reacted with thiazolidine 2,4 dione in the presence of an alkali or alkaline earth metal hydroxide, alkoxide or carboxylate.

19-21. -21. (canceled)

28-32. -32. (canceled)

33. A process of preparing rosiglitazone of formula (I), or a pharmaceutically acceptable salt thereof,

34. A process according to claim 33, wherein Hal represents fluoro.

35. A process according to claim 33, wherein said polar aprotic solvent is DMF.

49. A metabisulphite complex of formula (III):

50. A metabisulphite complex of formula (III) according to claim 49, wherein X is sodium or potassium.

51. A metabisulphite complex of formula (III) according to claim 50, wherein X is sodium.

52-64. -64. (canceled)