Process for recovering statin compounds from a fermentation broth

• US 20020187531A1
• Filed: 07/23/2002
• Published: 12/12/2002
• Est. Priority Date: 11/30/1999
• Status: Active Grant

• Current Assignee: Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag (Teva Pharmaceutical Industries Limited)
• Original Assignee: Biogal Gyogyszergyar Rt.
• Inventors: Szabo, Csaba, Keri, Vilmos, Deak, Lajos, Forgacs, Iiona, Nagyne, Edit Arvai
• Granted Patent: US 6,689,590 B2
• Time in Patent Office: Days
• US Class Current: 435/135
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 2602/28 Hydrogenated naphthalenes
• CPC Class Codes: C07C 67/52 by change in the physical state, e.g. crystallisation
• CPC Class Codes: C07C 69/013 Esters of alcohols having the esterified hydroxy group bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 69/33 esterified with hydroxy compounds having more than three hydroxy groups esters of sugars C07H
• CPC Class Codes: C12P 17/06 containing a six-membered hetero ring, e.g. fluorescein
• CPC Class Codes: C12P 7/42 Hydroxy-carboxylic acids

Abstract

A novel process for recovering a compound from a fermentation broth that includes the stages of forming an enriched solution of the compound by extraction, obtaining a salt of the compound from the enriched solution, purifying a salt of the compound and trans-salifying the salt of the compound to a metal salt of the compound is disclosed.

Claims

1. A process for isolating a sodium salt of a compound selected from pravastatin, compactin and lovastatin from a fermentation broth comprising the steps of:

a) forming an enriched solution of the compound;

b) obtaining a salt of the compound from the enriched solution;

c) purifying the salt of the compound;

d) trans-salifying the salt of the compound to a sodium salt of the compound by;

i) liberating the compound from its salt,

ii) contacting the compound with an aqueous sodium hydroxide solution thereby forming an aqueous solution of the sodium salt of the compound, and

iii) scavenging excess sodium ions by contacting the aqueous solution of the sodium salt of the compound with a water-insoluble ionic exchange resin; and

e) isolating the sodium salt of the compound from the aqueous solution of the sodium salt of the compound.

2. The process of claim 1 wherein the enriched solution is an enriched aqueous solution that is formed by the steps of:

a) contacting an acidic fermentation broth with an organic extraction solvent and thereby forming an organic extract of the compound;

b) back-extracting the organic extract by contacting with a basic aqueous solution thereby forming an aqueous extract; and

c) concentrating the aqueous extract thereby forming an enriched aqueous solution of the compound.

3. The process of claim 1 wherein the enriched solution is an enriched organic solution that is formed by the steps of:

a) contacting an acidic fermentation broth with an organic extraction solvent and thereby forming an organic extract of the compound;

b) back-extracting the organic extract by contacting with a basic aqueous solution thereby forming an aqueous extract of the compound; and

c) re-extracting the compound from the aqueous extract by contacting with an organic re-extraction solvent thereby forming an enriched organic solution of the compound.

4. The process of claim 2 wherein concentrating the aqueous extract is carried out by vacuum distillation.

5. The process of claim 2 wherein contacting the acidic fermentation broth with the organic extraction solvent is carried out at a pH of between about pH 1 and about pH 6.

6. The process of claim 2 wherein back-extracting with a basic aqueous solution is carried out at a pH of between about pH 7.0 and about pH 13.7.

7. The process of claim 2 wherein the organic extraction solvent is selected from the group consisting of C₂-C₄ alkyl formates, C₁-C₄ alkyl esters of C₂-C₄ alkyl carboxylic acids, dichloromethane, dichloroethane, chloroform, carbon tetrachloride and butyl methyl ketone.

8. The process of claim 7 wherein the organic extraction solvent is an acetate.

9. The process of claim 3 wherein contacting the acidic fermentation broth with an organic extraction solvent is carried out at a pH of between about pH 1 and about pH 6.

10. The process of claim 3 wherein back-extracting with a basic aqueous solution is carried out at a pH of between about pH 7.0 and about pH 13.7.

11. The process of claim 3 wherein re-extracting the compound with an organic solvent is carried out at a pH of between about pH 1 and about pH 6.

12. The process of claim 3 wherein the organic extraction solvent and the organic re-extraction solvent are each independently selected from the group consisting of C₂-C₄ alkyl formates, C₁-C₄ alkyl esters of C₂-C₄ alkyl carboxylic acids, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, butyl methyl ketone.

13. The process of claim 12 wherein the organic extraction solvent and organic re-extraction solvent are acetates.

14. The process of claim 13 wherein the organic extraction solvent and organic re-extraction solvent are i-butyl acetate.

15. The process of claim 1 wherein obtaining of the salt of the compound is carried out at temperature of between about −

10°

C. and about +60°

C.

16. The process of claim 1 wherein obtaining of the salt of the compound comprises precipitating the salt of the compound by adding a metal salt, ammonia, an amine or an ammonium salt to the enriched solution.

17. The process of claim 16 wherein the salt of the compound is precipitated by adding an ammonium salt.

18. The process of claim 17 wherein the ammonium salt is selected from the group consisting of NH₄Cl, NH₄Br, NH₄I, (NH₄)₂SO₄, NH₄NO₃, (NH₄)₃PO₄, (NH₄)₂S₂O₄, NH₄OAc and NH₄SCN.

19. The process of claim 18 wherein the ammonium salt is NH₄Cl.

20. The process of claim 16 wherein the salt of the compound is precipitated by adding ammonia gas.

21. The process of claim 16 wherein the salt of the compound is precipitated by adding ammonia gas and an ammonium salt.

22. The process of claim 16 wherein the salt of the compound is precipitated by adding a metal salt.

23. The process of claim 22 wherein the metal salt is selected from the group consisting of lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, copper salts, iron salts, nickel salts, manganese salts, tin salts, zinc salts and aluminum salts.

24. The process of claim 23 wherein the metal salt is selected from the salts containing the metal ions Li⁺, Na⁺, K⁺, Ca²⁺, Mg²⁺, Cu²⁺, Fe²⁺, Fe³⁺, Ni²⁺, Mn²⁺, Sn²⁺, Zn²⁺, Al³⁺ ions.

25. The process of claim 16 wherein the salt of the compound is precipitated by adding an amine salt.

26. The process of claim 25 wherein the amine salt has an amine component selected from the group consisting of C₁-C₃ primary, secondary and tertiary alkyl amines.

27. The process of claim 1 wherein the step of purifying the salt of the compound comprises the step of recrystallizing the salt of the compound.

28. The process of claim 27 wherein recrystallizing the salt of the compound comprises the steps of:

a) dissolving the salt of the compound in water thereby forming an aqueous solution of the salt of the compound;

b) diluting the aqueous solution of the salt of the compound with an anti-solvent; and

c) adding a salt having the same metal, ammonium or aminium ion as the salt of the compound.

29. The process of claim 28 wherein the anti-solvent is selected from the group consisting of ethyl acetate, i-butyl acetate, i-butanol, acetone, acetonitrile and ethanol.

30. The process of claim 28 wherein the salt having the same metal, ammonium ion or aminium ion as the salt of the compound is an ammonium salt.

31. The process of claim 30 wherein the ammonium salt is selected from the group consisting of NH₄Cl, NH₄Br, NH₄I, (NH₄)₂SO₄, NH₄NO₃, (NH₄)₃PO₄, (NH₄)₂S₂O₄, NH₄OAc and NH₄SCN

32. The process of claim 31 wherein the ammonium salt is NH₄Cl.

33. The process of claim 1 wherein liberating the compound from the salt of the compound comprises the steps of:

a) dissolving the salt of the compound in aqueous solvent,

b) adding a protic acid to the aqueous solvent, and

c) extracting the compound from the aqueous solvent into an organic solvent to form an organic solution of the compound,

further wherein the compound is contacted with the aqueous sodium hydroxide solution by back-extracting the organic solution of the compound with the aqueous sodium hydroxide solution.

34. The process of claim 33 wherein extracting the compound is carried out at a pH between about pH 1 and about pH 6.

35. The process of claim 33 wherein the organic solvent is selected from the group consisting of C₂-C₄ alkyl formates, C₁-C₄ alkyl C₂-C₄ alkanoates, dichloromethane, dichloroethane, chloroform, carbon tetrachloride and butyl methyl ketone.

36. The process of claim 35 wherein the organic solvent is i-butyl acetate.

37. The process of claim 33 wherein the back-extracting of the organic solution of the compound into an aqueous solution of sodium hydroxide is carried out at a pH of between about pH 6.5 and about pH 13.7.

38. The process of claim 1 wherein isolating the sodium salt of the compound comprises the steps of:

a) concentrating the aqueous solution of the sodium salt of the compound and

b) diluting the aqueous solution of the sodium salt of the compound with an organic solvent or organic solvent mixture.

39. The process of claim 1 wherein isolating the sodium salt of the compound comprises the step of lyophilizing the aqueous solution of the sodium salt of the compound.

40. The process of claim 38 wherein concentrating the aqueous solution of the sodium salt of the compound is carried out by vacuum distillation.

41. The process of claim 38 wherein concentrating the aqueous solution of the sodium salt of the compound is carried out by nano-filtration.

42. The process of claim 38 wherein the aqueous solution of the sodium salt of the compound is diluted with acetone.

43. The process of claim 38 wherein the aqueous solution of the sodium salt of the compound is diluted with an organic solvent mixture selected from the group consisting of acetone/acetonitrile mixtures, ethanol/acetonitrile mixtures and ethanol/ethyl acetate mixtures.

44. The process of claim 38 wherein isolating the sodium salt of the compound is carried out at a temperature of between about −

10°

C. and about +60°

C.

46. The pravastatin sodium of claim 45 wherein the total impurity content is about 0.5% or less by weight.

47. The pravastatin sodium of claim 46 wherein the total impurity content is about 0.2% or less by weight.

45. Pravastatin sodium substantially free of pravastatin lactone.