Processes for the preparation of D-chiro-inositol

• US 5,932,774 A
• Filed: 11/06/1995
• Issued: 08/03/1999
• Est. Priority Date: 11/06/1995
• Status: Expired due to Term

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Robinson, Gregg E., Bhatia, Ashok V., Chamberlin, Steven A., Riley, David A.
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US08/539,424
• Time in Patent Office: 1,366 Days
• Field of Search: 568/822, 568/832, 568/883
• US Class Current: 568/833
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 29/095 of esters of organic acids
• CPC Class Codes: C07C 35/16 Inositols
• 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

Abstract

A method for the preparation of D-chiro-inositol from kasugamycin, comprising the steps of: (a) reacting kasugamycin with an acetylating agent to form a crude hexa-acetate intermediate; (b) purifying the crude intermediate to form purified hexa-acetate intermediate; (c) deacetylating the purified intermediate to form D-chiro-inositol; and (d) isolating the D-chiro-inositol. The method permits efficient, large-scale preparation of D-chiro-inositol without the need for extensive chromatographic purification of the final D-chiro-inositol product.

Claims

1. A method for the preparation of D-chiro-inositol from kasugamycin, comprising the steps of:

(a) reacting kasugamycin with an acetylating agent in the presence of an acid-functionalized resin to form a crude hexa-acetate;

(b) purifying the crude hexa-acetate to form purified hexa-acetate;

(c) deacetylating the purified hexa-acetate to form D-chiro-inositol; and

(d) isolating the D-chiro-inositol.

2. A method according to claim 1 wherein the acid-functionalized resin is a resin-supported sulfonic acid.

3. A method according to claim 1 wherein the purification in step (b) comprises the sub-steps of:

(i) substantially removing the acetylating agent to form a residue;

(ii) diluting the residue in a suitable solvent system to form a solution of crude hexa-acetate;

(iii) filtering the solution of crude hexa-O-acetyl-D-chiro-inositol to form a solution of purified hexa-acetate; and

(iv) substantially removing the solvent.

4. A method according to claim 3 wherein the removal of acetylating agent in sub-step (i) is carried out by vacuum evaporation of the acetylating agent.

5. A method according to claim 3 wherein the solvent system in sub-step (ii) comprises a first polar solvent selected from the group consisting of acetone, methanol, ethanol, ethyl acetate, CH₃ CN, CH₂ Cl₂, CHCl₃, and 1,2-dichloroethane.

6. A method according to claim 5 wherein the solvent system additionally comprises a second non-polar solvent selected from the group consisting of long-chain hydrocarbons and aromatic hydrocarbons.

7. A method according to claim 6 wherein the second non-polar solvent is selected from the group consisting of pentane, hexane, heptane, benzene, xylene, and toluene.

8. A method according to claim 7 wherein the solvent system is a mixture of ethyl acetate and hexane or toluene in a ratio of about 1:

1.

9. A method according to claim 3 wherein the filtering in sub-step (iii) comprises passing the solution of crude hexa-acetate through a filter material selected from the group consisting of silica gel, alumina, activated carbon, diatomaceous earth, and a mixture of alumina and diatomaceous earth.

10. A method according to claim 9 wherein the filter material is silica gel.

11. A method according to claim 3 comprising the additional sub-step, between sub-steps (ii) and (iii), of neutralizing the solution of crude hexa-acetate.

12. A method according to claim 11 wherein the neutralization is carried out by washing the solution of crude hexa-acetate with an aqueous base solution.

13. A method according to claim 12 wherein the aqueous base solution is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

14. A method according to claim 3 comprising the additional sub-step, between sub-steps (iii) and (iv), of neutralizing the solution of purified hexa-acetate.

15. A method according to claim 14 wherein the neutralization is carried out by washing the solution of purified hexa-acetate with aqueous base solution.

16. A method according to claim 15 wherein the aqueous base solution is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

17. A method according to claim 3 comprising the additional sub-step, after sub-step (iv), of azeo-drying the purified hexa-acetate.

18. A method according to claim 17 wherein the azeo-drying is carried out using a solvent selected from the group consisting of toluene, isopropanol and n-propanol.

19. A method according to claim 1 wherein the deacetylation in step (c) is carried out by dissolving the hexa-acetate in a solvent selected from the group consisting of methanol and ethanol and adding a sufficient amount of a basic catalyst selected from the group consisting of lithium methoxide, sodium methoxide, barium methoxide, and potassium methoxide to produce deacetylation.

20. A method according to claim 19 wherein the basic catalyst is sodium methoxide.

21. A method according to claim 1 wherein the deacetylation in step (c) is carried out by reacting the hexa-acetate with a solvent and an acid.

22. A method according to claim 21 wherein the solvent is selected from the group consisting of methanol and ethanol.

23. A method according to claim 21 wherein the acid is selected from the group consisting of hydrochloric acid and sulfuric acid.

24. A method according to claim 21 wherein the deacetylation in step (c) is carried out by reacting the hexa-acetate with methanol and sulfuric acid.

25. A method according to claim 21 wherein the solvent is selected from the group consisting of methanol and ethanol.

26. A method according to claim 21 wherein the acid is selected from the group consisting of hydrochloric acid and sulfuric acid.

27. A method according to claim 1 comprising the additional step, after the isolation in step (d), of purifying the D-chiro-inositol by re-crystallization.

28. A method according to claim 27 wherein the re-crystallization of D-chiro-inositol comprises the sub-steps of:

(i) dissolving the D-chiro-inositol in water; and

(ii) precipitating the D-chiro-inositol from solution.

29. A method for the preparation of D-chiro-inositol from kasugamycin, comprising:

(a) reacting kasugamycin with an acetylating agent in the presence of an acid-functionalized resin to form a crude hexa-acetate mixture;

(b) concentrating the crude hexa-acetate mixture;

(c) extracting the crude hexa-acetate product with a solvent system;

(d) washing the crude hexa-acetate with water;

(e) concentrating the crude hexa-acetate solution to form a purified hexa-acetate;

(f) deacetylating the purified hexa-acetate to form D-chiro-inositol; and

(g) isolating the D-chiro-inositol.

30. A method according to claim 29 wherein crude hexa-acetate is concentrated by vacuum distillation.

31. A method according to claim 29 wherein the concentrated crude hexa-acetate is neutralized after extraction with a solvent system.

32. A method according to claim 29 wherein the neutralization is carried out by washing the solution of concentrated crude hexa-acetate with aqueous base solution.

33. A method according to claim 32 wherein the aqueous base solution is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

34. A method according to claim 29 wherein the neutralization is performed after forming a purified hexa-acetate.

35. A method according to claim 34 wherein the neutralization is carried out by washing the solution of purified hexa-acetate with aqueous base solution.

36. A method according to claim 35 wherein the aqueous base solution is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

37. A method according to claim 29 wherein the solvent system comprises a first polar solvent selected from the group consisting of ethyl acetate, CH₃ CN, CH₂ Cl₂, CHCl₃, and 1,2-dichloroethane.

38. A method according to claim 29 wherein the solvent system additionally comprises a second non-polar solvent selected from the group consisting of long-chain hydrocarbons and aromatic hydrocarbons.

39. A method according to claim 38 wherein the second non-polar solvent is selected from the group consisting of pentane, hexane, heptane, benzene, xylene, and toluene.

40. A method according to claim 39 wherein the solvent system is a mixture of ethyl acetate and hexane or toluene in a ratio of from about 1:

1 to about 10;

1.

41. A method according to claim 29 wherein substep(d) comprises washing the crude hexa-acetate product first with aqueous base solution and then followed by water.

42. A method according to claim 41 wherein the aqueous base solution is bicarbonate solution.

43. A method according to claim 29 wherein the crude hexa-acetate is concentrated by azeo-drying.

44. A method according to claim 43 wherein the azeo-drying is carried out using a solvent selected from the group consisting of toluene, isopropanol and n-propanol.

45. A method according to claim 29 wherein purified hexa-acetate is further purified by dissolving the pure hexa-acetate in a solvent with heat and then allowing it to cool.

46. A method according to claim 45 wherein the solvent is selected from the group consisting of:

1-butanol, 2-butanol, 1- propanol, 2-propanol, ethanol, methanol, and aqueous solutions of the above solvents.

47. A method according to claim 29 wherein D-chiro-inositol is further purified by re-crystallization.

48. A method according to claim 47 wherein the re-crystallization of D-chiro-inositol comprises the sub-steps of:

(i) dissolving the D-chiro-inositol in water; and

(ii) precipitating the D-chiro-inositol from solution.

49. A method according to claim 48 wherein said dissolved D-chiro-inositol is neutralized with a basic resin before precipitation.

50. A method according to claim 29 wherein the deacetylation step is carried out by reacting the hexa-acetate with a solvent and an acid.

51. A method according to claim 50 wherein the solvent is selected from the group consisting of methanol and ethanol.

52. A method according to claim 50 wherein the acid is selected from the group consisting of hydrochloric acid and sulfuric acid.

53. A method according to claim 50 wherein the deacetylation step is carried out by reacting the hexa-acetate with methanol and sulfuric acid.