Methods for producing triterpenoid derivatives

Abstract

In some aspects, the present disclosure provides methods for the preparation of omaveloxolone. Also provided herein are methods for the preparation of a compound having the Formula (III) wherein the variables are defined herein.

Description

Abstract In some respects, this disclosure provides methods for the preparation of omasorone. Methods for the preparation of compounds having formula (III) are also provided herein, wherein the variables are as defined herein.

Claims

WHAT IS CLAIMED IS:

1. A multi-step method for preparation of omaveloxolone from oleanolic acid, comprising the use of a compound of Formula I as a reagent in one or more steps, wherein Formula I is defined as:wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups.

2. The method of claim 1, wherein Ri, Ri', and Ri" are each propyl.

3. The method according to either claim 1 or claim 2, wherein the method comprises reacting oleanolic acid with an alkylating agent in a reaction mixture to form Compound A, wherein Compound A is defined as:

4. The method of claim 3, wherein the reaction mixture further comprises potassium carbonate.

5. The method according to either claim 3 or claim 4, wherein the reaction mixture further comprises 2-methyltetrahydrofuran.

6. The method according to any one of claims 3-5, wherein the reaction mixture further comprises tetrabutylammonium bromide.

7. The method according to any one of claims 3-6, wherein the alkylating agent is dimethyl sulfate.

8. The method according to any one of claims 3-7, wherein the reaction is carried out at a temperature of about 30°C.

9. The method according to any one of claims 3-8, wherein the reaction is carried out for about 1.0 h.

10. The method according to any one of claims 3-9, wherein the method further comprises contacting the reaction mixture with triethylamine at a second temperature of about 50°C for a second time period of about 3 h.

11. The method according to any one of claims 1-10, wherein the method further comprises reacting Compound A:with an oxidizing agent in a reaction mixture to form Compound B, wherein CompoundB is defined as:

12. The method of claim 11, wherein the oxidizing agent comprises meta-chloroperoxybenzoic acid.

13. The method according to either claim 11 or claim 12, wherein the molar ratio of Compound A to the oxidizing agent is about 4:5.

14. The method according to any one of claims 11-13, wherein the reaction mixture comprises dichloromethane.

15. The method according to any one of claims 11-14, wherein the reaction is carried out at a temperature of about 25°C.

16. The method according to any one of claims 11-15, wherein the reaction is carried out at a time period of about 15 h.

17. The method according to any one of claims 11-16, wherein the method further comprises contacting the reaction mixture with a solution of sodium bicarbonate and isolating the organic layer.

18. The method of claim 17, wherein the method further comprises contacting the isolated organic layer with methanesulfonic acid.

19. The method according to any one of claims 1-18, wherein the method further comprises reacting Compound B:with an oxidizing agent in a reaction mixture to form Compound C, wherein CompoundC is defined as:

20. The method of claim 19, wherein the oxidizing agent is pyridinium perbromide.

21. The method according to either claim 19 or claim 20, wherein the reaction mixture comprises a molar ratio of Compound B to the oxidizing agent of from about 1 : 1 to about 1 :2.

22. The method according to any one of claims 19-21, wherein the reaction mixture further comprises toluene.

23. The method according to any one of claims 19-22, wherein the method further comprises reacting Compound B with the oxidizing agent at a temperature of about 33°C.

24. The method according to any one of claims 19-23, wherein the method further comprises reacting Compound B with the oxidizing agent for a reaction time period of about 2 h.

25. The method according to any one of claims 1 -24, wherein the method further comprises reacting Compound C:with an oxidizing agent in the presence of a compound of Formula I:in a reaction mixture to form Compound D, wherein Compound D is defined as:wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; oralkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups.

26. The method of claim 25, wherein Ri, Ri', and Ri" are each propyl.

27. The method of either claim 25 or claim 26, wherein the reaction mixture comprises a molar ratio of Compound C to the compound of Formula I from about 1 : 1 to about 1 :2.

28. The method according to any one of claims 25-27, wherein the reaction mixture further comprises diisopropylethylamine.

29. The method of claim 28, wherein the reaction mixture comprises a molar ratio of Compound C to diisopropylethylamine from about 1 : 1 to about 1 :2.

30. The method according to any one of claims 25-29, wherein the oxidizing agent is dimethylsulfoxide.

31. The method of claim 30, wherein the reaction mixture comprises a molar ratio of Compound C to dimethylsulfoxide from about 1 :5 to about 1 :7.

32. The method according to any one of claims 25-31, wherein the method further comprises reacting Compound C with the compound of Formula I under an inert atmosphere.

33. The method according to any one of claims 25-32, wherein the method comprises contacting Compound C with a solution comprising the compound of Formula I.

34. The method of claim 33, wherein the concentration of the compound of Formula I in the solution is about 50% by weight.

35. The method according to any one of claims 25-34, wherein the solution comprises ethyl acetate.

36. The method according to any one of claims 25-35, wherein the reaction between Compound C and dimethylsulfoxide in the presence of the compound of Formula I is carried out at a temperature of about 25 °C.

37. The method according to any one of claims 25-36, wherein the reaction between Compound C and dimethylsulfoxide in the presence the compound of Formula I is carried ourt for a reaction time period of about 3 h.

38. A method for the preparation of a compound of Formula III comprising obtaining a compound of Formula II:and reacting the compound of Formula II with an oxidizing agent in the presence of a compound of Formula I:in a reaction mixture to form a compound of Formula III:wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8),dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups; andR2 is:Ci-Cis-acyl or Ci-Cis-alkyl, wherein either of these groups is substituted or unsubstituted.

39. The method of claim 38, wherein Ri, Ri', and Ri" are each propyl.

40. The method of either claim 38 or claim 39, wherein R2 is Ci-Cis-acyl or substituted Ci-Cis-acyl.

41. The method of claim 40, wherein R2 is substituted Ci-Cis-acyl.

42. The method of claim 41, wherein R2 is -CO2CH3.

43. The method according to any one of claims 38-42, wherein the reaction mixture comprises a molar ratio of the compound of Formula II to the compound of Formula I from about 1 : 1 to about 1 :2.

44. The method according to any one of claims 38-43, wherein the reaction mixture further comprises diisopropylethylamine.

45. The method of claim 44, wherein the reaction mixture comprises a molar ratio of the compound of Formula II to diisopropylethylamine from about 1 : 1 to about 1 :2.

46. The method according to any one of claims 38-45, wherein the reaction mixture further comprises dimethylsulfoxide.

47. The method according to claim 46, wherein the reaction mixture comprises a molar ratio of the compound of Formula II to dimethylsulfoxide from about 1 :5 to about 1 :7.

48. The method according to any one of claims 38-47, wherein the method further comprises reacting a compound of Formula II with the compound of Formula I under an inert atmosphere.

49. The method according to any one of claims 38-48, wherein reacting the compound of Formula II with the compound of Formula I further comprises contacting the compound of Formula II with a solution comprising the compound of Formula I.

50. The method of claim 49, wherein the concentration of the solution is about 50% by weight.

51. The method according to any one of claims 38-50, wherein the solution further comprises ethyl acetate.

52. The method according to any one of claims 38-51, wherein the method further comprises reacting the compound of Formula II with the compound of Formula I at a temperature of about 25 °C.

53. The method according to any one of claims 38-52, wherein the method further comprises reacting the compound of Formula II with the compound of Formula I for a reaction time period of about 3 h.

54. A method for the preparation of Compound A comprising obtaining oleanolic acid, and reacting oleanolic acid with an alkylating agent in a reaction mixture to form Compound A:wherein the reaction mixture comprises a solvent that is immiscible with water.

55. The method of claim 54, wherein the reaction mixture further comprises a base.

56. The method of claim 55, wherein the base is potassium carbonate.

57. The method according to any one of claims 54-56, wherein the reaction mixture further comprises a phase-transfer catalyst.

58. The method of claim 57, wherein the phase-transfer catalyst is tetrabutylammonium bromide.

59. The method according to any one of claims 54-58, wherein the alkylating agent is dimethyl sulfate.

60. The method according to any one of claims 54-59, wherein the solvent comprises 2-methyltetrahydrofuran.

61. The method according to any one of claims 54-60, wherein the method further comprises an aqueous purification step.

62. The method according to any one of claims 54-61, wherein the reaction is carried out at a temperature from about 0°C to about 100°C.

63. The method of claim 62, wherein the temperature is about 30°C.

64. The method according to any one of claims 54-63, wherein the reaction is carried out for a reaction time period from about 0.5 h to about 3.0 h.

65. The method of claim 64, wherein the reaction time period is about 1.0 h.

66. The method according to any one of claims 54-65, wherein Compound A is prepared in greater than 90% purity, as measured by high performance liquid chromatography.

67. The method of claim 66, wherein Compound A is prepared in greater than 95% purity, as measured by high performance liquid chromatography.

68. The method of claim 67, wherein Compound A is prepared in greater than 98% purity, as measured by high performance liquid chromatography.

69. A method for the preparation of Compound C, comprising obtaining Compound B:and reacting Compound B with pyridinium perbromide in a reaction mixture to form Compound C:

70. The method of claim 69, wherein the molar ratio of Compound B to pyridinium perbromide is from about 1 : 1 to about 1 :2.

71. The method of either claim 69 or claim 70, wherein the reaction mixture comprises a solvent.

72. The method of claim 71, wherein the solvent is immiscible with water.

73. The method of claim 72, wherein the solvent comprises toluene.

74. The method according to any one of claims 69-73, wherein the reaction is carried out at a reaction time period from about 1 h to about 4 h.

75. The method of claim 74, wherein the reaction time period is about 2 h.

76. The method according to any one of claims 69-75, wherein the reaction is carried out at a temperature from about 0°C to about 100°C.

77. The method of claim 76, wherein the temperature is about 33°C.

78. The method according to any one of claims 69-77, wherein Compound C is prepared in greater than 90% purity, as measured by high performance liquid chromatography.

79. The method of claim 78, wherein Compound C is prepared in greater than 95% purity, as measured by high performance liquid chromatography.

80. The method of claim 79, wherein Compound C is prepared in greater than 98% purity, as measured by high performance liquid chromatography.

81. A method for the preparation of omavel oxoIone comprising:(a) reactingwith dimethyl sulfate and potassium carbonate in the presence of tetrabutylammonium bromide to form(b) reactingwith meta-chloroperoxybenzoic acid to form(c) reactingwith pyridinium perbromide to form(d) reactingwithdiisopropylethylamine and dimethylsulfoxide to form(e) reactingwith sodium methoxide to form(f) reactingwith hydroxylamine and hydrochloric acid to form(g) reactingwith sodium methoxide to formwith pyridine to form(j) reactingunder conditions suitable to form(k) reactingwith diphenylphosphoryl azide and triethylamine to form(1) heatingto form(m) reactingunder conditions suitable to form(n)to form omaveloxolone.

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