Processes and intermediates for producing azaindoles

• US 8,513,414 B2
• Filed: 07/03/2012
• Issued: 08/20/2013
• Est. Priority Date: 07/05/2011
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Tanoury, Gerald J., Jung, Young Chun, Magdziak, Derek, Looker, Adam, Kline, Billie J., Jurcik, Vclav, Dominguez Olmo, Beatriz
• Primary Examiner(s): VAJDA, KRISTIN ANN
• Application Number:
  US13/541,504
• Publication Number:
  US 20130102782A1
• Time in Patent Office: 413 Days
• Field of Search: 544/328
• US Class Current: 544/328
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids

Abstract

The present invention relates to processes and intermediates for the preparation of compounds useful as inhibitors of Janus kinases (JAK).

Claims

1. A process for preparing a compound of Formula I:

2. The process of claim 1, wherein the organic solvent of step i) is an aprotic solvent.

3. The process of claim 2, wherein the aprotic solvent is acetonitrile, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, methyl tert-butyl ether, or any combination thereof.

4. The process of claim 1, wherein the organic solvent of step i) is a protic solvent.

5. The process of claim 4, wherein the protic solvent is an alcohol selected from methanol, propanol, isopropanol, butanol, tert-butanol, or any combination thereof.

6. The process of claim 1, wherein the base of step i) is an inorganic base.

7. The process of claim 6, wherein the inorganic base comprises tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium carbonate, disodium carbonate, trisodium phosphate, disodium hydrogen phosphate, or any combination thereof.

8. The process of claim 7, wherein the inorganic base comprises an alkali metal hydroxide.

9. The process of claim 8, wherein the alkali metal hydroxide comprises NaOH, KOH, or any combination thereof.

10. The process of claim 1, wherein the transition metal catalyst of step i) is a palladium catalyst.

11. The process of claim 10, wherein the palladium catalyst of step i) comprises palladium(II)acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), or any combination thereof.

12. The process of claim 10, wherein the palladium catalyst of step i) comprises

13. The process of claim 1, wherein the reaction of step i) is performed at a temperature between about 50°

C. and about 110°

C.

14. The process of claim 13, wherein the reaction of step i) is performed at a temperature between about 60°

C. and about 95°

C.

15. The process of claim 14, wherein the reaction of step i) is performed at a temperature between about 70°

C. and about 80°

C.

16. The process of claim 1, further comprising the steps of:

ii) deprotecting a compound of Formula 3 to generate a compound of Formula 4;

17. The process of claim 16, wherein step ii) comprises deprotecting the compound of Formula 3 in the presence of a base.

18. The process of claim 17, wherein the base comprises an inorganic base.

19. The process of claim 18, wherein the inorganic base is an alkali metal hydroxide.

20. The process of claim 19, wherein the alkali metal hydroxide is NaOH, KOH, or any combination thereof.

21. The process of claim 16, wherein the reaction of step iii) occurs in the presence of an organic base.

22. The process of claim 21, wherein the organic base of step iii) comprises a tertiary amine.

23. The process of claim 22, wherein the tertiary amine comprises N,N-diisopropylethylamine, triethylamine, or any combination thereof.

24. The process of claim 16, wherein the coupling agent of step iii) comprises propylphosphonic anhydride.

25. The process of claim 16, wherein the organic solvent of step iii) comprises a halogenated hydrocarbon, an alkyl substituted tetrahydrofuran, or any combination thereof.

26. The process of claim 25, wherein the organic solvent comprises an alkyl substituted tetrahydrofuran comprising 2-methyltetrahydrofuran.

27. The process of claim 1, further comprising the steps of:

iva) reacting a compound of Formula 5 with bromine in an organic solvent to generate a compound of Formula 6;

28. The process of claim 1, further comprising the steps of:

ivb) reacting a compound of Formula 5 with p-toluenesulfonyl chloride to generate a compound of Formula 9;

29. The process of claim 1, further comprising the step of:

viiia) reacting a compound of Formula 10, wherein R⁸ is a —

C_1-4 alkyl, with a compound of Formula 11

30. The process of claim 29, further comprising the steps of:

ixa) deprotecting the compound of Formula 12 and the compound of Formula 13 in the presence of an inorganic acid to generate a mixture comprising the compound of Formula 2 and a compound of Formula 14;

31. The process of claim 29, further comprising the steps of:

viiib) reacting a compound of Formula 11 with an acid salt of a compound of Formula 15 in the presence of a solvent and a base to generate the compound Formula 2

32. The process of claim 31, wherein the base of step viiib) is an inorganic base selected from tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium carbonate, disodium carbonate, trisodium phosphate, disodium hydrogen phosphate, or any combination thereof.

33. The process of claim 31, wherein the solvent of step viiib) comprises water.

34. The process of claim 33, wherein the solvent of step viiib) further comprises an alcohol selected from methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, or any combination thereof.

35. The process of claim 31, wherein the reaction of step viiib) is performed at a temperature of from about 70°

C. to about 120°

C.

36. The process of claim 35, wherein the reaction of step viiib) is performed at a temperature of from about 80°

C. to about 100°

C.

91. The process of claim 16, wherein HNR⁶R⁷ is 2,2,2-trifluoroethylamine.

92. The process of claim 27, wherein the compound of Formula 5 is selected from

93. The process of claim 27, wherein the compound of Formula 6 is selected from

94. The process of claim 28, wherein the compound of Formula 9 is selected from

95. The process of claim 29, wherein the compound of Formula 10 is selected from

96. The process of claim 30, wherein the compound of Formula 14 is selected from

97. The process of claim 31, wherein the compound of Formula 11 is selected from

98. The process of claim 1, wherein:

the compound of Formula I is;

37. A process for preparing a compound of Formula 4:

38. The process of claim 37, wherein the organic solvent of step ia) is an alcohol.

39. The process of claim 38, wherein the alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or any combination thereof.

40. The process of claim 37, wherein the base of step ia) is an inorganic base.

41. The process of claim 40, wherein the inorganic base is an alkali metal hydroxide.

42. The process of claim 41, wherein the alkali metal hydroxide is NaOH, KOH, or any combination thereof.

43. The process of claim 37, wherein the reaction of step ia) is performed at a temperature between about 50°

C. and about 110°

C.

44. The process of claim 43, wherein the reaction of step ia) is performed at a temperature between about 60°

C. and about 95°

C.

45. The process of claim 44, wherein the reaction of step ia) is performed at a temperature between about 70°

C. and about 80°

C.

46. The process of claim 37, wherein the deprotection of step ii) is performed in the presence of a base.

47. The process of claim 46, wherein the base is an inorganic base.

48. The process of claim 47, wherein the inorganic base is an alkali metal hydroxide.

49. The process of claim 48, wherein the alkali metal hydroxide is KOH, NaOH, or any combination thereof.

50. The process of claim 37, further comprising the steps:

viiib) reacting a compound of Formula 11 with an acid salt of a compound of Formula 15 in the presence of a solvent and a base to generate the compound Formula 2;

51. The process of claim 50, wherein the base of step viiib) is an inorganic base selected from tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium carbonate, disodium carbonate, trisodium phosphate, disodium hydrogen phosphate, or any combination thereof.

52. The process of claim 50, wherein the solvent of step viiib) comprises water.

53. The process of claim 52, wherein the solvent of step viiib) further comprises an alcohol selected from methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, or any combination thereof.

54. The process of claim 50, wherein the reaction of step viiib) is performed at a temperature of from about 70°

C. to about 120°

C.

55. The process of claim 54, wherein the reaction of step viiib) is performed at a temperature of from about 80°

C. to about 100°

C.

56. A process for preparing a compound of Formula 1:

57. The process of claim 56, wherein the organic solvent in step iva) is an aprotic solvent.

58. The process of claim 57, wherein the aprotic solvent is dimethylformamide.

59. The process of claim 56, wherein the reaction in step iva) is performed at a temperature of about −

5°

C. to about 30°

C.

60. The process of claim 59, wherein the reaction of step iva) is performed at a temperature of about 0°

C. to about 10°

C.

61. The process of claim 56, wherein the reaction of step va) is performed in the presence of sodium hydride.

62. The process of claim 61, wherein the reaction of step va) is performed at a temperature of about 0°

C. to about 30°

C.

63. The process of claim 62, wherein the reaction of step va) is performed at a temperature of about 5°

C. to about 25°

C.

64. The process of claim 63, wherein the reaction of step va) is performed at a temperature of about 10°

C. to about 20°

C.

65. The process of claim 56, wherein the strong lithium base of step vi) is n-butyl lithium.

66. The process of claim 56, wherein the reaction of step vi) is performed at a temperature of about −

100°

C. to about −

70°

C.

67. The process of claim 66, wherein the reaction of step vi) is performed at a temperature of about −

90°

C. to about −

80°

C.

68. The process of claim 56, wherein the organic solvent of step vii) is a halogenated hydrocarbon.

69. The process of claim 68, wherein the halogenated hydrocarbon is dichloromethane or dichloroethane.

70. The process of claim 56, wherein the esterification reaction of step vii) is performed at a temperature of about 0°

C. to about 60°

C.

71. The process of claim 70, wherein the esterification reaction of step vii) is performed at a temperature of about 10°

C. to about 40°

C.

72. The process of claim 71, wherein the esterification reaction of step vii) is performed at a temperature of about 20°

C. to about 30°

C.

73. A process for preparing a compound of Formula 1:

74. The process of claim 73, wherein the reaction of step ivb) is performed in the presence of sodium hydride.

75. The process of claim 73, wherein the strong lithium base of step vi) is n-butyl lithium.

76. The process of claim 73, wherein the reaction of step vi) is performed at a temperature of about −

100°

C. to about −

70°

C.

77. The process of claim 76, wherein the reaction of step vi) is performed at a temperature of about −

90°

C. to about −

80°

C.

78. The process of claim 73, wherein the organic solvent of step vii) is a halogenated hydrocarbon.

79. The process of claim 78, wherein the halogenated hydrocarbon is dichloromethane or dichloroethane.

80. The process of claim 73, wherein the esterification reaction in step vii) is performed at a temperature of about 0°

C. to about 60°

C.

81. The process of claim 80, wherein the esterification reaction in step vii) is performed at a temperature of about 10°

C. to about 40°

C.

82. The process of claim 81, wherein the esterification reaction in step vii) is performed at a temperature of about 20°

C. to about 30°

C.

83. A process for preparing a compound of Formula 2

84. The process of claim 83, further comprising the steps of:

ixa) deprotecting the compound of Formula 12 and the compound of Formula 13 in the presence of an inorganic acid to generate a mixture of a compound of Formula 2 and a compound of Formula 14;

85. A process for preparing a compound of Formula 2:

86. The process of claim 85, wherein the base of step viiib) is an inorganic base selected from tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium carbonate, disodium carbonate, trisodium phosphate, disodium hydrogen phosphate, or any combination thereof.

87. The process of claim 85, wherein the solvent of step viiib) comprises water.

88. The process of claim 87, wherein the solvent of step viiib) further comprises an alcohol selected from methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, or any combination thereof.

89. The process of claim 85, wherein the reaction of step viiib) is performed at a temperature of from about 70°

C. to about 120°

C.

90. The process of claim 89, wherein the reaction of step viiib) is performed at a temperature of from about 80°

C. to about 100°

C.

99. A process for preparing (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide of Formula Ia:

100. The process of claim 99, further comprising the step of reacting

101. A process for preparing 2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)propanamide of Formula Ib:

102. The process of claim 101, further comprising the step of reacting

103. A solid form of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) designated as Form E.

104. The solid Form E of claim 103, characterized by one or more peaks corresponding to 2-theta values measured in degrees of 7.1±

0.2, 8.2±

0.2, 23.9±

0.2, and 24.8±

0.2 in an X-ray powder diffraction pattern.

105. A solid form of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) designated as Form B.

106. The solid Form B of claim 105, characterized by one or more peaks corresponding to 2-theta values measured in degrees of 9.2±

0.2, 18.1±

0.2, 19.1±

0.2, and 32.0±

0.2 in an X-ray powder diffraction pattern.

107. The solid Form B of claim 106, further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 21.4±

0.2, 30.1±

0.2, 29.9±

0.2, and 26.1±

0.2 in an X-ray powder diffraction pattern.

108. A solid form of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) designated as Form B.

109. A solid form of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia) designated as Form A.

110. The solid Form A of claim 109, characterized by one or more peaks corresponding to 2-theta values measured in degrees of 23.7±

0.2, 11.3±

0.2, 19.3±

0.2, and 15.4±

0.2 in an X-ray powder diffraction pattern.

111. The solid Form A of claim 110, further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 28.9±

0.2 and 21.5±

0.2 in an X-ray powder diffraction pattern.