Method for synthesizing Chk1 inhibitors

Abstract

This invention provides a synthetic process for the large-scale production of SRA737, a Chk1 inhibitor, and related heterocyclic compounds, characterized by low impurities and simple operation. [Solution] In some embodiments, the disclosed compound is a novel synthetic intermediate (Formula X) of SRA737 (Formula VIII). In some embodiments, the compound is a protected form of SRA737, i.e., the compound is masked with a protecting organic group that, when exposed to suitable conditions, is removed to produce SRA737. In some embodiments, the disclosure provides novel compositions, compounds, and solvates containing very low concentrations of palladium impurities. In some embodiments, the compound is an active pharmaceutical ingredient (API) compound.

Claims

1. Formula I: 【Chemistry 1】 A compound, wherein, in the formula, R １ is C １－１２ alkyl, substituted C １－１２ alkyl, C １－１２ alkenyl, substituted C １－１２ alkenyl, C １－１２ alkynyl, substituted C １－１２ alkynyl, C １－１２ alkoxy, substituted C １－１２ alkoxy, C ３－８ cycloalkyl, substituted C ３－８ cycloalkyl, C ３－８ heterocycloalkyl, substituted C ３－８ heterocycloalkyl, C １－１２ amino, C １－１２ substituted amino, phenyl, substituted phenyl, C ３－８ heteroaryl, and substituted C ３－８ heteroaryl, and is selected from The compound wherein the compound is a dimethylformamide (DMF) solvate.

2. R １ However, C １－１２ Alkoxy or substituted C １－１２ The compound according to claim 1, wherein it is an alkoxy.

3. R １ However, C １－１２ Alkyl or substituted C １－１２ The compound according to claim 1, wherein it is alkyl.

4. R １ However, C ３－８ Heterocycloalkyl or C ３－８ The compound according to claim 1, wherein it is a heteroaryl compound.

5. R １ However, -OC(CH ３ ) ３ The compound according to claim 1.

6. A compound according to any one of claims 1 to 5, which is substantially purified and crystalline.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, and / or N-oxide thereof, and at least one pharmaceutically acceptable carrier or excipient.

8. The pharmaceutical composition according to claim 7, wherein the composition contains one or more palladium compounds as impurities in an amount of 1 mol% or less.

9. The pharmaceutical composition according to claim 7, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.5 mol% or less.

10. The pharmaceutical composition according to claim 7, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.1 mol% or less.

11. The pharmaceutical composition according to claim 7, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.05 mol% or less.

12. The pharmaceutical composition according to claim 7, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.01 mol% or less.

13. The pharmaceutical composition according to claim 7, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.005 mol% or less.

14. The pharmaceutical composition according to claim 7, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.001 mol% or less.

15. The pharmaceutical composition according to claim 7, wherein the composition contains one or more organic compounds as impurities in an amount of 1 mol% or less.

16. The pharmaceutical composition according to claim 7, wherein the composition contains one or more organic compounds as impurities in an amount of 0.5 mol% or less.

17. The pharmaceutical composition according to claim 7, wherein the composition contains one or more organic compounds as impurities in an amount of 0.1 mol% or less.

18. The pharmaceutical composition according to claim 7, wherein the composition contains one or more organic compounds as impurities in an amount of 0.05 mol% or less.

19. The pharmaceutical composition according to claim 7, wherein the composition contains one or more organic compounds as impurities in an amount of 0.01 mol% or less.

20. The pharmaceutical composition according to claim 7, wherein the composition contains one or more organic compounds as impurities in an amount of 0.005 mol% or less.

21. The pharmaceutical composition according to claim 7, wherein the composition contains one or more organic compounds as impurities in an amount of 0.001 mol% or less.

22. The pharmaceutical composition according to claim 7, wherein the composition comprises one or more organic compounds and one or more palladium compounds as impurities, collectively comprising 1 mol% or less.

23. The pharmaceutical composition according to claim 7, wherein the composition contains one or more organic compounds and one or more palladium compounds as impurities, in a total amount of 0.5 mol% or less.

24. The pharmaceutical composition according to claim 7, wherein the composition contains one or more organic compounds and one or more palladium compounds as impurities, in a total amount of 0.1 mol% or less.

25. The pharmaceutical composition according to claim 7, wherein the composition contains, in total, 0.05 mol% or less of one or more organic compounds and one or more palladium compounds as impurities.

26. The pharmaceutical composition according to claim 7, wherein the composition contains, as impurities, one or more organic compounds and one or more palladium compounds in total amount of 0.01 mol% or less.

27. The pharmaceutical composition according to claim 7, wherein the composition comprises one or more organic compounds and one or more palladium compounds as impurities, collectively comprising 0.005 mol% or less.

28. The pharmaceutical composition according to claim 7, wherein the composition comprises one or more organic compounds and one or more palladium compounds as impurities, collectively comprising 0.001 mol% or less.

29. The pharmaceutical composition according to any one of claims 7 to 28, wherein the composition is formulated for parenteral administration.

30. The pharmaceutical composition according to any one of claims 7 to 28, wherein the composition is formulated for intravenous administration.

31. The pharmaceutical composition according to any one of claims 7 to 28, wherein the composition is formulated for subcutaneous administration.

32. The pharmaceutical composition according to any one of claims 7 to 28, wherein the composition is formulated for enteral administration.

33. The pharmaceutical composition according to claim 32, wherein the composition is formulated for oral administration.

34. A process for preparing a solvate according to any one of claims 1 to 6, comprising crystallizing the solvate from a mixture comprising a compound of formula I, water, and dimethylformamide (DMF).

35. Formula II: 【Chemistry 2】 The crystalline solid form of the compound.

36. The solid form according to claim 35, having an X-ray powder diffraction pattern with peaks at approximately 12.9°, 18.1°, 20.6°, 21.6°, 22.3°, 26.5°, and 27.8° with respect to two theta.

37. The solid form according to claim 35, having substantially the X-ray powder diffraction pattern shown in Figure 2.

38. The solid form according to any one of claims 35 to 37, having a differential scanning calorimetry (DSC) thermogram that includes an endothermic peak at approximately 215.1°C.

39. A solid form according to any one of claims 35 to 38, having substantially the differential scanning calorimetry (DSC) thermogram shown in Figure 3.

40. A solid form according to any one of claims 35 to 39, wherein the thermogravimetric analysis (TGA) is substantially as shown in Figure 4.

41. A solid form according to any one of claims 35 to 40, which is substantially purified.

42. Formula VIII: 【Transformation 3】 The crystalline solid form of the compound.

43. The solid form according to claim 42, having an X-ray powder diffraction pattern with peaks at approximately 7.8°, 10.5°, 12.1°, 16.0°, 16.8°, 17.0°, 17.7°, 18.0°, 20.5°, 21.0°, 21.9°, 24.3°, 25.2°, 26.1°, 27.0°, 32.3°, and 36.0° with respect to two theta.

44. The solid form according to claim 42, having substantially the X-ray powder diffraction pattern shown in Figure 6.

45. A solid form according to any one of claims 42 to 44, which is substantially purified.

46. Formula IX: 【Chemistry 4】 The crystalline solid form of the compound salt.

47. The solid form according to claim 46, having an X-ray powder diffraction pattern with respect to two theta, including peaks at approximately 5.9°, approximately 11.3°, approximately 11.8°, approximately 14.5°, approximately 14.8°, approximately 17.8°, approximately 18.4°, approximately 18.7°, approximately 19.0°, approximately 19.3°, approximately 20.2°, approximately 20.6°, approximately 20.9°, approximately 21.2°, approximately 21.7°, approximately 23.0°, approximately 23.7°, approximately 24.0°, approximately 24.4°, and approximately 24.7°.

48. The solid form according to claim 46, having substantially the X-ray powder diffraction pattern shown in Figure 7.

49. A solid form according to any one of claims 46 to 48, which is substantially purified.

50. Formula X: 【Transformation 5】 The crystalline solid form of the compound.

51. The solid form according to claim 50, having an X-ray powder diffraction pattern with peaks at approximately 5.6°, 11.1°, 14.8°, 16.7°, 19.0°, 19.4°, 24.4°, and 28.0° with respect to two theta.

52. The solid form according to claim 50, having substantially the X-ray powder diffraction pattern shown in Figure 5.

53. A solid form according to any one of claims 50 to 52, which is substantially purified.

54. A pharmaceutical composition comprising a compound or solid according to any one of claims 35 to 53, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, and / or N-oxide thereof, and at least one pharmaceutically acceptable carrier or excipient.

55. The pharmaceutical composition according to claim 54, wherein the composition contains one or more palladium compounds as impurities in an amount of 1 mol% or less.

56. The pharmaceutical composition according to claim 54, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.5 mol% or less.

57. The pharmaceutical composition according to claim 54, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.1 mol% or less.

58. The pharmaceutical composition according to claim 54, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.05 mol% or less.

59. The pharmaceutical composition according to claim 54, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.01 mol% or less.

60. The pharmaceutical composition according to claim 54, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.005 mol% or less.

61. The pharmaceutical composition according to claim 54, wherein the composition contains one or more palladium compounds as impurities in an amount of 0.001 mol% or less.

62. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds as impurities in an amount of 1 mol% or less.

63. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds as impurities in an amount of 0.5 mol% or less.

64. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds as impurities in an amount of 0.1 mol% or less.

65. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds as impurities in an amount of 0.05 mol% or less.

66. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds as impurities in an amount of 0.01 mol% or less.

67. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds as impurities in an amount of 0.005 mol% or less.

68. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds as impurities in an amount of 0.001 mol% or less.

69. The pharmaceutical composition according to claim 54, wherein the composition comprises one or more organic compounds and one or more palladium compounds as impurities, totaling 1 mol% or less.

70. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds and one or more palladium compounds as impurities, in a total amount of 0.5 mol% or less.

71. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds and one or more palladium compounds as impurities, in a total amount of 0.1 mol% or less.

72. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds and one or more palladium compounds as impurities, in a total amount of 0.05 mol% or less.

73. The pharmaceutical composition according to claim 54, wherein the composition contains one or more organic compounds and one or more palladium compounds as impurities, in a total amount of 0.01 mol% or less.

74. The pharmaceutical composition according to claim 54, wherein the composition comprises one or more organic compounds and one or more palladium compounds as impurities, in a total amount of 0.005 mol% or less.

75. The pharmaceutical composition according to claim 54, wherein the composition comprises one or more organic compounds and one or more palladium compounds as impurities, in a total amount of 0.001 mol% or less.

76. The pharmaceutical composition according to any one of claims 54 to 75, wherein the composition is formulated for parenteral administration.

77. The pharmaceutical composition according to any one of claims 54 to 75, wherein the composition is formulated for intravenous administration.

78. The pharmaceutical composition according to any one of claims 54 to 75, wherein the composition is formulated for subcutaneous administration.

79. The pharmaceutical composition according to any one of claims 54 to 75, wherein the composition is formulated for enteral administration.

80. The pharmaceutical composition according to claim 79, wherein the composition is formulated for oral administration.

81. Formula VII: 【Transformation 6】 A process for producing the compound, a) Under cross-coupling reaction conditions, formula V: 【Transformation 7】 The compound of formula VI: 【Transformation 8】 To provide the compound of formula VII by coupling it with the compound of the above formula, b) The process includes crystallizing and isolating the compound of formula VII from the mixture, The process, wherein Pg is an organic group that is an amino protecting group, and LvG is an organic group that is a leaving group.

82. The aforementioned process, a) To provide a first mixture comprising the compound of formula V, the compound of formula VI, a catalyst, a ligand, and DMF, b) To provide a second mixture comprising an inorganic base and DMF, wherein the second mixture is heated to about 125 to 135°C, c) The process according to claim 81, further comprising combining the first mixture with the second mixture to provide a third mixture, wherein the temperature of the third mixture is maintained at about 125 to 135°C.

83. Pg is C １－１２ Alkoxycarbonyl or substituted C １－１２ The process according to claim 82, wherein the protecting group is an alkoxycarbonyl protecting group.

84. Pg is C １－１２ Alkylcarbonyl or substituted C １－１２ The process according to claim 82, wherein the alkylcarbonyl protecting group is used.

85. Pg is 【Chemistry 9】 The process according to claim 82, wherein the group is (tert-butoxycarbonyl or Boc group).

86. The process according to claim 82, wherein a palladium compound is used under the cross-coupling reaction conditions.

87. The process according to claim 82, wherein the copper compound is used under the cross-coupling reaction conditions.

88. The process according to claim 86, wherein the cross-coupling reaction conditions include a palladium compound, an organophosphorus compound, an inorganic base, and an organic solvent.

89. The process according to claim 88, wherein the palladium compound is a Pd(II) compound.

90. The palladium compound is Pd(OAc) ２ The process according to claim 89, wherein the organophosphorus compound is (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine.

91. The inorganic base is K ３ PO ４ The process according to claim 90.

92. The process according to claim 91, wherein the organic solvent is a polar aprotic organic solvent.

93. The process according to claim 92, wherein the polar aprotic organic solvent is dimethylformamide (DMF).

94. The process according to any one of claims 88 to 93, wherein the amount of palladium is 0.3 mol% or less.

95. The process according to any one of claims 88 to 93, wherein the amount of palladium is 0.25 mol% or less.

96. The process according to any one of claims 81 to 95, wherein water is added to the reaction mixture to crystallize the compound of formula VII.

97. The compound of formula V above, 【Chemistry 10】 The process according to any one of claims 81 to 96.

98. The process according to any one of claims 81 to 97, wherein LvG is chlorine.

99. Formula VIII: 【Chemistry 11】 A process for producing the compound, a) Equation III: 【Chemistry 12】 The compound of formula II: 【Chemistry 13】 Coupling with the compound, formula XII: 【Chemistry 14】 To provide the compound, b) Under cross-coupling reaction conditions, formula XII: 【Chemistry 15】 The compound of formula VI: 【Chemistry 16】 Coupling with the compound, formula X: 【Chemistry 17】 To provide the compound, c) Crystallizing and isolating the compound of formula X from the mixture, d) The process comprising subjecting the compound of formula X to deprotection conditions to provide the compound of formula VIII.

100. The aforementioned process, d) To provide a first mixture comprising the compound of formula XII, the compound of formula VI, a catalyst, a ligand, and DMF, e) To provide a second mixture comprising an inorganic base and DMF, wherein the second mixture is heated to about 125 to 135°C, f) The process according to claim 99, further comprising combining the first mixture with the second mixture to provide a third mixture, wherein the temperature of the third mixture is maintained at about 125 to 135°C.

101. The process according to claim 99, wherein the deprotection condition includes contacting the compound of formula X with trimethylsilyl iodide (TMSI) in acetonitrile.

102. Formula IX: [Chemistry 18] A process for producing a compound salt of, a) Equation VIII: 【Chemistry 19】 To provide a first mixture comprising the compound, acetic acid, water, and alcohol, b) To provide a second mixture by combining the first mixture with citric acid, c) Formula IX: 【Chemistry 20】 The process comprises crystallizing and isolating a compound salt from the second mixture.

103. The process according to claim 102, wherein the first mixture is prepared by combining the compound of formula VIII, acetic acid, water, and alcohol at about 30 to 45°C.

104. The process according to claim 103, wherein the second mixture is prepared by combining the first mixture with citric acid at about 20 to 25°C.

105. The process according to any one of claims 102 to 104, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, tert-butanol, and isopropanol.

106. The process according to claim 105, wherein the alcohol is ethanol.

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