PROCESSES OF PREPARING A JAK1 INHIBITOR AND NEW FORMS THERETO

• US 20150344497A1
• Filed: 04/29/2015
• Published: 12/03/2015
• Est. Priority Date: 04/30/2014
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Zhou, Jiacheng, Liu, Pingli, Wu, Yongzhong, Wang, Dengjin, Jia, Zhongjiang, Qiao, Lei, Frietze, William, Xia, Michael, Chen, Shili, Dai, Yingrui
• Granted Patent: US 9,802,957 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 309/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/14 Ortho-condensed systems

Abstract

This invention relates to processes for preparing a JAK1 inhibitor having Formula Ia:

as well as new forms of the inhibitor.

Claims

1. A process of preparing a compound of Formula Ia:

2. The process of claim 1, wherein the first strong base is an alkoxide base.

3. The process of claim 1, wherein the first strong base is an alkali metal C_1-6 alkoxide.

4. The process of claim 1, wherein the first strong base is potassium tert-butoxide.

5. The process of claim 1, wherein the compound of Formula Ib is present in a composition comprising the compound of Formula Ib and the compound of Formula Ia prior to said reacting of said compound of Formula Ib with said strong base.

6. The process of claim 1, wherein the compound of Formula Ia is prepared as a compound of Formula II:

7. The process of claim 1, wherein the composition comprising a compound of Formula Ia and a compound of Formula Ib is prepared by a process comprising reacting a composition comprising a compound of Formula IIIa and a compound of Formula IIIb:

8. The process of claim 7, wherein before reacting a composition comprising a compound of Formula IIIa and a compound of Formula IIIb, the compound of Formula IV is reacted with said C_1-6 alkyloxonium reagent in the second solvent component.

9. The process of claim 7, wherein the C_1-6 alkyloxonium reagent is triethyloxonium tetrafluoroborate.

10. The process of claim 7, wherein the composition comprising a compound of Formula IIIa and a compound of Formula IIIb is prepared by a process comprising reacting a composition comprising a compound of Formula Va and a compound of Formula Vb:

11. The process of claim 10, wherein the hydrogenation catalyst is palladium on carbon.

12. The process of claim 10, wherein the composition comprising a compound of Formula Va and a compound of Formula Vb is prepared by a process comprising reacting a compound of Formula VI:

13. The process of claim 12, wherein the compound of Formula VI, or salt thereof, is a salt of Formula VIa:

14. The process of claim 12, wherein X is chloro.

15. The process of claim 12, wherein the first tertiary amine base is N-ethyl-N-isopropylpropan-2-amine.

16. The process of claim 12, wherein the compound of Formula VI, or salt thereof, is a salt of Formula VIa:

17. The process of claim 12, wherein the compound of Formula VI, or salt thereof, is produced by a process comprising reacting a compound of Formula VIII:

18. The process of claim 17, wherein the deprotection conditions involve reacting the compound of Formula VIII with a first strong acid.

19. The process of claim 17, wherein the first strong acid is HCl.

20. The process of claim 17, wherein P¹ is t-butoxycarbonyl.

21. The process of claim 17, wherein the compound of Formula VIII is prepared by a process comprising reacting a compound of Formula IX:

22. The process of claim 21, wherein the second strong base is an C_1-6 alkoxide base.

23. The process of claim 22, wherein the alkoxide base is sodium methoxide.

24. The process of claim 21, wherein said compound of Formula IX is prepared by a process comprising reacting a compound of Formula X:

25. The process of claim 24, wherein the second strong acid is p-toluenesulfonic acid.

26. The process of claim 24, wherein said compound of Formula X is prepared by a process comprising:

(i) reacting a compound of Formula XII;

27. The process of claim 26, wherein before (i), the compound of Formula XXI is reacted with the third strong base in said seventh solvent component.

28. The process of claim 26, wherein R^a and R^b are each ethyl.

29. The process of claim 26, wherein the third strong base is potassium tert-butoxide.

30. The process of claim 26, wherein said compound of Formula XII is prepared by a process comprising oxidizing a compound of Formula XIII:

31. The process of claim 30, wherein said oxidizing comprises adding a first oxidizing agent to the compound of Formula XIII to form a first mixture.

32. The process of claim 31, wherein the first oxidizing agent is 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO).

33. The process of claim 31, wherein said adding of said first oxidizing agent is conducted in the presence of tetra-N-butylammonium chloride.

34. The process of claim 30, wherein the oxidizing further comprises adding a base and a second oxidizing agent to said first mixture.

35. The process of claim 34, wherein the second oxidizing agent is an N-halosuccinimide compound.

36. The process of claim 34, wherein the second oxidizing agent is N-chlorosuccinimide.

37. The process of claim 30, wherein said compound of Formula XIII is prepared by a process comprising reacting a compound of Formula XV:

38. The process of claim 37, wherein said compound of Formula XV is prepared by a process comprising reacting a compound of Formula XVI:

39. The process of claim 38, wherein the first reducing agent is lithium borohydride.

40. The process of claim 17, wherein the compound of Formula VIII is prepared by a process comprising reacting a compound of Formula XVII:

41. The process of claim 40, wherein the hydrogenation catalyst is palladium on carbon.

42. The process of claim 40, wherein said compound of Formula XVII is prepared by

(i) reacting a compound of Formula XVIII:

43. The process of claim 42, wherein Y⁻

is Cl⁻

.

44. The process of claim 42, wherein R^a1, R^b1, and R^c1 are each methyl.

45. The process of claim 42, wherein R^a1, R^b1, and R^c1 are each n-butyl.

46. The process of claim 42, wherein the fourth strong base is potassium tert-butoxide.

47. The process of claim 42, wherein the fourth strong base is lithium hexamethyldisilazide.

48. The process of claim 42, wherein said compound of Formula XVIII is formed by a process comprising reacting a compound of Formula XIX:

49. The process of claim 48, wherein the weak organic acid is acetic acid.

50. The process of claim 48, wherein said compound of Formula XIX is formed by a process comprising:

(1) reacting a compound of Formula XX;

51. The process of claim 50, wherein the compound of Formula XXIII is ethyl chloroformate.

52. The process of claim 50, wherein the second tertiary amine base is N-methylmorpholine.

53. The process of claim 50, further comprising reducing said compound of Formula XXIV with a second reducing agent.

54. The process of claim 53, wherein said second reducing agent is sodium borohydride.

73. The process of claim 5, wherein the composition comprising a compound of Formula Ia and a compound of Formula Ib is prepared by a process comprising reacting a composition comprising a compound of Formula IIIa and a compound of Formula IIIb:

74. The process of claim 73, wherein said (R)-4-methoxy-2,2,5-trimethyl-2,5-dihydrooxazole is prepared by reacting (R)-2,2,5-trimethyloxazolidin-4-one:

75. The process of claim 74, wherein the steps of reacting (R)-2,2,5-trimethyloxazolidin-4-one with trimethyloxonium tetrafluoroborate to form (R)-4-methoxy-2,2,5-trimethyl-2,5-dihydrooxazole and reacting (R)-4-methoxy-2,2,5-trimethyl-2,5-dihydrooxazole with a composition comprising a compound of Formula Ma and a compound of Formula IIIb are conducted in the same pot without isolation of (R)-4-methoxy-2,2,5-trimethyl-2,5-dihydrooxazole.

76. The process of claim 5, wherein the composition comprising a compound of Formula Ia and a compound of Formula Ib is prepared by a process comprising reacting a composition comprising a compound of Formula IIIa and a compound of Formula IIIb:

77. The process of claim 76, wherein said (R)-ethyl 2-hydroxypropanimidate is prepared by reacting (R)-1-cyanoethyl acetate:

78. The process of claim 77, wherein said strong acid used in the reaction of (R)-1-cyanoethyl acetate with ethanol is hydrogen chloride.

79. The process of claim 78, wherein said (R)-1-cyanoethyl acetate is formed by reacting (R)-1-amino-1-oxopropan-2-yl acetate:

80. The process of claim 79, wherein said (R)-1-amino-1-oxopropan-2-yl acetate is prepared by protecting (R)-2-hydroxypropanamide:

81. The process of claim 80, wherein said third tertiary amine base is 4-methylmorpholine.

55. An anhydrous form of a compound of Formula Ia:

56. The form of claim 55, wherein the anhydrous form is crystalline.

57. A process of forming the anhydrous form of a compound of Formula Ia of claim 55, comprising:

(i) adding n-heptane to a first mixture comprising a compound of Formula II;

58. The process of claim 57, wherein the first solvent component further comprises methanol.

59. The process of claim 58, further comprising before (i):

(ii) dissolving the compound of Formula II in methanol to form a second mixture comprising the compound of Formula Ia and a second solvent component comprising methanol;

(iii) polish filtering the second mixture; and

(iv) adding ethyl acetate to the second mixture to form the first mixture.

60. The process of claim 58, further comprising heating the first mixture to a temperature from about 60°

C. to about 75°

C.

61. The process of claim 58, comprising removing at least a portion of the ethyl acetate and methanol to form the first mixture via distillation.

62. A compound of Formula VIII:

63. The compound of claim 62, wherein P¹ is t-butoxycarbonyl.

64. A salt of Formula VIa:

65. A compound of Formula Va, Vb, IIIa, or IIIb:

66. A process for preparing a compound of Formula II:

67. The process of claim 66, wherein said suspending is conducted at about room temperature.

68. The process of claim 66, wherein the solvent component is water.

69. A process of preparing a compound of Formula II:

70. The process of claim 69, further comprising, prior to said isolating, the steps of:

(a) dissolving 2-((2R,5S)-5-(2-((R)-1-hydroxyethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)tetrahydro-2H-pyran-2-yl)acetonitrile in a solvent component comprising isopropanol to form a second mixture; and

(b) adding water to said second mixture to form said first mixture, wherein the solvent component comprises isopropanol and water.

71. The process of claim 69, further comprising removing at least a portion of said solvent component from said first mixture prior to said isolating.

72. The process of claim 69, where (a) and (b) are conducted at a temperature from about 40°

C. to about 60°

C.