PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR

• US 20150183805A1
• Filed: 03/11/2015
• Published: 07/02/2015
• Est. Priority Date: 03/06/2013
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Liu, Pingli, Wang, Dengjin, Wu, Yongzhong, Cao, Ganfeng, Xia, Michael
• Granted Patent: US 9,221,845 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 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

This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.

Claims

1-32. -32. (canceled)

33. A compound of Formula VII:

34. The compound of claim 33, having Formula VIIa:

35. A process, comprising:

reacting a compound of Formula VIII;

36. The process according to claim 35, wherein the coupling agent is 1,8-diazabicyclo[5,4,0]undecene.

37. The process according to claim 36, wherein 1.05 to about 1.2 equivalents of coupling agent is used based on the compound of Formula VIII.

38. The process according to claim 37, wherein the reacting of the compound of Formula VIII with the compound of Formula IX is conducted in a solvent component comprising acetonitrile.

39. The process according to claim 37, wherein the reacting of the compound of Formula VIII with the compound of Formula IX is conducted in a solvent component comprising acetonitrile at a temperature of about 40°

C. to about 60°

C.

40. The process according to claim 39, wherein 1 to 1.2 equivalents of the compound of Formula IX are used based on the compound of Formula VIII.

41. The process according to claim 35, wherein the process comprises reacting a compound of Formula VIII:

42. The process according to claim 41, wherein the coupling agent is 1,8-diazabicyclo[5,4,0]undecene.

43. The process according to claim 42, wherein 1.05 to about 1.2 equivalents of coupling agent is used based on the compound of Formula VIII.

44. The process according to claim 43, wherein the reacting of the compound of Formula VIII with the compound of Formula IXa is conducted in a solvent component comprising acetonitrile.

45. The process according to claim 42, wherein the reacting of the compound of Formula VIII with the compound of Formula IXa is conducted in a solvent component comprising acetonitrile at a temperature of about 40°

C. to about 60°

C.

46. The process according to claim 45, wherein 1 to 1.2 equivalents of the compound of Formula IXa are used based on the compound of Formula VIII.

47. The process according to claim 41, further comprising reacting the compound of Formula VIIa with a compound of Formula IVa:

48. The process according to claim 47, wherein the catalyst is tetrakis(triphenylphosphine)palladium(0).

49. The process according to claim 48, wherein the base is sodium bicarbonate.

50. The process according to claim 49, wherein the sodium bicarbonate is present in 4 equivalents or more based on the compound of Formula VIIa.

51. The process according to claim 50, wherein the second solvent component comprises 1,4-dioxane and water.

52. The process according to claim 51, wherein the 1,4-dioxane and water are present in a 1:

1 volume ratio.

53. The process according to claim 52, wherein the compounds of Formula VIIa and IVa are present in about a 1:

1 molar ratio.

54. The process according to claim 41, further comprising reacting the compound of Formula VIIa with a compound of Formula IVa:

55. A compound of Formula VIII:

56. A process of preparing a compound of claim 55, or a salt thereof, comprising reacting a compound of Formula VI:

57. The process according to claim 56, wherein the compound of Formula X, or salt thereof, is 2-(azetidin-3-ylidene)acetonitrile hydrochloride.

58. The process according to claim 57, wherein the reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride.

59. The process according to claim 57, wherein the reducing agent is sodium triacetoxyborohydride.

60. The process according to claim 59, wherein about 1.5 to about 2.5 equivalents of the reducing agent are used based on the compound of Formula X, or salt thereof.

61. The process according to claim 59, wherein about 2 equivalents of the reducing agent are used based on the compound of Formula X, or salt thereof.

62. The process according to claim 60, wherein the reacting of the compound of Formula VI and the compound of Formula X, or salt thereof, are conducted in a solvent component comprising dichloromethane.