PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR

• US 20140256941A1
• Filed: 03/05/2014
• Published: 09/11/2014
• Est. Priority Date: 03/06/2013
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Liu, Pingli, Wu, Yongzhong, Cao, Ganfeng, Xia, Michael, Wang, Dengjin
• Granted Patent: US 8,987,443 B2
• Time in Patent Office: Days
• US Class Current: 544/280
• 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. A process, comprising:

reacting a compound of Formula III;

2. The process according to claim 1, wherein P¹ is benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc), t-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N′

,N′

-dimethylhydrazinyl, methoxymethyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), 2-tetrahydropyranyl (THP), 1,1-diethoxymethyl, (trimethylsilyl)ethoxymethyl (SEM), N-pivaloyloxymethyl (POM) or tert-butoxycarbonyl.

5. The process according to claim 1, wherein the compound of Formula III has Formula IIIa:

8. The process according to claim 1, wherein the compound of Formula IV has Formula IVa:

9. The process according to claim 1, wherein the Suzuki coupling conditions comprise heating a reaction mixture comprising the compound of Formula III, the compound of Formula IV, a Suzuki coupling catalyst, a base and a solvent component.

10. The process according to claim 9, wherein the Suzuki coupling catalyst is Pd(dppf)₂Cl₂, [1,1′

-bis(dicyclohexylphosphino)ferrocene]dichloropalladium (II), tetrakis(triphenylphosphine)palladium(0), or tetrakis(tri(o-tolyl)phosphine)palladium(0).

11. The process according to claim 9, wherein the Suzuki coupling catalyst is [1,1′

-bis(dicyclohexylphosphino)ferrocene]dichloropalladium (II).

12. The process according to claim 9, wherein the base is sodium carbonate, potassium carbonate, or cesium fluoride.

13. The process according to claim 9, wherein the base is cesium fluoride.

17. The process according to claim 1, further comprising deprotecting the compound of Formula II to form a compound of Formula V:

20. The process according to claim 1, wherein the process comprises reacting a compound of Formula IIIa:

21. The process according to claim 20, further comprising deprotecting the compound of Formula IIa to form a compound of Formula V:

22. The process according to claim 21, further comprising reacting the compound of Formula V, or salt thereof, with a compound of Formula VI:

23. The process according to claim 22, wherein the compound of Formula V, or salt thereof, is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitirile dihydrochloride salt.

27. The process according to claim 22, wherein the reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride.

28. The process according to claim 22, wherein the reducing agent is sodium triacetoxyborohydride.

32. The process according to claim 22, further comprising reacting the compound of Formula I with adipic acid to form the adipate salt of the compound of Formula I.

3-4. -4. (canceled)

6-7. -7. (canceled)

14-16. -16. (canceled)

18-19. -19. (canceled)

24-26. -26. (canceled)

29-31. -31. (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.

39. The process according to claim 36, 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.

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.

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.

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.

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

37-38. -38. (canceled)

40. (canceled)

43-44. -44. (canceled)

46. (canceled)

50-53. -53. (canceled)

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 56, wherein the reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride.

59. The process according to claim 56, wherein the reducing agent is sodium triacetoxyborohydride.

60-62. -62. (canceled)