PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR

• US 20160347734A1
• Filed: 12/21/2015
• Published: 12/01/2016
• Est. Priority Date: 03/06/2013
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Inventors: Liu, Pingli, Wang, Dengjin, Wu, Yongzhong, Cao, Ganfeng, Xia, Michael
• Granted Patent: US 9,714,233 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. 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:

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.

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)

9-16. -16. (canceled)

18-19. -19. (canceled)

24-31. -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.

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.

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

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

37-40. -40. (canceled)

43-46. -46. (canceled)

48-53. -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:

57-62. -62. (canceled)