Processes and intermediates for making a JAK inhibitor

• US 9,221,845 B2
• Filed: 03/11/2015
• Issued: 12/29/2015
• 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: Cao, Ganfeng
• Primary Examiner(s): VAJDA, KRISTIN ANN
• Application Number:
  US14/645,046
• Publication Number:
  US 20150183805A1
• Time in Patent Office: 293 Days
• Field of Search: 544/280, 546/13, 546/193
• 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 compound of Formula VII:

2. The compound of claim 1, having Formula VIIa:

3. A process, comprising:

reacting a compound of Formula VIII;

4. The process according to claim 3, wherein the coupling agent is 1,8-diazabicyclo[5,4,0]undecene.

5. The process according to claim 4, wherein 1.05 to about 1.2 equivalents of coupling agent is used based on the compound of Formula VIII.

6. The process according to claim 5, wherein the reacting of the compound of Formula VIII with the compound of Formula IX is conducted in a solvent component comprising acetonitrile.

7. The process according to claim 5, 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.

8. The process according to claim 7, wherein 1 to 1.2 equivalents of the compound of Formula IX are used based on the compound of Formula VIII.

9. The process according to claim 3, wherein the process comprises reacting a compound of Formula VIII:

10. The process according to claim 9, wherein the coupling agent is 1,8-diazabicyclo[5,4,0]undecene.

11. The process according to claim 10, wherein 1.05 to about 1.2 equivalents of coupling agent is used based on the compound of Formula VIII.

12. The process according to claim 11, wherein the reacting of the compound of Formula VIII with the compound of Formula IXa is conducted in a solvent component comprising acetonitrile.

13. The process according to claim 10, 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.

14. The process according to claim 13, wherein 1 to 1.2 equivalents of the compound of Formula IXa are used based on the compound of Formula VIII.

15. The process according to claim 9, further comprising reacting the compound of Formula VIIa with a compound of Formula IVa:

16. The process according to claim 15, wherein the catalyst is tetrakis(triphenylphosphine)palladium(0).

17. The process according to claim 16, wherein the base is sodium bicarbonate.

18. The process according to claim 17, wherein the sodium bicarbonate is present in 4 equivalents or more based on the compound of Formula VIIa.

19. The process according to claim 18, wherein the second solvent component comprises 1,4-dioxane and water.

20. The process according to claim 19, wherein the 1,4-dioxane and water are present in a 1:

1 volume ratio.

21. The process according to claim 20, wherein the compounds of Formula VIIa and IVa are present in about a 1:

1 molar ratio.

22. The process according to claim 9, further comprising reacting the compound of Formula VIIa with a compound of Formula IVa:

23. A compound of Formula VIII:

24. A process of preparing a compound of claim 23, or a salt thereof, comprising reacting a compound of Formula VI:

25. The process according to claim 24, wherein the compound of Formula X, or salt thereof, is 2-(azetidin-3-ylidene)acetonitrile hydrochloride.

26. The process according to claim 25, wherein the reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride.

27. The process according to claim 25, wherein the reducing agent is sodium triacetoxyborohydride.

28. The process according to claim 27, 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.

29. The process according to claim 27, wherein about 2 equivalents of the reducing agent are used based on the compound of Formula X, or salt thereof.

30. The process according to claim 28, 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.