Processes and intermediates for making a JAK inhibitor

• US 8,987,443 B2
• Filed: 03/05/2014
• Issued: 03/24/2015
• Est. Priority Date: 03/06/2013
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Liu, Pingli, Wang, Dengjin, Wu, Yongzhong, Cao, Ganfeng, Xia, Michael
• Primary Examiner(s): VAJDA, KRISTIN ANN
• Application Number:
  US14/197,701
• Publication Number:
  US 20140256941A1
• Time in Patent Office: 384 Days
• Field of Search: 544/280
• 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.

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

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

5. 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.

6. The process according to claim 5, 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).

7. The process according to claim 5, wherein the Suzuki coupling catalyst is [1,1’

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

8. The process according to claim 5, wherein the base is sodium carbonate, potassium carbonate, or cesium fluoride.

9. The process according to claim 5, wherein the base is cesium fluoride.

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

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

12. The process according to claim 11, further comprising deprotecting the compound of Formula IIa to form a compound of Formula V:

13. The process according to claim 12, further comprising reacting the compound of Formula V, or salt thereof, with a compound of Formula VI:

14. The process according to claim 13, 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-y1)acetonitirile dihydrochloride salt.

15. The process according to claim 13, wherein the reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride.

16. The process according to claim 13, wherein the reducing agent is sodium triacetoxyborohydride.

17. The process according to claim 13, further comprising reacting the compound of Formula I with adipic acid to form the adipate salt of the compound of Formula I.