Processes and intermediates for making a JAK inhibitor

Patent metadata

Field	Value
Publication number	US-9714233-B2
Application number	US-201514976583-A
Country	US
Kind code	B2
Filing date	Dec 21, 2015
Priority date	Mar 6, 2013
Publication date	Jul 25, 2017
Grant date	Jul 25, 2017

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.

First claim

What is claimed is:

1. A process of preparing a compound of Formula I:

or a salt thereof, comprising:
reacting a compound of Formula IIIa:

with a compound of Formula IVa:

under Suzuki coupling conditions to form a compound of Formula IIa:

deprotecting the compound of Formula IIa by reacting with an inorganic acid to form a compound of Formula V:

and
reacting the compound of Formula V with a compound of Formula VI:

in the presence of a reducing agent to form a compound of Formula I, or a salt thereof.

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

3. The process according to claim 2 , wherein the Suzuki coupling catalyst is Pd(dppf) 2 Cl 2 , [1,1′-bis(dicyclohexylphosphino)ferrocene]dichloropalladium (II), tetrakis(triphenylphosphine)palladium(0), or tetrakis(tri(o-tolyl)phosphine)palladium(0).

4. The process according to claim 2 , wherein the Suzuki coupling catalyst is [1,1′-bis(dicyclohexylphosphino)ferrocene]dichloropalladium (II).

5. The process according to claim 2 , wherein the base is sodium carbonate, potassium carbonate, or cesium fluoride.

6. The process according to claim 2 , wherein the base is cesium fluoride.

7. The process according to claim 6 , wherein the cesium fluoride is present in 3 equivalents or more based on the compound of Formula IVa.

8. The process according to claim 2 , wherein the solvent component comprises tert-butanol and water.

9. The process according to claim 1 , wherein the compounds of Formula IIIa and IVa are present in about a 1:1 molar ratio.

10. The process according to claim 1 , wherein the inorganic acid is present in an amount of 5 to 8 equivalents based on the compound of Formula IIa, and wherein the inorganic acid is hydrochloric acid.

11. The process according to claim 1 , wherein the inorganic acid is hydrochloric acid.

12. The process according to claim 1 , wherein said reacting of the compound of Formula V with the compound of Formula VI is carried out in the presence of at least two equivalents of a second base.

13. The process according to claim 12 , wherein the second base is a tertiary amine.

14. The process according to claim 12 , wherein the second base is triethylamine.

15. The process according to claim 1 , wherein the reducing agent is sodium cyanoborohydride or sodium triacetoxyborohydride.

16. The process according to claim 1 , wherein the reducing agent is sodium triacetoxyborohydride.

17. The process according to claim 16 , wherein greater than 1 equivalent of sodium triacetoxyborohydride is used based on the compound of Formula V.

18. The process according to claim 1 , wherein greater than 1 equivalent of the compound of Formula VI is used based on the compound of Formula V.

19. The process according to claim 1 , wherein the reacting of the compound of Formula V with the compound of Formula VI is performed in a halogenated solvent.

20. The process according to claim 19 , wherein the halogenated solvent is dichloromethane.

21. The process according to claim 1 , further comprising reacting the compound of Formula I with adipic acid to form the adipate salt of the compound of Formula I.

Assignees

• Incyte Corp
• Incyte Holdings Corp

Inventors

• Liu Pingli
• Wang Dengjin
• Wu Yongzhong
• Cao Ganfeng
• Xia Michael

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07F5/04

  Esters of boric acids · CPC title

• C07F5/025

  Boronic and borinic acid compounds · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title