Processes and intermediates for making a JAK inhibitor
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.
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.