Processes and intermediates for making a JAK inhibitor
View Patent ↗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 compound of Formula VII:
or a salt thereof; wherein:
R 1 and R 2 are each independently H or C 1-6 alkyl; or
R 1 and R 2 , together with the two oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocycloalkyl ring, which is optionally substituted with 1, 2, 3, or 4 C 1-4 alkyl groups.
2. The compound of claim 1 , having Formula VIIa:
or a salt thereof.
3. A process, comprising:
reacting a compound of Formula VIII:
with a compound of Formula IX:
in the presence of a coupling agent to form a compound of claim 1 ; wherein:
R 1 and R 2 are each independently H or C 1-6 alkyl; or
R 1 and R 2 , together with the two oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5- to 6-membered heterocycloalkyl ring, which is optionally substituted with 1, 2, 3, or 4 C 1-4 alkyl groups.
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:
with a compound of Formula IXa:
in the presence of a coupling agent to form a compound of Formula VIIa:
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:
under Suzuki coupling conditions to form a compound of Formula I:
wherein the Suzuki coupling conditions comprise heating a reaction mixture comprising the compound of Formula VIIa, the compound of Formula IVa, a Suzuki coupling catalyst, a base and a second solvent component.
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:
under Suzuki coupling conditions to form a compound of Formula I:
wherein the Suzuki coupling conditions comprise heating a reaction mixture comprising the compound of Formula VIIa, the compound of Formula IVa,
tetrakis(triphenylphosphine)palladium(0), sodium bicarbonate, and a second solvent component, wherein the second solvent component comprises water and 1,4-dioxane.
23. A compound of Formula VIII:
or a salt thereof.
24. A process of preparing a compound of claim 23 , or a salt thereof, comprising reacting a compound of Formula VI:
with a compound of Formula X:
or a salt thereof, in the presence of a reducing agent.
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.