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, comprising reacting a compound of Formula III:
or a salt thereof, with a compound of Formula IV:
in the presence of a reducing agent to form a compound of Formula II:
or a salt thereof, provided said reducing agent is not sodium cyanoborodeuteride;
wherein P 1 is a protecting group.
2. The process according to claim 1 , wherein said protecting group is —CH 2 OCH 2 CH 2 Si(CH 3 ) 3 .
3. The process according to claim 1 , wherein said reducing agent is selected from sodium cyanoborohydride and sodium triacetoxyborohydride.
4. The process according to claim 1 , wherein said reducing agent is sodium triacetoxyborohydride.
5. The process according to claim 1 , wherein the compounds of Formula II, III, and IV are each a free base.
6. The process according to claim 1 , further comprising deprotecting a compound of Formula II, or said salt thereof, to form a compound of Formula I:
or a salt thereof.
7. The process according to claim 6 , wherein said deprotecting comprises treating with boron trifluoride etherate, followed by treating with aqueous ammonium hydroxide.
8. The process according to claim 6 , wherein said process further comprises reacting the compound of Formula I with adipic acid to form the adipate salt.
9. The process according to claim 6 , wherein the compounds of Formula I, II, III, and IV are each a free base.
10. The process according to claim 6 , wherein said process further comprises:
(a) heating the compound of Formula I in methanol at reflux to form a mixture;
(b) after (a), adding methyl isobutyl ketone to the mixture;
(c) after (b), removing a portion of solvent by distillation at an internal temperature of 40° C. to 50° C. to form a concentrated mixture;
(d) after (c), adding methanol to the concentrated mixture to form a diluted mixture;
(e) after (d), heating the diluted mixture at reflux to form a mixture;
(f) after (e), adding methyl isobutyl ketone to the mixture;
(g) after (f), removing a portion of solvent by distillation at an internal temperature of 40° C. to 50° C. to form a concentrated mixture;
(h) after (g), adding adipic acid and methanol to the concentrated mixture;
(i) after (h), heating the mixture at reflux;
(j) after (i), removing a portion of solvent by distillation at an internal temperature of 40° C. to 50° C. to form a concentrated mixture;
(k) after (j), adding heptane to the mixture; and
(l) after (k), stirring the mixture at room temperature to form the adipic acid salt of the compound of Formula I.
11. The process according to claim 6 , wherein the compound of Formula IV, or a salt thereof, is produced by a process comprising deprotecting a compound of Formula V:
or a salt thereof.
12. The process according to claim 11 , wherein said deprotecting comprises reacting with aqueous acid.
13. The process according to claim 12 , wherein said acid is hydrochloric acid.
14. The process according to claim 11 , wherein the compounds of Formula I, II, III, IV, and V are each a free base.
15. The process according to claim 11 , wherein said compound of Formula V, or a salt thereof, is produced by a process comprising reacting a compound of Formula VI:
with a compound of Formula VII:
in the presence of a coupling agent.
16. The process according to claim 15 , wherein the coupling agent is benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP).