Processes and intermediates for making a JAK inhibitor

• US 9,487,521 B2
• Filed: 09/06/2012
• Issued: 11/08/2016
• Est. Priority Date: 09/07/2011
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Inventors: Zhou, Jiacheng, Wu, Yongzhong, Liu, Pingli, Cao, Ganfeng
• Primary Examiner(s): Moore, Susanna
• Application Number:
  US13/605,331
• Publication Number:
  US 20130060026A1
• Time in Patent Office: 1,524 Days
• Field of Search: 544/280, 514/265.1
• US Class Current: 1/1
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/113 with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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 said protecting group is —

CH₂OCH₂CH₂Si(CH₃)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:

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:

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:

16. The process according to claim 15, wherein the coupling agent is benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP).