Processes and intermediates for producing azaindoles

• US 8,796,453 B2
• Filed: 07/12/2013
• Issued: 08/05/2014
• Est. Priority Date: 07/05/2011
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Tanoury, Gerald J., Jung, Young Chun, Magdziak, Derek, Looker, Adam, Kline, Billie J., Jurck, Vclav, Dominguez Olmo, Beatriz
• Primary Examiner(s): VAJDA, KRISTIN ANN
• Application Number:
  US13/940,421
• Publication Number:
  US 20130303764A1
• Time in Patent Office: 389 Days
• Field of Search: 544/328
• US Class Current: 544/328
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids

Abstract

The present invention relates to processes and intermediates for the preparation of compounds useful as inhibitors of Janus kinases (JAK).

Claims

1. A process for preparing a compound of Formula 4:

2. The process of claim 1, wherein the organic solvent of step ia) is an alcohol.

3. The process of claim 2, wherein the alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or any combination thereof.

4. The process of claim 1, wherein the base of step ia) is an inorganic base.

5. The process of claim 4, wherein the inorganic base is an alkali metal hydroxide.

6. The process of claim 5, wherein the alkali metal hydroxide is NaOH, KOH, or any combination thereof.

7. The process of claim 1, wherein the reaction of step ia) is performed at a temperature between about 50°

C. and about 110°

C.

8. The process of claim 7, wherein the reaction of step ia) is performed at a temperature between about 60°

C. and about 95°

C.

9. The process of claim 8, wherein the reaction of step ia) is performed at a temperature between about 70°

C. and about 80°

C.

10. The process of claim 1, wherein the deprotection of step ii) is performed in the presence of a base.

11. The process of claim 10, wherein the base is an inorganic base.

12. The process of claim 11, wherein the inorganic base is an alkali metal hydroxide.

13. The process of claim 12, wherein the alkali metal hydroxide is KOH, NaOH, or any combination thereof.

14. The process of claim 1, further comprising the steps:

viiib) reacting a compound of Formula 11 with an acid salt of a compound of Formula 15 in the presence of a solvent and a base to generate the compound Formula 2;

15. The process of claim 14, wherein the base of step viiib) is an inorganic base selected from tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium carbonate, disodium carbonate, trisodium phosphate, disodium hydrogen phosphate, or any combination thereof.

16. The process of claim 14, wherein the solvent of step viiib) comprises water.

17. The process of claim 16, wherein the solvent of step viiib) further comprises an alcohol selected from methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, or any combination thereof.

18. The process of claim 14, wherein the reaction of step viiib) is performed at a temperature of from about 70°

C. to about 120°

C.

19. The process of claim 18, wherein the reaction of step viiib) is performed at a temperature of from about 80°

C. to about 100°

C.