Processes for preparing JAK inhibitors and related intermediate compounds

• US 9,000,161 B2
• Filed: 02/07/2013
• Issued: 04/07/2015
• Est. Priority Date: 01/15/2009
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Zhou, Jiacheng, Liu, Pingli, Lin, Qiyan, Meloni, David, Pan, Yongchun, Xia, Michael, Li, Mei, Yue, Tai-Yuen, Metcalf, Brian W.
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US13/761,742
• Publication Number:
  US 20130253190A1
• Time in Patent Office: 789 Days
• Field of Search: None
• US Class Current: 544/280
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 7/083 Syntheses without formation of a Si-C bond
• CPC Class Codes: C07F 7/10 containing nitrogen having a Si-N linkage
• CPC Class Codes: C07F 7/1892 by reactions not provided for in C07F7/1876 - C07F7/1888
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention is related to processes for preparing chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines of Formula III, and related synthetic intermediate compounds. The chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines are useful as inhibitors of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases.

Claims

1. A process of preparing a compound of Formula III:

2. The process according to claim 1, wherein said composition comprises an enantiomeric excess of a (R)- or (S)-enantiomer of the compound of Formula Ia;

and said hydrogenation catalyst is a ruthenium or rhodium catalyst having L₁;

wherein L₁ is a chiral phosphine ligand.

3. The process according to claim 2, wherein said enantiomeric excess is equal to or greater than about 90%.

4. The process according to claim 2, wherein said enantiomeric excess is equal to or greater than about 99%.

5. The process according to claim 2, wherein said chiral phosphine ligand is selected from one of the following:

6. The process according to claim 2, wherein said composition comprises an enantiomeric excess of the (S)-enantiomer of the compound of Formula Ia.

7. The process according to claim 6, wherein L₁ is selected from one of the following ligands:

8. The process according to claim 2, wherein said composition comprises an enantiomeric excess of the (R)-enantiomer of the compound of Formula Ia.

9. The process according to claim 8, wherein L₁ is selected from one of the following ligands:

12. The process according to claims 1 or 10, wherein P₁ is —

CH₂OC(═

O)C(CH₃)₃ or —

CH₂OCH₂CH₂Si(CH₃)₃.

13. The process according to claims 1 or 10, wherein R₁ is cyclopentyl.

23. The process according to claims 1, 10, 14 or 17, wherein said compound of Formula III is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile.

24. The process according to claim 23, further comprising reacting the compound of Formula III with phosphoric acid to form a phosphate salt of said compound of Formula III.

25. The process according to any of claims 1, 10, 14, or 17, wherein R₁ is n-butyl or n-pentyl.

10. A process of preparing a compound of Formula III:

11. The process according to claim 10, wherein said dehydrating conditions comprises trichloroacetyl chloride in the presence of triethylamine.

14. A process of preparing a compound of Formula III:

15. The process according to claim 14, wherein said first base is cesium carbonate.

16. The process according to claim 14, wherein said second base is 1,8-diazabicyclo undec-7-ene (DBU).

19. The process according to claims 14 or 17 wherein the mobile phase comprises isopropanol and hexanes, wherein said isopropanol is present in an amount of about 25% to about 10% by volume.

20. The process according to claims 14 or 17 wherein said chromatography unit is a stimulated moving bed (SMB) chromatography unit equipped with a set of eight columns or a chiral column unit, wherein each column is packed with a chiral stationary phase.

21. The process according to claims 14 or 17, wherein P₁ is —

CH₂C(═

O)C(CH₃)₃ or —

CH₂OCH₂CH₂Si(CH₃)₃.

22. The process according to claims 14 or 17, wherein R₁ is cyclopentyl.

17. A process of preparing a compound of Formula III:

18. The process according to claim 17, wherein said base is potassium t-butoxide.