Process for preparing 5-fluoro-1H-pyrazolo [3,4-B] pyridin-3-amine and derivatives therof

• US 8,598,361 B2
• Filed: 01/11/2012
• Issued: 12/03/2013
• Est. Priority Date: 07/31/2007
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Jimenez, Juan-Miguel, Miller, Andrew, Collier, Philip, Green, Jeremy, Gao, Huai, Dros, Albert, Hamon, Sylvain
• Primary Examiner(s): Seaman, D M
• Application Number:
  US13/347,926
• Publication Number:
  US 20120232275A1
• Time in Patent Office: 692 Days
• Field of Search: 546/270.7, 546/119
• US Class Current: 546/270.7
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to a process for the synthesis of 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine in high yield and purity. The present invention also relates to processes for the synthesis of 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine derivatives. These processes are useful for preparing biologically active compounds, particularly certain GSK-3 inhibitors, or derivatives thereof.

Claims

1. A process for preparing a compound of formula 5:

2. The process of claim 1, further comprising the step of treating the compound of formula 2 with suitable amide formation conditions to form a compound of formula 3:

3. The process of claim 2, further comprising the step of reducing the compound of formula 3 under suitable reduction conditions to form a compound of formula 4:

4. The process of claim 3, further comprising the step of cyclizing a compound of formula 4 with H₂NNH₂.H₂O under suitable cyclization conditions to form the compound of formula 5.

5. The process of any one of claims 2-4, wherein the de-chlorination conditions comprise adding a palladium catalyst, a suitable base, and a suitable acid.

6. The process of claim 5, wherein said palladium catalyst is selected from Pd(OAc)₂ or PPh₃, said base is Et₃N, and said acid is formic acid.

7. The process of claim 5, wherein said de-chlorination reduction is done at a temperature below 60°

C.

8. The process of claim 7, wherein said de-chlorination reaction is done at a temperature of about 50°

C.

9. The process of claim 8, wherein the de-chlorination reaction is done in DMF.

10. The process of claim 9, wherein the reaction is cooled to about 0°

C. upon completion and mixed with water.

11. The process of claim 10, wherein said mixture is filtered through celite.

12. The process of claim 5, wherein the amide formation condition comprises the following two steps:

(a) formation of an acid chloride from the carboxylic acid of formula 2;

(b) reaction of the acid chloride with ammonia.

13. The process of claim 12, wherein the carboxylic acid is combined with a chlorinating agent selected from oxalyl chloride or thionyl chloride in the presence of DMF or DCM.

14. The process of claim 12, wherein ammonia is bubbled into a solution of the acid chloride in an aprotic solvent.

15. The process of claim 3, wherein the reduction conditions comprise adding TFAA dropwise to a cooled suspension of the amide in the presence of base and solvent.

16. The process of claim 4, wherein the cyclization conditions are selected from heating the starting material with hydrazine monohydrate in the presence of butanol until completion.