Process of producing cycloalkylcarboxamido-indole compounds

• US 10,071,979 B2
• Filed: 04/15/2015
• Issued: 09/11/2018
• Est. Priority Date: 04/22/2010
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Tanoury, Gerald J., Harrison, Cristian, Littler, Benjamin Joseph, Rose, Peter Jamison, Hughes, Robert Michael, Jung, Young Chun, Siesel, David Andrew, Lee, Elaine Chungmin, Belmont, Daniel T., Nugent, William A.
• Primary Examiner(s): Grazier, Nyeemah A
• Application Number:
  US14/687,286
• Publication Number:
  US 20150218122A1
• Time in Patent Office: 1,245 Days
• Field of Search: 548454, 548466, 548491
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/10 Expectorants
• CPC Class Codes: A61P 11/12 Mucolytics
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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: C07C 209/74 : by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
• CPC Class Codes: C07C 225/06 : and acyclic
• CPC Class Codes: C07D 209/12 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 317/46 : condensed with one six-membered ring
• CPC Class Codes: C07D 317/60 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention features processes for preparing compounds, such as (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound 1), useful for treating CFTR mediated diseases such as cystic fibrosis.

Claims

1. A method of preparing a compound of formula III:

2. The method of claim 1, wherein in formula IIIA, o is 1 and R₂ is F.

3. The method of claim 1, wherein in step a), the halogenating reagent is N-bromosuccinimide.

4. The method of claim 1, wherein in step a), the first organic solvent is an aprotic solvent.

5. The method of claim 1, wherein in step a), the first organic solvent is ethyl acetate.

6. The method of claim 1, wherein step a) takes place at about 2°

C. to 42°

C.

7. The method of claim 1, wherein in formula IIIB, o is 1, R₂ is F, and Hal is Br.

8. The method of claim 1, wherein in formula IIIC, P is benzyl.

9. The method of claim 1, wherein in step b), the second organic solvent is an aprotic solvent.

10. The method of claim 1, wherein in step b), the second organic solvent is toluene.

11. The method of claim 1, wherein in step b), the reaction with a compound of formula IIIC takes place at about 60°

C. to 100°

C.

12. The method of claim 1, wherein in step b), reduction is carried out with hydrogen.

13. The method of claim 1, wherein in step b), the acid is p-toluenesulfonic acid.

14. The method of claim 1, wherein in formula IIID, o is 1, R₂ is F, Hal is Br, A^⊖

is Tos⁻

, and P is benzyl.

15. The method of claim 1, wherein in formula IIIE, R₃ is C(CH₃)₂CH₂O(benzyl).

16. The method of claim 1, wherein in step c) the base is an inorganic base.

17. The method of claim 1, wherein in step d), the third organic solvent is an aprotic solvent.

18. The method of claim 1, wherein in step d), the third organic solvent is acetonitrile.

19. The method of claim 1, wherein step d) takes place at about 60°

C. to 100°

C.

20. The method of claim 1, wherein in step d), the catalyst is a palladium catalyst.

21. The method of claim 1, wherein in step d), the catalyst is selected from palladium(II)acetate, Pd(dppf)Cl₂, Pd(dba)₂, tetrakis(triphenylphosphine)palladium(0), (MeCN)₂PdCl₂, or tris(dibenzylideneacetone)dipalladium(0).

22. The method of claim 1, wherein in step d), the catalyst is palladium(II)acetate.

23. A compound of formula III:

24. The compound or salt of claim 23, wherein o is 1 and R₂ is F.

25. The compound or salt of claim 23, wherein R₃ is C(CH₃)₂CH₂O(benzyl).

26. The compound or salt of claim 23, wherein P is acetyl, benzoyl, benzyl, methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, methoxytrityl, p-methoxybenzyl, pivaloyl, tetrahydropyranyl, trityl, or trimethylsilyl.

27. The compound or salt of claim 26, wherein P is benzyl.

28. The compound or salt of claim 23, wherein the compound is