Process of producing cycloalkylcarboxamido-indole compounds

Patent metadata

Field	Value
Publication number	US-10071979-B2
Application number	US-201514687286-A
Country	US
Kind code	B2
Filing date	Apr 15, 2015
Priority date	Apr 22, 2010
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

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.

First claim

We claim:

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

wherein, independently for each occurrence:
R 2 is —R J , —OR J , —N(R J ) 2 , —NO 2 ,
halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ;

R J is hydrogen or C 1-6 aliphatic;
R 3 is C 1-6 aliphatic optionally substituted with OH, OP, —O—C 1-6 aliphatic, aryl, heteroaryl, —O-aryl, or —O-heteroaryl;
P is a protecting group; and
o is an integer from 0 to 3;

comprising the steps of:
a) reacting a compound of formula IIIA:

wherein, independently for each occurrence:
R 2 is —R J , —OR J , —N(R J ) 2 , —NO 2 ,
halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ;

R J is hydrogen or C 1-6 aliphatic; and
o is an integer from 0 to 3;

with a halogenating reagent in a first organic solvent to form a compound of formula IIIB:

wherein, independently for each occurrence:
R 2 is —R J , —OR J , —N(R J ) 2 , —NO 2 ,
halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ;

R J is hydrogen or C 1-6 aliphatic;
is an integer from 0 to 3; and
Hal is a halide;
b) reacting the compound of formula IIIB in a second organic solvent with a compound of formula IIIC:

wherein:
P is a protecting group;

followed by reduction and treatment with acid to form a compound of formula IIID:

wherein:
R 2 is —R J , —OR J , —N(R J ) 2 , —NO 2 ,
halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ;

R J is hydrogen or C 1-6 aliphatic;
o is an integer from 0 to 3;
Hal is a halide;
P is a protecting group; and
A ⊖ is an anion;
c) neutralizing a compound of formula IIID in the presence of a base to form a compound of formula IIID-a:

wherein:
R 2 is —R J , —OR J , —N(R J ) 2 , —NO 2 ,
halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ;

R J is hydrogen or C 1-6 aliphatic;
o is an integer from 0 to 3;
Hal is a halide; and
P is a protecting group;
d) reacting a compound of formula IIID-a in a third organic solvent with a compound of formula IIIE:

wherein, independently for each occurrence:
R 3 is a C 1-6 aliphatic optionally substituted with OH, OP, —O—C 1-6 aliphatic, aryl, heteroaryl, —O-aryl, or —O-heteroaryl;

in the presence of a catalyst to form a compound of formula III.

2. The method of claim 1 , wherein in formula IIIA, o is 1 and R 2 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, R 2 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, R 2 is F, Hal is Br, A ⊖ is Tos − , and P is benzyl.

15. The method of claim 1 , wherein in formula IIIE, R 3 is C(CH 3 ) 2 CH 2 O(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)Cl 2 , Pd(dba) 2 , tetrakis(triphenylphosphine)palladium(0), (MeCN) 2 PdCl 2 , 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:

or a salt thereof,
wherein, independently for each occurrence:
R 2 is —R J , —OR J , —N(R J ) 2 , —NO 2 ,
halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , or —COCOR J ;

R J is hydrogen or C 1-6 aliphatic;
R 3 is C 1-6 aliphatic optionally substituted with OH, OP, —O—C 1-6 aliphatic, aryl, heteroaryl, —O-aryl, or —O-heteroaryl;
P is a protecting group; and
o is an integer from 0 to 3.

24. The compound or salt of claim 23 , wherein o is 1 and R 2 is F.

25. The compound or salt of claim 23 , wherein R 3 is C(CH 3 ) 2 CH 2 O(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

Assignees

• Vertex Pharma

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

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title