Process of producing cycloalkylcarboxamido-indole compounds
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.
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