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 - 19 . (canceled)
20 . A method for preparing a compound of formula II:
wherein, independently for each occurrence:
ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
Hal is a halide;
R 1 is independently selected from —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;
m is an integer from 0 to 3 inclusive; and
n is an integer from 1 to 4 inclusive;
comprising the steps of
a) reacting a compound of formula IIA in a first organic solvent
wherein, independently for each occurrence:
ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R 1 is independently selected from —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;
m is an integer from 0 to 3 inclusive; and
Hal is a halide;
with a compound of formula IIB:
wherein
X is CN or CO 2 R;
R is C 1-6 aliphatic or aryl; and
R J is hydrogen or C 1-6 aliphatic, to form a compound of formula IIC:
wherein, independently for each occurrence:
ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R 1 is independently selected from —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;
X is CN or CO 2 R;
R is C 1-6 aliphatic or aryl; and
m is an integer from 0 to 3 inclusive;
b) removing the —CO 2 R J group from compound IIC in a second organic solvent to form a compound of formula I:
wherein, independently for each occurrence:
ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R 1 is independently selected from —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;
X is CN or CO 2 R;
R is C 1-6 aliphatic or aryl; and
m is an integer from 0 to 3 inclusive;
c) reacting a compound of formula I with a compound of formula IID in the presence of a base:
wherein, independently for each occurrence:
Hal is a halide; and
q is an integer from 0 to 3 inclusive; to produce a compound of formula IIE:
wherein, independently for each occurrence:
ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R 1 is independently selected from —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;
m is an integer from 0 to 3 inclusive;
X is CN or CO 2 R;
R is C 1-6 aliphatic or aryl; and
n is an integer from 1 to 4 inclusive;
d) sequentially reacting a compound of formula IIE with a hydroxide base and acid to form a compound of formula F:
wherein, independently for each occurrence:
ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R 1 is independently selected from —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;
m is an integer from 0 to 3 inclusive; and
n is an integer from 1 to 4 inclusive; and
e) reacting a compound of formula IIF with a halogenating agent in a third organic solvent to form a compound of formula II.
21 . (canceled)
22 . The method of claim 20 , wherein in step a), the first organic solvent is toluene.
23 - 24 . (canceled)
25 . The method of claim 20 , wherein in step a), ring A is
26 - 28 . (canceled)
29 . The method of claim 20 , wherein in formula IIC, ring A is
m is 0, X is CN, and R J is Et.
30 . (canceled)
31 . The method of claim 20 , wherein in step b), the second solvent is dimethylsulfoxide.
32 . The method of claim 20 , wherein in formula I, ring A is
m is 0, and X is CN.
33 . The method of claim 20 , wherein in step c), the base is an inorganic base.
34 . The method of claim 20 , wherein in formula IID, one Hal is Cl and the other Hal is Br.
35 . The method of claim 20 , wherein in step d), the base is NaOH.
36 . (canceled)
37 . The method of claim 20 , wherein in step d), reaction with a hydroxide base takes place at about 60° C. to 100° C.
38 . The method of claim 20 , wherein in formula IIE, ring A is
m is 0, n is 1, and X is CN.
39 - 40 . (canceled)
41 . The method of claim 20 , wherein in step e), the halogenating agent is SOCl 2 .
42 . (canceled)
43 . The method of claim 20 , wherein in formula IIF, ring A is
m is 0, and n is 1.
44 . The method of claim 20 , wherein in formula II, ring A is
m is 0, n is 1, and Hal is Cl.
45 - 117 . (canceled)