Processes and intermediates for preparing fused heterocyclic kinase inhibitors
View Patent ↗This invention relates to processes and intermediates for manufacturing fused heterocyclic-type kinase inhibitor compounds, such as thienopyridine-based compounds, and to processes and intermediates for preparing intermediates that are useful in the manufacture of fused heterocyclic-type kinase inhibitor compounds, such as thienopyridine-based compounds, particularly at an industrial level.
1. A process for preparing a compound of Formula (A):
and pharmaceutically acceptable salts thereof,
wherein
D is pyridine optionally substituted with 1 to 5 independently selected R 38 ;
M is
Z is —O—;
Ar is phenyl; and
G is
wherein
each R 38 is independently selected from —(CH 2 ) j NR 39 (CH 2 ) n R 36 and —(CH 2 ) n NR 36 R 39 , wherein each j is an integer independently ranging from 0 to 4 and n is an integer ranging from 0 to 6;
R 36 is selected from the group consisting of H, —OH, C 1 -C 6 alkyl, —(CH 2 ) n O(CH 2 ) i OR 37 , —(CH 2 ) n CN(CH 2 ) n OR 37 , —(CH 2 ) n CN(CH 2 ) n R 37 , and —(CH 2 ) n OR 37 , wherein each n is an integer independently ranging from 0 to 6 and i is an integer ranging from 2 to 6;
R 37 is selected from H, —O—C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 alkyl;
R 39 is selected from the group consisting of H and C 1 -C 6 alkyl;
R 13 is —H,
Q is phenyl optionally substituted with between zero and four halogens;
R 11 and R 12 are H
the process comprising
reacting a compound represented by the Formula (A-1)
wherein
PG is a R 38 substituent protected with a protecting group; and
RG 1 is —NH 2 ; with a compound represented by the Formula (A-2):
RG 2 -G 1 (A-2),
wherein RG 2 G 1 is
wherein the reaction is performed at 70° C. in a mixture of isopropanol and acetonitrile, such that the reaction of —RG 1 with RG 2 -G 1 forms
and removing the protecting group.
2. The process according to claim 1 , wherein G is selected from the group consisting of
3. The process according to claim 1 , wherein D is substituted with one R 38 , wherein R 38 is —(CH 2 ) j NR 39 (CH 2 ) n R 36 , wherein j is an integer from 0 to 4, n is an integer from 0 to 6, R 39 is H or C 1 -C 6 alkyl, and R 36 is —(CH 2 ) n OR 37 , wherein n is an integer ranging from 0 to 6, and R 37 is H or C 1 -C 6 alkyl.
4. The process according to claim 1 wherein RG 2 -G 1 is