Diazepinoquinolines, synthesis thereof, and intermediates thereto
The present invention relates to methods for synthesizing compounds useful as 5HT 2C agonists or partial agonists, derivatives thereof, and to intermediates thereto.
1. A method for preparing a compound of formula II:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1;
R 1 and R 2 are each independently halogen, —CN, phenyl, —R, —OR, —C 1-6 perfluoroalkyl, or —OC 1-6 perfluoroalkyl;
each R is independently hydrogen or a C 1-6 alkyl group; and
R 7 is hydrogen or C 1-6 alkyl,
comprising the steps of:
(a) providing a compound of formula E
wherein:
R 1 and R 2 are each independently halogen, —CN, phenyl, —R, —OR, —C 1-6 perfluoroalkyl, or —OC 1-6 perfluoroalkyl; and
each R is independently hydrogen or a C 1-6 alkyl group,
(b) treating said compound of formula E with a chiral agent to form a compound of formula D-1:
wherein:
R 1 and R 2 are each independently halogen, —CN, phenyl, —R, —OR, —C 1-6 perfluoroalkyl, or —OC 1-6 perfluoroalkyl;
each R is independently hydrogen or a C 1-6 alkyl group; and
X is a chiral agent,
(c) obtaining a compound of formula D by suitable physical means:
wherein:
R 1 and R 2 are each independently halogen, —CN, phenyl, —R, —OR, —C 1-6 perfluoroalkyl, or —OC 1-6 perfluoroalkyl;
each R is independently hydrogen or a C 1-6 alkyl group; and
X is a chiral agent,
(d) treating said compound of formula D with a suitable base to provide a compound of formula C:
wherein:
R 1 and R 2 are each independently halogen, —CN, phenyl, —R, —OR, —C 1-6 perfluoroalkyl, or —OC 1-6 perfluoroalkyl; and
each R is independently hydrogen or a C 1-6 alkyl group,
(e) alkylating said compound of formula C to form a compound of formula B:
wherein:
n is 1;
R 1 and R 2 are each independently halogen, —CN, phenyl, —R, —OR, —C 1-6 perfluoroalkyl, or —OC 1-6 perfluoroalkyl;
each R is independently hydrogen or a C 1-6 alkyl group; and
PG 2 is a suitable amino protecting group,
(f) deprotecting said compound of formula B to form a compound of formula A
wherein:
n is 1;
R 1 and R 2 are each independently halogen, —CN, phenyl, —R, —OR, —C 1-6 perfluoroalkyl, or —OC 1-6 perfluoroalkyl; and
each R is independently hydrogen or a C 1-6 alkyl group, and
(g) reacting said compound of formula A with formaldehyde, or an equivalent thereof, to form a compound of formula II.
2. The method according to claim 1 , wherein each n is 1 and R 1 and R 2 are both hydrogen.
3. The method according to claim 1 , wherein said formaldehyde is aqueous formaldehyde.
4. The method according to claim 1 , wherein the alkylation at step (e) is achieved by reacting said compound of formula C with
in the presence of a suitable acid to form a compound of formula B:
wherein n is 1 and PG 2 is acetyl.