Synthetic methods for spiro-oxindole compounds
View Patent ↗This invention is directed to methods of preparing certain spiro-oxindole derivatives, which are useful for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain.
1. A method of preparing a compound of formula (I):
or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof;
wherein the method comprises:
a) treating a compound of formula (7):
or a pharmaceutically acceptable salt thereof, with a base under suitable conditions to form a compound of formula (8):
or a pharmaceutically acceptable salt thereof; and
b) treating the compound of formula (8):
or a pharmaceutically acceptable salt thereof, with a compound of formula (9):
or a pharmaceutically acceptable salt thereof, under suitable conditions to provide the compound of formula (I), or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof.
2. The method of claim 1 further comprising a preparation of the compound of formula (7), wherein the method comprises treating a compound of formula (6):
or a pharmaceutically acceptable salt thereof, under standard Mitsunobu reaction conditions to form the compound of formula (7), or a pharmaceutically acceptable salt thereof.
3. The method of claim 2 further comprising a preparation of the compound of formula (6), wherein the method comprises treating a compound of formula (5):
or a pharmaceutically acceptable salt thereof, with an aldehyde under suitable conditions to form the compound of formula (6), or a pharmaceutically acceptable salt thereof.
4. The method of claim 3 further comprising a preparation of the compound of formula (5), wherein the method comprises treating a compound of formula (4):
or a pharmaceutically acceptable salt thereof, under suitable conditions to form the compound of formula (5), or a pharmaceutically acceptable salt thereof.
5. The method of claim 4 further comprising a preparation of the compound of formula (4), wherein the method comprises:
a) reacting a compound of formula (2):
or a pharmaceutically acceptable salt thereof, with a Grignard reagent of formula (3):
under suitable conditions to form an intermediate product; and
b) reacting the intermediate product of a) with a compound of formula (1):
or a pharmaceutically acceptable salt thereof, under suitable conditions to form the compound of formula (4), or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 further comprising resolving the compound of formula (I), or a pharmaceutically acceptable salt thereof, as a mixture of enantiomers, under suitable conditions; to yield a compound of formula (I-S):
or a pharmaceutically acceptable salt thereof, and a compound of formula (I-R):
or a pharmaceutically acceptable salt thereof.
7. A method of preparing a compound of formula (I):
or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof, wherein the method comprises:
a) reacting a compound of formula (2):
or a pharmaceutically acceptable salt thereof, with a Grignard reagent of formula (3):
under suitable conditions to form an intermediate product; and
b) reacting the intermediate product of a) with a compound of formula (1):
or a pharmaceutically acceptable salt thereof, under suitable conditions to form a compound of formula (4):
or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof;
c) treating the compound of formula (4), or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof, under suitable conditions to form a compound of formula (5):
or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof;
d) treating the compound of formula (5), or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof, with an aldehyde under suitable conditions to form a compound of formula (6):
or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof;
e) treating the compound of formula (6), or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof, under standard Mitsunobu reaction conditions to form a compound of formula (7):
or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof;
f) treating the compound of formula (7) or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof, with a base under suitable conditions to form a compound of formula (8):
or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof;
g) treating the compound of formula (8):
or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof, with a compound of formula (9):
or a pharmaceutically acceptable salt thereof, under suitable conditions to provide the compound of formula (I), or a pharmaceutically acceptable salt thereof, as a single stereoisomer or enantiomer or a mixture thereof.
8. The method of claim 7 further comprising resolving the compound of formula (I), or a pharmaceutically acceptable salt thereof, as a mixture of enantiomers, under suitable conditions to yield a compound of formula (I-S):
or a pharmaceutically acceptable salt thereof, and a compound of formula (I-R):
or a pharmaceutically acceptable salt thereof.