Preparation of pregabalin and related compounds
View Patent ↗Materials and Methods for preparing (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid and structurally related compounds via enzymatic kinetic resolution are disclosed.
1. A method of making a compound of Formula 1,
or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof, in which
R 1 and R 2 are different and are each independently selected from hydrogen atom, C 1-12 alkyl, C 3-12 cycloalkyl, and substituted C 3-12 cycloalkyl,
the method comprising:
(a) reducing a cyano moiety of a compound of Formula 3,
or a salt thereof, to yield the compound of Formula 2 or a salt thereof;
wherein R 1 and R 2 are as defined above and R 3 in Formula 3 is C 1-12 alkyl, C 3-12 cycloalkyl, or aryl-C 1-6 alkyl;
(b) reacting a compound of Formula 2,
or a salt thereof, with an acid and water to yield the compound of Formula 1 or a salt thereof; and
(c) optionally converting the compound of Formula 1 or a salt thereof into a pharmaceutically acceptable complex, salt, solvate or hydrate, wherein R 1 and R 2 in Formula 2 are as defined in Formula 1.
2. The method of claim 1 , wherein R 1 is a hydrogen atom and R 2 is isobutyl.
3. The method of claim 1 , further comprising:
(a) contacting a compound of Formula 4,
with an enzyme to yield the compound of Formula 3, or a salt thereof, and a compound of Formula 5,
wherein the enzyme is adapted to enantioselectively hydrolyze the compound of Formula 4 to the compound of Formula 3 or a salt thereof;
(b) isolating the compound of Formula 3 or a salt thereof; and
(c) optionally racemizing the compound of Formula 5 to yield the compound of Formula 4, wherein
R 1 , R 2 , and R 3 in Formula 4 and Formula 5 are as defined in Formula 3; and
R 4 in Formula 4 and Formula 5 is the same as or different than R 3 and is C 1-12 alkyl, C 3-12 cycloalkyl, or aryl-C 1-6 alkyl.
4. The method of claim 3 , wherein R 1 is a hydrogen atom and R 2 is isobutyl.