A
number of racemic syntheses have been reported that require
separation using chiral auxiliaries along with several asymmetric reduction methods starting with the commercially available
(Bosche Scientific, LLC) oxcarbazepine 48. The scheme highlights
two asymmetric approaches, asymmetric reduction of ketone
48 followed by esterification or asymmetric
hydrogenation of vinyl acetate 50 to give the acetate directly.
Thus asymmetric reduction of oxcarbazepine 48 was accomplished
using Ru(Cl2)(p-cymene)2 as the catalyst, (S,S)-TsDAEN
with formic acid as the stoichiometric reductant in a mixed solvent
system at reflux followed by cooling to 80°C. Addition of
MTBE, followed by a slow cooling to room temperature afforded
the crystals of alcohol 49, which were collected by filtration and
dried to obtain a 95% isolated yield in 97.8% ee. Several experiments
were described in the patent varying (1) catalyst loading,
(2) equivalents of formic acid, (3) pH of the reaction, (4) reaction
time and (5) the use of a phase transfer catalyst. Employment of
the phase transfer catalyst gave 90% yield and >99.9% ee of the
product with less than 2 ppm residual ruthenium content. Alcohol
49 was then converted to eslicarbazepine acetate IX by
reacting with acetic anhydride in the presence of DMAP and pyridine
in refluxing dichloromethane. After aqueous work-up, the
crude product was crystallized from isopropanol to give the desired
product eslicarbazepine acetate (IX) in 90% yield with
99.96% purity with undetectable amount of R isomer. In the second
approach, the acetate intermediate 50 was formed first in
88% yield which was then reduced via catalytic hydrogenation in
the presence of the preformed catalyst 51 to give eslicarbazepine
acetate (IX) in 94% ee. No yield was given for the formation of
the product using this route.
