Resolution of Halogenated Mandelic Acids through Enantiospecific Co-Crystallization with Levetiracetam

Abstract

The resolution of halogenated mandelic acids using levetiracetam (LEV) as a resolving agent via forming enantiospecific co-crystal was presented. Five halogenated mandelic acids, 2-chloromandelic acid (2-ClMA), 3-chloromandelic acid (3-ClMA), 4-chloromandelic acid (4-ClMA), 4-bromomandelic acid (4-BrMA), and 4-fluoromandelic acid (4-FMA), were selected as racemic compounds. The effects of the equilibrium time, molar ratio of the resolving agent to racemate, amount of solvent, and crystallization temperature on resolution performance were investigated. Under the optimal conditions, the resolution efficiency reached up to 94% and the enantiomeric excess (%e.e.) of (R)-3-chloromandelic acid was 63%e.e.. All five halogenated mandelic acids of interest in this study can be successfully separated by LEV via forming enantiospecific co-crystal, but the resolution performance is significantly different. The results showed that LEV selectively co-crystallized with S enantiomers of 2-ClMA, 3-ClMA, 4-ClMA, and 4-BrMA, while it co-crystallized with R enantiomers of 4-FMA. This indicates that the position and type of substituents of racemic compounds not only affect the co-crystal configuration, but also greatly affect the efficiency of co-crystal resolution.

Chiral resolution methods for racemic pharmaceuticals based on cocrystal formation

“…Chiral resolution of cocrystals can exhibit enantiospecific behavior with one of the enantiomers, leading to a high yield in one crystallization step, in contrast to forming diastereomeric salts. 38,39…”

“…Chiral resolution of cocrystals can exhibit enantiospecific behavior with one of the enantiomers, leading to a high yield in one crystallization step, in contrast to forming diastereomeric salts. 38,39 There are some possible approaches for obtaining cocrystals for chiral resolution, which are discussed as follows.…”

Enantiomer separation of 2‐halomandelic acids via diastereomeric salt formation with chiral N‐substituted 2‐amino‐2‐phenylethanols

“…10 The enantioseparation of racemic o-Cl-MA via diastereomeric salt formation using chiral amines has been reported. [11][12][13][14][15][16] However, the enantioseparation of o-halomandelic acids (o-X-MA) with larger halogen groups has been less explored. These halogen-substituted MAs enable the synthesis of pharmaceuticals and natural products via further derivatization, such as ortho-arylation.…”

Separation of Etiracetam Enantiomers Using Enantiospecific Cocrystallization with 2-Chloromandelic Acid

“… 16 Recently, enantioseparation has been achieved for a range of halogenated mandelic acids using cocrystallization with levetiracetam as a resolving agent. 17 Although one of the two diastereomers involved in the separation of the halogenated mandelic acid enantiomers will be similar to that used in the separation of the levetiracetam enantiomers, the potential second diastereomeric cocrystal in the two cases is distinct, which means that the ability to use enantioseparation in the first case does not indicate that the second case will also be successful. This led to a question whether halogenated mandelic acids could be a viable resolving agent for the enantiopurification of levetiracetam.…”

“…In addition, cocrystals of S -ETI with other compounds have also been found, with coformers including R -α-ketoglutaric acid and d -tartaric acid . Recently, enantioseparation has been achieved for a range of halogenated mandelic acids using cocrystallization with levetiracetam as a resolving agent . Although one of the two diastereomers involved in the separation of the halogenated mandelic acid enantiomers will be similar to that used in the separation of the levetiracetam enantiomers, the potential second diastereomeric cocrystal in the two cases is distinct, which means that the ability to use enantioseparation in the first case does not indicate that the second case will also be successful.…”