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

[Image: see text] Chirality plays an important role in the pharmaceutical industry since the two enantiomers of a drug molecule usually display significantly different bioactivities, and hence, most products are produced as pure enantiomers. However, many drug precursors are synthesized as racemates, and hence, enantioseparation has become a significant process in the industry. Cocrystallization is one of the attractive crystallization approaches to obtain the desired enantiomer from racemic compounds. In this work, we propose a chiral resolution route for an antiepileptic drug, S-etiracetam (S-ETI), via enantiospecific cocrystallization with S-2-chloro-S-mandelic acid (CLMA) as a coformer. The experiments indicate that the system is highly enantiospecific; S-2CLMA cocrystallizes only with S-ETI but not with R-ETI or RS-ETI. Therefore, the chiral purification of S-ETI can be achieved efficiently with a 69.1% yield and close to 100% enantiopurity from the racemic solution. Additionally, structural simulations of the S-ETI:S-2CLMA cocrystal reveal that the cocrystal structure has higher thermodynamic stability than that of R-ETI:S-2CLMA by about 5.5 kcal/mol (per cocrystal formula unit), which helps to confirm the favorability of the enantiospecification in this system.