The title compound has been obtained from racemic zopliclone (I) by several related procedures. Demethylation of (I) to afford (II) has been achieved by treatment with diethyl azodicarboxylate (DEAD) in boiling toluene, followed by mild hydrolysis with NH4Cl in refluxing EtOH. In a higher yield demethylation procedure, treatment of (I) with chloroethyl chloroformate produced carbamate (III), which was further hydrolyzed to (II) in boiling MeOH. Resolution of racemic N-demethyl zopiclone (II) has been accomplished via formation of the diastereomeric salts with N-Z-L-phenylalanine or, alternatively, by means of semi-preparative chiral HPLC. In a related strategy, racemic zopiclone (I) was first resolved using D-malic acid to provide the (S)-enantiomer (IV). This was then dealkylated by means of either DEAD or employing the chloroethyl chloroformate method.
Eszopiclone can also be obtained by optical resolution of zopiclone by several different methods: i) crystallization of the D-(+)-O,O'-dibenzoyltartaric acid salt in acetonitrile, followed by treatment with NaOH in dichloromethane/water; ii) crystallization of the (+)-malic acid salt in MeOH/acetone followed by treatment with KHCO3 in MeOH water and extraction with dichloromethane/ethyl acetate; iii) chiral chromatography over a Chiralpak AS column; iv) capillary electrophoresis in the presence of octakis-(2,3,6-tri-O-methyl)-g-cyclodextrin.