The esterification of (rac)-6-(5-chloro-3-pyridyl)-5-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-7-one rac-(I) with vinyl chloroformate (II) in pyridine gives the racemic carbonate rac-(III), which is submitted to an enantioselective hydrolysis with Candida antarctica (SP 435L) lipase in dioxane/benzyl alcohol yielding a mixture of rac-(I), which is recycled, and enantiomerically pure (95% e.e.) (S)-(III). Finally, this compound is condensed with 1-methylpiperazine (IV) in acetone.
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.
The reaction of pyrazine-2,3-dicarboxylic acid anhydride (I) with 2-amino-5-chloropyridine (II) in refluxing acetonitrile gives 3-(5-chloro-2-pyridyl)carbamoyl pyrazine-2-carboxylic acid (III), which is cyclized by treatment with refluxing SOCl2 affording 6-(5-chloropyrid-2-yl)-5,7-dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine (IV). The partial reduction of (IV) with KBH4 in dioxane-water yields 6-(5-chloro-2-pyridyl)-7-hydroxy-5,6-dihydropyrrolo[3,4-b]pyrazin-5-one (V), which is finally esterified with 4-methylpiperazine-1-carbonyl chloride (VI) by means of NaH in DMF.
The esterification of (rac)-6-(5-chloro-3-pyridyl)-5-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-7-one rac-(I) with chloromethyl chloroformate (V) in pyridine gives the racemic carbonate rac-(III), which is submitted to an enantioselective hydrolysis with Candida antarctica (SP 435L) lipase in dioxane/benzyl alcohol yielding a mixture of rac-(I), which is recycled, and enantiomerically pure (96% e.e.) (S)-(III). Finally, this compound is condensed with 1-methylpiperazine (IV) in acetone.
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.