Investigation On Enantioseparation Of Zopiclone, A Sedative Hypnotic Drug

Resolution of racemates into enantiomers is an important way of obtaining optically pure chemical compounds. The interaction of optically pure drug molecules with receptors (ion channels, enzyme and carriers which provide a chiral biological context) generally manifests itself as a difference in biological activity. More than 50% of the commercial drugs available worldwide have stereogenic centers and most of them are marketed as racemates at present. Increased understanding of the pharmacokinetics and mechanism of action of these chemicals in biological system has led to the development of drugs in optically pure form, zopiclone is rapid-acting nonbenzodiazepine hypnotic for the treatment of insomnia. An isomer of zopiclone, for referred to as S-( + )-zopiclone, is mainly responsible for the parent drug's hypnotic effects and avoids the adverse effects such as bitter taste in the mouth, drowsiness and tiredness in the morning associated with the administration of the racemic mixture of zopiclone. In this paper, the resolution of zopiclone by fractional crystallization of its diasteoisomers was studied.Selection of the resolution method and synthesis of optically pure resolving agents: According to the "three point interaction principle" and experience, we chose N-( - )-benzoylglutamic acid, N-( + )-tosylglutamic acid, L-(-)-malic acid and D-(+)-O,O'-dibenzoyltartaric acid as resolving agent. N-(+)-tosylglutamic acid and N-(-)-benzoylglutamic acid were synthesized. The synthetic process was improved.Preparation of ( + )-zopiclone: With N-( + )-tosylglutamic acid, N-(-)-benzoylglutamic acid and D-(+)-O,O' -dibenzoyltartaric acid as candidate resolving agent, the selection of resolving agent was performed. The results showed that all these three resolving agents resolved zopiclone to its (+)-enantiomers. As D-(+)-O,O' -dibenzoyltartaric acid had greatest resolving efficiency, it was selected to resolve zopiclone to its (+)-enantiomers. Optimization of resolution conditions and affecting factors on resolution such as solvent, the molecular ratio of racemate to resolving agent, method of reaction, concentration of racemate, crystallization temperature and crystallization time were studied. The best conditions were: acetonitrile as solvent, molecular ratio of racemate to resolving agent 1.0:1.0, usingdichloromethane as reaction media, concentration of racemate 14mg/ml, crystallization temperature 5℃, crystallization time 24 hours. The procedure: with D-(+)-O,O'-dibenzoyltartaric acid as resolving agent, dichloromethane as reaction media, acetonitrile as solvent, zopiclone was fractional crystallized at 5℃ for 24h to give a crystalline product. After alkalization, extraction, desiccation and crystallization, (+)-zopiclone was obtained, with a yield of 70%, mp202-204℃,[α]D20=+133° (c=0.20, acetone ).Preparation of (-)-zopiclone: L-(-)-malic acid was chosen as resolving agent. Optimization of resolution conditions and affecting factors on resolution such as solvent, the molecular ratio of racemate to resolving agent, method of reaction, concentration of racemate, crystallization temperature and crystallization time were studied. The best conditions were: ethanol/acetone as solvent, molecular ratio of racemate to resolving agent 1.0:1.0, using heating as method of reaction, concentration of racemate 20mg/ml, crystallization temperature 1℃, crystallization time 8 days. The procedure: with L-(-)-malic acid as resolving agent, ethanol/methanol(15:85,v/v) as solvent, zopiclone was fractional crystallized at 1℃ for 8d to give a crystalline product. After alkalization, extraction, desiccation and crystallization, (-)-zopiclone was obtained, with a yield of 72%, mp202-204℃,[α] D20=-134° (c=0.20, acetone ).