催眠镇静药佐匹克隆拆分工艺研究
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摘要
拆分是获得光学活性化学物质的重要手段。手性药物分子由于其作用对象即受体(如离子通道、酶和载体等)具有不对称性，因而药物的两个对映体分子对作用对象通常产生不同的作用效果。目前，大多数药物以外消旋体给药为主，而以光学纯的对映体给药是大多数手性药物的发展趋势。佐匹克隆为吡咯烷酮类化合物，具有镇静、催眠和肌肉松弛作用，由法国Rhone-poulenc Rorer公司于1987年开发以外消旋体上市。佐匹克隆以外消旋体服用时可产生副作用如口苦、次晨乏力、思睡、头痛等，以光学纯的(+)-佐匹克隆给药可在发挥催眠作用的同时避免以外消旋体服用时可能产生的副作用。本文通过将佐匹克隆外消旋体与光学纯的有机酸拆分剂形成非对映异构体盐对其进行拆分。
拆分途径的确定和拆分剂的合成：结合课题需要以及现有拆分技术的发展现状，综合现有“三点作用力原则”和“结构相似”经验规则等拆分指导理论，选择常用的碱类化合物拆分剂酒石酸、苹果酸和谷氨酸衍生物用作佐匹克隆的拆分剂，通过最为常用的形成和分离非对映异构体法对佐匹克隆进行了拆分。合成了拆分剂N-(+)-对甲苯磺酰谷氨酸和N-(—)-苯甲酰谷氨酸，对合成条件进行了改进。
(+)-佐匹克隆的制备：通过选择实验以D-(+)-O，O′-二苯甲酰酒石酸、N-(+)-对甲苯磺酰谷氨酸和N-(—)-苯甲酰谷氨酸作为佐匹克隆拆分剂进行拆分剂选择。结果为三者都可拆分得(+)-佐匹克隆，选择其中拆分效率较好的D-(+)-O，O′，-二苯甲酰酒石酸作为拆分剂拆分佐匹克隆。对影响拆分的因素如溶剂、底物与拆分剂投料比、反应物溶解方式、底物浓度、结晶时间和结晶温度等进行了考察，最佳结果为：乙腈为溶剂；D-(+)-O，O′-二苯甲酰酒石酸与佐匹克隆摩尔投料比为1.0：1.0；佐匹克隆14mg／ml；反应物溶解方式为将佐匹克隆和D-(+)-O，O′-二苯甲酰酒石酸于二氯甲烷中反应，反应完毕后减压蒸出二氯甲烷，然后加入乙腈结晶；结晶温度5℃；结晶时间24h进行拆分。结合后处理程序，操作如下：将D-(+)-O，O′-二苯甲酰酒石酸(32.22g，O.09mol)的二氯甲烷(300ml)溶液加热回流后，往其中滴加佐匹克隆(34.97g，0.09mol)的二氯甲烷(300ml)溶液，澄清后，蒸出大部分二氯甲烷后用乙腈(2500ml)于5℃结晶24h。所得盐用二氯甲烷(270ml)回流溶解，加入乙腈(300ml)于5℃结晶1h，所得盐按上述方法用二氯甲烷和乙腈重结晶一次。过滤、洗涤、干燥得产品精品结晶。取之置于250ml水与250ml二氯甲烷的混合液中，用2mol／L的NaOH溶液碱
化至 pH值为 11，分出有机后，水层用二氯甲烷革取c00m卜3X 合并有机相，
以无水＊币。干燥过夜，减压蒸出二氯甲烷，用乙脂重结晶o100m1）得无色
晶体（＋）一佐匹克隆（12249，总收率 70％），mP202－204℃，【a］D＋ 13be3“（c一020，
丙酮）。
（一卜佐匹克隆的制备：选择L十一肝苹果酸作为拆分剂拆分佐匹克隆。对
影响拆分的因素溶剂和底物浓度通过均匀实验进行了优化，同时对其他影响因
素如底物与拆分剂投料比、反应物溶解方式、结晶时间和结晶温度等进行了考
察。最佳结果为：乙醇／丙酮一 5。85，则为溶剂；L＜一卜苹果酸与佐匹克隆摩尔
投料比为10二0；佐匹克隆20mg／ml；反应物溶解方式为加热处理；结晶温度
l℃；结晶时间sd进行拆分。结合后处理程序，操作如下：将佐匹克隆（100，
2．6mmo加D入至L－（一）一苹果酸（0．3 sg，2．6mmol）的乙醇／丙酮O0ml，15：85，v／v）混
合溶液中，水浴加热回流，溶液澄清后，继续回流1．5－Zh。冷却至室温，然后于
IC下静置结晶8天。过滤十燥得粗品。按下述方法重结晶一次：将所得晶体加
入乙醇／丙酮（15m，15：85，v；’v大合溶剂中，水浴加热回流，溶液澄清后，继续回
流1．5．Zh。冷却至室温，然后于l℃下静置结晶2天，过滤、洗涤、干燥得产品
结晶。取之置于 50ml水与 ZSml h氯甲烷的混合液中，用 Zmol／L的 NaOH溶
液碱化至pH值为10，分出有机层，水层用H氯甲烷革取15m卜3X 合并有机
相，以无水NZm。干燥过夜，减压蒸出二氯甲烷，加入乙酸乙酯重结晶（约5ml）
得无色晶体（一卜佐匹克隆O，收率72％卜mP202《04℃，k叫D—13be3”
（C＝0．20，丙酮）。
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 pa
per, 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, using
dichloromethane 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 ).
拆分途径的确定和拆分剂的合成：结合课题需要以及现有拆分技术的发展现状，综合现有“三点作用力原则”和“结构相似”经验规则等拆分指导理论，选择常用的碱类化合物拆分剂酒石酸、苹果酸和谷氨酸衍生物用作佐匹克隆的拆分剂，通过最为常用的形成和分离非对映异构体法对佐匹克隆进行了拆分。合成了拆分剂N-(+)-对甲苯磺酰谷氨酸和N-(—)-苯甲酰谷氨酸，对合成条件进行了改进。
(+)-佐匹克隆的制备：通过选择实验以D-(+)-O，O′-二苯甲酰酒石酸、N-(+)-对甲苯磺酰谷氨酸和N-(—)-苯甲酰谷氨酸作为佐匹克隆拆分剂进行拆分剂选择。结果为三者都可拆分得(+)-佐匹克隆，选择其中拆分效率较好的D-(+)-O，O′，-二苯甲酰酒石酸作为拆分剂拆分佐匹克隆。对影响拆分的因素如溶剂、底物与拆分剂投料比、反应物溶解方式、底物浓度、结晶时间和结晶温度等进行了考察，最佳结果为：乙腈为溶剂；D-(+)-O，O′-二苯甲酰酒石酸与佐匹克隆摩尔投料比为1.0：1.0；佐匹克隆14mg／ml；反应物溶解方式为将佐匹克隆和D-(+)-O，O′-二苯甲酰酒石酸于二氯甲烷中反应，反应完毕后减压蒸出二氯甲烷，然后加入乙腈结晶；结晶温度5℃；结晶时间24h进行拆分。结合后处理程序，操作如下：将D-(+)-O，O′-二苯甲酰酒石酸(32.22g，O.09mol)的二氯甲烷(300ml)溶液加热回流后，往其中滴加佐匹克隆(34.97g，0.09mol)的二氯甲烷(300ml)溶液，澄清后，蒸出大部分二氯甲烷后用乙腈(2500ml)于5℃结晶24h。所得盐用二氯甲烷(270ml)回流溶解，加入乙腈(300ml)于5℃结晶1h，所得盐按上述方法用二氯甲烷和乙腈重结晶一次。过滤、洗涤、干燥得产品精品结晶。取之置于250ml水与250ml二氯甲烷的混合液中，用2mol／L的NaOH溶液碱
化至 pH值为 11，分出有机后，水层用二氯甲烷革取c00m卜3X 合并有机相，
以无水＊币。干燥过夜，减压蒸出二氯甲烷，用乙脂重结晶o100m1）得无色
晶体（＋）一佐匹克隆（12249，总收率 70％），mP202－204℃，【a］D＋ 13be3“（c一020，
丙酮）。
（一卜佐匹克隆的制备：选择L十一肝苹果酸作为拆分剂拆分佐匹克隆。对
影响拆分的因素溶剂和底物浓度通过均匀实验进行了优化，同时对其他影响因
素如底物与拆分剂投料比、反应物溶解方式、结晶时间和结晶温度等进行了考
察。最佳结果为：乙醇／丙酮一 5。85，则为溶剂；L＜一卜苹果酸与佐匹克隆摩尔
投料比为10二0；佐匹克隆20mg／ml；反应物溶解方式为加热处理；结晶温度
l℃；结晶时间sd进行拆分。结合后处理程序，操作如下：将佐匹克隆（100，
2．6mmo加D入至L－（一）一苹果酸（0．3 sg，2．6mmol）的乙醇／丙酮O0ml，15：85，v／v）混
合溶液中，水浴加热回流，溶液澄清后，继续回流1．5－Zh。冷却至室温，然后于
IC下静置结晶8天。过滤十燥得粗品。按下述方法重结晶一次：将所得晶体加
入乙醇／丙酮（15m，15：85，v；’v大合溶剂中，水浴加热回流，溶液澄清后，继续回
流1．5．Zh。冷却至室温，然后于l℃下静置结晶2天，过滤、洗涤、干燥得产品
结晶。取之置于 50ml水与 ZSml h氯甲烷的混合液中，用 Zmol／L的 NaOH溶
液碱化至pH值为10，分出有机层，水层用H氯甲烷革取15m卜3X 合并有机
相，以无水NZm。干燥过夜，减压蒸出二氯甲烷，加入乙酸乙酯重结晶（约5ml）
得无色晶体（一卜佐匹克隆O，收率72％卜mP202《04℃，k叫D—13be3”
（C＝0．20，丙酮）。
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 pa
per, 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, using
dichloromethane 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 ).
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York: Wiley-interscience, 1994.
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[54] Fogassy E, Kozma D. Formation of Quasi-racemic diastereoisomeric salts as a structural cause for efficient optical resolutions. Tetrahedron Letter, 1995, 36(28): 5069-5070.
[55] 贺嫒．N-脂肪酰基谷氨酸的制备．聊城师院学报，1994，7：55-58．
[56] 张蒂根．N-长链酰基谷氨酸的制备及特性．江西科学，1994，12：145-150．
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