脲衍生物型手性固定相拆分噻利洛尔对映体

Separation of Celiprolol Enantiomer by High Performance Liquid Chromatography with Urea Derivative as Chiral Stationary Phase

用脲衍生物型手性固定相直接拆分了药物对映体噻利洛尔。优化的正相色谱流动相的组成为正己烷／１，２－二氯乙烷／乙醇（７７∶２１∶２，Ｖ／Ｖ／Ｖ）。实验表明，流动相中乙醇含量的改变对分离度产生了较大的影响；不同极性调节剂的使用表现出了不同的拆分效果。最后讨论了异构体的出峰次序，认为异构体与固定相的手性中心之一的氢键作用力是造成异构体分离的主要因素。

Celiprolol enantiomer was resolved directly by using normal phase HPLC with urea derivative as chiral stationary phase (CSP). The resolution condition was optimized by varying the content of ethanol and 1,2 dichloroethane in the mobile phase. The effects of the two components on stereoselectivity factor (α) and stereochemical resolution factor (R s) are demonstrated. The higher the 1,2 dichloroethane content the faster the elution of solute is, but the lower the values of α and R s are. For a suitable content of ethanol in mobile phase, the maximum resolution factor(R s) can be obtained. Ethanol is a strong proton donor and proton accepter . Its strong hydrogen bond interaction with solute and CSP is important for the direct resolution. In order to obtain both the low retention time and a high R s, we chose the mobile phase with n hexane∶1,2 dichloroethane∶ethanol(V/V/V)=77∶21∶2. Other organic modifiers such as methanol, iso propanol, n butanol and acetonitrile were also used. Iso propanol, methanol and n butanol showed longer retention time and lower values of α and R s than ethanol. Acetonitrile is only a proton accepter and has weak hydrogen bond interaction with solute and CSP, so resolution wasn′t obtained. The elution order of enantiomer was also discussed. We thought that the hydrogen bond interaction between solute and the (S) val component of CSP may mainly control the chiral recognition. The interaction strength is different between (R) and (S) celiprolol, so the celiprolol enantiomer was resolved. And the elution order is S, R.