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2010 4 29 Minseok Kang

Journal of Chromatography A. Separation of α - cyclohexylmandelic acid enantiomers using biphasic chiral recognition high-speed counter-current chromatography. Shengqiang Tonga,b , Jizhong Yanb ,∗, Yi- Xin Guana ,∗∗, Yaner Fub,c , Yoichiro Ito. 2010 4 29 Minseok Kang.

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2010 4 29 Minseok Kang

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  1. Journal of Chromatography A Separation of α-cyclohexylmandelicacid enantiomers using biphasic chiral recognition high-speed counter-current chromatography ShengqiangTonga,b, JizhongYanb,∗, Yi-XinGuana,∗∗, YanerFub,c, Yoichiro Ito 2010 4 29 Minseok Kang

  2. Enantiomer & diastereomer

  3. Characteristics In nature , they usually exist in only one of the one of the two possible enantiomeric forms.

  4. Characteristics Oftentimes, Only a single enantiomer of a chiral molecule is desired. Because some enantiomers show completely different biological activities than their optical isomers. DOSAGE (S)-citalopram , ( aka Lexapro ) 2 (R)-citalopram (aka Celexa ) 1

  5. Enatiomeric separation by chromatography Using Auxiliary chiral reagent Convert to diastereomer Achiral separation technique (Indirect) Adding chiral selectors to mobile phase Chiral separation technique (Direct) Chiral separation technique (Direct) Using chiralStantionary phase Application of LC , GC , SEC , CCC , CPC

  6. Target Drug precursor Synthesis Oxybutynin (+)-enantiomer Chemical structure of (±)--cyclohexylmandelic acid. (Lespedamine; Hexahydrobenzilic acid) Drug for Urinary incotinence

  7. Experiment progress Chiral selector Determine Distribution ratio Separation factor Sample capacity Solvent systems Recovery of solutes

  8. Chiral selector Highly selective in the liquid phase Considerations Combination of solvent does not destroy selectivity and retains the capacity to elute chiral isomers of interest Upper organic Lipophillicchiral selector ( (- )-isobuthyltartrate Lower aqueous Hydrophillicchiral selector ( hydroxypropyl-beta-cyclodextrin)

  9. Chiral selector 1. Chiral selector should be soluble in only one phase 2. Racemic mixtures should be easily soluble in both phases 3. For a perfect separation , Distribution ratio is about 1 Solvent system Adjust Lipophillicchiral selector

  10. Determine Distribution ratio Maximum ratio is 3:1 ( tartrate : HP-beta-CD )

  11. pH effect Ionic CHMA is formed with high pH in the aqueous phase Finally pH 2.68 was selected for the CCC separation

  12. Temperature & Thermodynamic effect Apply “ Van’t Hoff equation “ Chemical thermodynamics relates the change in Temperature to the change in the equilibrium constant given the standard enthalpy change for the progress

  13. Temperature & Thermodynamic effect If the enthalpy change of reaction is assumed to be constant with temperature , a plot gives a straight line.

  14. Theorogical considerations Schematic diagram of chemodynamic equilibrium between the racemates (A±) and chiral selector (CS) in the separation column based on biphasic recognition.

  15. Sample capacity We may derive the langmuir isotherm by treating the adsorption process as we would any other equilibrium process the number of filled surface sites (SP) is proportional to θ, the number of unfilled sites (S* ) is proportional to 1-θ

  16. Sample capacity (-)-enantiomer (+)-enantiomer Langmuirian isotherms and estimation of the operating conditions in chiral CCC separation of-CHMA. Parameters for Langmuirian isotherms: a+ = 1.594; b+=−0.0322; a−= 3.215; b−= 0.197 Loading limits : molar ratio CS/analyte = 1:1 Sample volume : less than 5% of total column volume

  17. HSCCC chromatogram (TBE – 20A] 3.5mg 12mg 7mg 22mg N-hexane : MtBE : 0.1M phosphate salt buffer (pH=2.68)

  18. HSCCC chromatogram (TBE – 300A] 440mg 99.5% , 186mg 99.5% , 190mg Silica-gel column (remove CSs) Recovery : 85-88%

  19. Conclusion 1. A chiral separation method for complete resolution of the racemic mixture on a preparative scale was established 2. But Further purification step is needed to recover enantiomers in isloated form. 3. The success of a CCC enantioseparation is highly dependent on the choice of the solvent system.

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