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Characteristics In nature, they usually exist in only one of the one of the two possible enantiomeric forms.
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2010 4 29 Minseok Kang
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
Journal of Chromatography A
Enantiomer & diastereomer
Characteristics
In nature , they usually exist in only one of the one of the two possible enantiomeric forms.
Characteristics
Oftentimes, Only a single enantiomer of a chiral molecule is desired.
Because some enantiomers show completely different biological activities than their optical isomers.
(S)-citalopram , ( aka Lexapro )
(R)-citalopram(aka Celexa )
DOSAGE
2
1
Enatiomeric separation by chromatography
Using Auxiliary chiral reagent
Convert to diastereomer
Adding chiral selectors to
mobile phase
Using chiral Stantionary
phase
Achiral separation technique(Indirect)
Chiral separation technique(Direct)
Chiral separation technique(Direct)
Application of LC , GC , SEC , CCC , CPC
Chemical structure of (±)--cyclohexylmandelic acid.
(Lespedamine; Hexahydrobenzilic acid)
Oxybutynin(+)-enantiomer
Target
Drug for Urinary incotinence
Synthesis
Drug precursor
Experiment progress
Determine Distribution ratio Separation factor
Sample capacity Recovery of solutes
Chiral selector
Solvent systems
Chiral selector
Upper organic
Lower aqueousHydrophillic chiral selector
( hydroxypropyl-beta-cyclodextrin)
Highly selective in the liquid phase
Combination of solvent does not destroy selectivity and retains the capacity to elute chiral isomers of interest
Lipophillic chiral selector( (- )-isobuthyl tartrate
Considerations
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 Lipophillic chiral selector
Chiral selector
Determine Distribution ratio
D1 , α1 HP-β-CD 0.1M in aqD2, α2 (-)-2-Ethylhexyltartrate 0.3M in
org
Maximum ratio is 3:1 ( tartrate : HP-beta-CD )
pH effect
Ionic CHMA is formed with high pH in the aqueous phaseFinally pH 2.68 was selected for the CCC separation
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
Temperature & Thermodynamic effect
If the enthalpy change of reaction is assumed to be constant with temperature , a plot gives a straight line.
Theorogical considerations
Schematic diagram of chemodynamic equilibrium between the racemates(A±) and chiral selector (CS) in the separation column based on biphasic recognition.
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
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
Sample capacity
(-)-enantiomer
(+)-enantiomer
Loading limits : molar ratio CS/analyte = 1:1
Sample volume : less than 5% of total column volume
HSCCC chromatogram (TBE – 20A]
N-hexane : MtBE : 0.1M phosphate salt buffer (pH=2.68)
3.5mg
7mg
12mg
22mg
HSCCC chromatogram (TBE – 300A]
Silica-gel column (remove CSs)
440mg
Recovery : 85-88%
99.5% , 186mg99.5% , 190mg
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.