Kewen Tang

Enantiomeric separation of oxybutynin by recycling high-speed counter-current chromatography with hydroxypropyl-β-cyclodextrin as chiral selector.

Recycling high-speed counter-current chromatography was successfully applied to the preparative separation of oxybutynin enantiomers. The two-phase solvent system consisted of n-hexane, methyl tert-butyl ether, and 0.1 mol/L phosphate buffer solution (pH = 5.0) with the volume ratio of 6:4:10. Hydroxypropyl-β-cyclodextrin was employed as the chiral selector. The influence of factors on the chiral separation process, including the concentration of chiral selector, the equilibrium temperature, the pH value of the aqueous phase were investigated. Under optimum separation conditions, 15 mg of oxybutynin racemate was separated with the purities of both the enantiomers over 96.5% determined by high-performance liquid chromatography. Recovery for the target compounds reached 80-82% yielding 6.00 mg of (R)-oxybutynin and 6.15 mg of (S)-oxybutynin. Technical details for recycling elution mode were discussed.

Studies on Enantioselective Liquid–Liquid Extraction of Amino-(4-nitro-phenyl)-acetic Acid Enantiomers: Modeling and Optimization

BINAP-metal complexes were prepared as extractant for enantioselective liquid-liquid extraction (ELLE) of amino-(4-nitro-phenyl)-acetic acid (NPA) enantiomers. The influence of process variables, including types of organic solvents and metal precursor, concentration of ligand, pH, and temperature on the efficiency of the extraction, were investigated experimentally. An interfacial reaction model was established for insightful understanding of the chiral extraction process. Important parameters required for the model were determined. The experimental data were compared with model predictions to verify the model prediction, It was found that the interfacial reaction model predicted the experimental results accurately. By modeling and experiment, an optimal extraction condition with pH of 7 and host (extractant) concentration of 1 mmol/L was obtained and high enantioselectivity (αop ) of 3.86 and performance factor (pf) of 0.1949 were achieved.

Study on inclusion interaction of hydrophilic 2-chloromandelic acid with hydroxypropyl-β-cyclodextrin

The inclusion interaction between hydroxypropyl-β-cyclodextrin (HP-β-CD) and hydrophilic 2-chloromandelic acid (CMA) was studied by ultraviolet (UV) absorption spectrophotometer. A reliable determination of the complex stoichiometry was provided by the continuous variation technique. 1H NMR spectrum and Thermo-gravimetric/differential thermal analyzer (TG/DTA) techniques were explored to further characterize the inclusion complex, and molecular modeling was used to investigate the mechanism of inclusion interaction. The results showed that HP-β-CD reacted with R,S-CMA to form inclusion complexes, with 1:1 stoichiometry and inclusion stability constants KR and KS were 24 and 39 L/mol determined from UV data by the method of Benesi-Hildebrand’s. Molecular modeling confirmed experimental observation and indicated that the hydrogen bonding interaction plays an important role in the interactive inclusion between HP-β-CD and CMA. Besides, compared with the HP-β-CD, molecular modeling showed R, S-CMA interact with β-CD through different binding modes, in which Vander Waals is the main intermolecular force between β-CD and R-CMA (or S-CMA) while without obvious hydrogen bonding interaction.

Equilibrium Studies on Liquid-Liquid Reactive Extraction of Phenylsuccinic Acid Enantiomers Using Hydrophilic β-CD Derivatives Extractants

Abstract This paper deals with the enantioseparation of phenylsuccinic acid (H 2 A) enantiomers by liquid-liquid reactive extraction using β -CD derivatives as aqueous selectors. Cyclodextrin and its derivatives can interact with guest molecules selectively to form complexes with different stabilities. Cyclodextrin derivatives are not soluble in organic liquids, but highly soluble in water. In this work, hydroxypropyl- β -cyclodextrin (HP- β -CD), hydroxyethyl- β -cyclodextrin (HE- β -CD) and methyl- β -cyclodextrin (Me- β -CD) were selected as chiral selectors in aqueous phase for the reactive extraction of phenylsuccinic acid enantiomers from organic phase to aqueous phase. The results show that the efficiency of the extraction depends, often strongly, on a number of process variables, including the types of organic solvents and β -CD derivatives, the concentrations of the extractants and H 2 A enantiomers, pH and temperature. HP- β -CD, HE- β -CD and Me- β -CD have stronger recognition abilities for R -phenylsuccinic acid than for S -phenylsuccinic acid. Among the three kinds of β -CD derivatives, HP- β -CD has the strongest separation ability. Excellent enantioseparation was achieved under the optimal conditions of pH of 2.5 and temperature of 5°C with a maximum enantioselectivity ( a ) of 2.38. Reactive extraction of enantiomers with hydrophilic β -CD derivatives is of strong chiral separation ability and can be hopeful for separations of various enantiomers at a large-scale.

Fractional reactive extraction for symmetrical separation of 4-nitro-D,L-phenylalanine in centrifugal contactor separators: experiments and modeling.

The enantioselective liquid-liquid extraction of 4-nitro-D,L-phenylalanine (D,L-Nphy) using PdCl2 {(s)-BINAP} as extractant in dichloroethane was studied experimentally in a countercurrent cascade of 10 centrifugal contactor separators (CCSs) at 5°C, involving flow ratio, extractant concentration, and Cl(-) concentration. The steady-state enantiomeric excess (ee) in both stream exits was 90.86% at a 93.29% yield. The predicted value was modeled using an equilibrium stage approach. The correlation between model and experiment was satisfactory. The model was applied to optimize the production of both enantiomers in >97% ee and >99% ee. 14 stages and 16 stages are required for 97% ee and 99% ee for both enantiomers, respectively.

Experimental and Model Studies on Continuous Separation of 2-Phenylpropionic Acid Enantiomers by Enantioselective Liquid-Liquid Extraction in Centrifugal Contactor Separators.

Multistage enantioselective liquid-liquid extraction (ELLE) of 2-phenylpropionic acid (2-PPA) enantiomers using hydroxypropyl-β-cyclodextrin (HP-β-CD) as extractant was studied experimentally in a counter-current cascade of centrifugal contactor separators (CCSs). Performance of the process was evaluated by purity (enantiomeric excess, ee) and yield (Y). A multistage equilibrium model was established on the basis of single-stage model for chiral extraction of 2-PPA enantiomers and the law of mass conservation. A series of experiments on the extract phase/washing phase ratio (W/O ratio), extractant concentration, the pH value of aqueous phase, and the number of stages was conducted to verify the multistage equilibrium model. It was found that model predictions were in good agreement with the experimental results. The model was applied to predict and optimize the symmetrical separation of 2-PPA enantiomers. The optimal conditions for symmetric separation involves a W/O ratio of 0.6, pH of 2.5, and HP-β-CD concentration of 0.1 mol L(-1) at a temperature of 278 K, where eeeq (equal enantiomeric excess) can reach up to 37% and Yeq (equal yield) to 69%. By simulation and optimization, the minimum number of stages was evaluated at 98 and 106 for eeeq > 95% and eeeq > 97%.

Experimental and Model Study on Enantioselective Reactive Extraction of 2-chlorophenylglycine Enantiomers with BINAP-Metal Complexes

Equilibrium study on enantionselective extraction of 2-chlorophenylglycine (CPG) enantiomers with S-BINAP-metal complexes as selector was performed. A reactive extraction model with an interfacial reaction of CPG enantiomers with S-BINAP-metal complex was established. The extraction system shows good selectivity towards CPG enantiomers. [(S-BINAP)Cu(CH3CN)][PF6] (BINAP-Cu) exhibits the highest selectivity among the selectors studied. Efficiency of the extraction depends, often strongly, on a number of process variables, including types of organic solvents and metal precursors, concentration of the selector, the pH, and the temperature. The model quantitatively predicts extraction performance as a function of key operating parameters, providing a simple computational approach to process optimization. High enantioselectivity of 3.01 was obtained.

Kinetic Study for Biphasic Recognition Chiral Extraction of Naproxen Enantiomers with Hydrophobic L-iso-butyl Tartrate and Hydrophilic Hydroxypropyl-β-Cyclodextrin

The kinetics of biphasic recognition chiral extraction of naproxen (HA) enantiomers was investigated to determine the extraction mechanism, with hydrophobic L-iso-butyl tartrate (L-IBTA) in the organic phase and hydrophilic hydroxypropyl-β-cyclodextrin (HP--CD) in the aqueous phase. The two-phase homogeneous reaction model was selected over the interfacial reaction model, because there is a clear physical solubility of naproxen enantiomers in both the aqueous phase and the organic phase. The reactions between the HA enantiomers and L-iso-butyl tartrate in a stirred cell fall in Regime 3; the extraction is accompanied by two fast chemical reactions in the diffusion film. The reactions have been found to be first order with respect to HA enantiomers and second order with respect to L-IBTA. The forward rate constants for S-HA and R-HA are 1.26 × 10−4 mol−2 m6 s−1 and 2.52 × 10−4 mol−2 m6 s−1, respectively. With the increase of HP--CD concentration in the aqueous phase, high enantioselectivity was obtained, but the extraction rates decreased. These data will be useful in the design of extraction processes.