Studies On The Ionic Liquid-like Biphasic System For Enantioseparation Of Chiral Drug

Chiral compounds widely exist in nature and organisms,and it’s found that more than half of drugs have chiral centers.Different enantiomers of chiral drugs have different pharmacological activities.Often,one enantiomer has high efficacy and small side effects,while the other enantiomer has no pharmacological effects or even produces side effects.Therefore,preparation of a single optically pure drug enantiomer is of great significance.Currently,the most convenient and efficient method for preparing single enantiomers is chiral liquid-liquid extraction.In this paper,a biphasic system was constructed using a green and environmentally friendly chiral ionic liquid in order to perform chiral resolution.The enantiomeric separation of two types of chiral drugs,includingβ-blockers represented by propranolol and nonbisteroid anti-inflammatory drugs represented by flurbiprofen,was explored with chiral ionic liquid acting as both a solvent and a chiral extractant.The extraction conditions are optimized to provide ideas and preliminary research for the subsequent resolution process.Study on enantioseparation of lores by chiral liquid-liquid extraction of hydrophobic eutectic solvent（DES）/water biphasic system including the following:using menthol with chiral source as hydrogen bond acceptor（HBA）,lactic acid,malic acid and long chain carboxylic acid as hydrogen bond donors（HBD）,five hydrophobic eutectic solvents were synthesized.Then a eutectic solvent/water two-phase system was constructed to investigate the phase formation rules of the system.The experimental results show that the ability of hydrophobic DES to form biphasic with water depends on the solubility of HBD.The increase in water solubility of HBD will lead to the decreases of its ability.The chiral liquid-liquid extraction of menthol-lactic acid/water biphasic system was used for enantioseparation of the propranolol enatiomers,and the extraction conditions were explored.The experimental results show that menthol-lactic acid preferentially recognizes R-propranolol.The extraction effect is best when the ratio of DES and H₂O is 1:1.25,the concentration of propranolol is 0.6 mg/m L,the p H value of the aqueous phase is 6.0,and the extraction time is 6 hours.Adding the chiral extractant HP-β-CD(when concentration is 2.0×10^-5mol/L)can form biphasic recognition chiral liquid-liquid extraction system,and the enantiomeric excess in the DES phase can reach39.65%.The reuse DES/water biphasic system still has good enantioseparation effects,and the system is effective for the other four types of Lolol drugs（metoprolol,atenolol,naldolol,and arololol）.Study on enantioseparation of ibuprofen drugs by chiral liquid-liquid extraction using chiral ionic liquid（IL）/organic solvent biphasic system including the following:Using green non-toxic choline hydroxide as a cation,the natural chiral L-amino acid as anion,chiral choline amino acid ionic liquid was synthesized.Then a biphasic system constructed with organic solvents and chiral choline amino acid ionic liquid.Choline-L-tryptophan ionic liquid/1,2-dichloroethane biphasic system was selected for chiral liquid-liquid extraction to resolve flurbiprofen enantiomers.The experimental results show that[Ch][Trp]preferentially recognizes R-flurbiprofen.When the biphasic volume ratio is 1:1,initial concentration of flurbiprofen racemate is 0.6mg/m L and the p H is 4.0,the extraction effect is the best.The addition of the chiral extractant DIPT at a concentration of 0.004 mol/L has a bidirectional recognition effect.The enantiomeric excess in the 1,2-dichloroethane phase can reach 43.85%.The IL/organic solvent biphasic system after reused for many cycles still has good chiral resolution.The system also has a certain enantioseparation effect on the other three ibuprofen drugs（ibuprofen,ketoprofen and indoprofen）,and the effect increases with the complexity of the drug structure.