Study On Enantioseparation Of Metoprolol By Enantioselective Liquid-Liquid Extraction

Metoprolol is widely used in clinic to treat cardiovascular diseases.It has been reported that(S)-metoprolol has much higher affinity for adrenaline than(R)-metoprolol and its inhibitory effect on isolated hearts is 33 times that that of(R)-metoprolol,while(R)-metoprolol can cause side effects such as dizziness and hallucinations.Therefore,obtaining optically pure(S)-metoprolol is of great significance for improving the effectiveness and safety of drugs.Enantioselective liquid-liquid extraction with industrialization prospects has the advantages of simple operation,low requirements on equipments,being capable of continuous production,etc.In this work,the green enantioseparation of metoprolol was studied by enantioselective liquid-liquid extraction.The main contents can be summarized as follows:1.The interaction between different amino acid ionic liquids(AAIL)and metoprolol enantiomers was studied by quantum chemical calculation using density functional theory.Electrostatic potential analysis was used to predict the interaction sites between AAIL and metoprolol enantiomers,thus improving the computational efficiency of geometric optimization.Based on geometric optimization,the interaction energy difference could be used to guide the selection and prediction of AAIL kinds.The topological analysis of electron density and reduced density function were used to analyze the chiral recognition mechanism.2.The results of quantum chemical calculation were verified by enantioselective liquid-liquid extraction experiments and the experimental results were consistent with the quantum chemical calculation results.The system with 1-butyl-3-methylimidazolium L-tryptophan([Bmim][L-Trp])as the chiral selector has a higher enantioselectivity for metoprolol.And the influences of the concentration of chiral selector,the organic solvents,the initial concentration of metoprolol,the pH of aqueous phase and temperature on the distribution coefficients and the enantioselectivity were investigated using[Bmim][L-Trp]as a chiral selector.And the suitable conditions of the enantioselective liquid-liquid extraction process were given.3.In order to develop a green and clean extraction separation process,a hydrophobic deep eutectic solvent(DES)was substituted for the traditional organic solvent for enantioselective liquid-liquid extraction of metoprolol.The different kinds of low-viscosity hydrophobic DES with menthol as a hydrogen bond acceptor were synthesized.And menthol-based DES was characterized by structural characterization and melting point,viscosity,hydrophobicity and so on.Using the synthesized DES as the oil phase,the influences of different types of hydrophobic DES system,chiral selector types and concentration,temperature and the pH of the aqueous phase on the enantioseparation of metoprolol were investigated.And the suitable conditions were given.