Study On Enantioseparation Of Ketoprofen Through Chiral Liquid-liquid Extraction

Ketoprofen is a non-steroidal anti-inflammatory chiral drug,which has been widely used in clinical trials.It has been reported that only S-ketoprofen shows good performance on anti-inflammation,anti-rheumatism and analgesia,while R-ketoprofen almost has no pharmacological activities.Therefore enantioseparation of ketoprofen enantiomers has important practical value.In this paper,the enantioseparation process of ketoprofen racemate was studied by chiral liquid-liquid extraction.The main content can be summarized as follows:1.Enantioseparation of ketoprofen enantiomers using 1-butyl-3-methylimidazole L-tryptophan by extraction:Effect of four amino acid ionic liquids(1-butyl-3-methylimidazole L-tryptophan and 1-butyl-3-methylimidazole L-glutamic acid,1-butyl-3-methylimidazole L-phenyIalanine and 1-butyl-3-methylimidazole L-serine)on the extraction and resolution of ketoprofen enantiomers was studied.Through experimental comparison,[Bmim][L-Trp]was finally selected as a chiral extractant.The distribution behavior of ketoprofen enantiomers was performed in the extraction system,which is established by organic phase and adding[Bmim][L-Trp]in aqueous phase.The influences of the organic solvent,the concentration of chiral extractant,racemic ketoprofen,the pH of methanol aqueous solution and the volume fraction of methanol in the aqueous solution on enantioseparation were studied.The results show that enantioselectivity up to 1.30 was attained when 1,2-dichloroethane was used as organic solvent,the volume fraction of methanol in the aqueous solution was 10%,the aqueous soltion pH was 2.0,and the concentration of[Bmim][L-Trp]and racemic ketoprofen was 0.04 mol·L-1 and 100 ppm respectively.2.Study on enantioseparation of ketoprofen enantiomers by biphasic recognition chiral extraction:The distribution behavior of ketoprofen enantiomers was performed in the extraction system,which is established by adding diethyl tartrate in organic phase and[Bmim][L-Trp]in aqueous phase.The influences of the organic solvent,the concentration of chiral extractant,racemic ketoprofen,the pH of methanol aqueous solution on enantioseparation were studied.The results indicated that diethyl D-tartrate preferentially recognition S-ketoprofen,whereas diethyl L-tartrate had reverse recognition.The results showed that enantioselectivity up to 1.44 was attained when 1,2-dichloroethane was used as organic solvent,the aqueous soltion pH was 2.0,and the concentration of diethyl D-tartrate,[Bmim][L-Trp]and racemic ketoprofen was 0.3 mol·L-1,0.04 mol·L-1 and 100 ppm respectively.3.Simulation study on the interaction between amino acid ionic liquid and ketoprofen:Density Functional Theory(DFT)is used to conduct microscopic analysis of the interactions between amino acid ionic liquids and ketoprofen.Electrostatic Potential analysis(ESP)is used to predict the interaction sites.The geometrically optimized complexes are subjected to interaction energy calculation and Reduced Density Gradient function(RDG)analysis is performed.The simulation results show that both of[Bmim][L-Trp]and[Bmim][L-Ser]have a large interaction energy difference between R-ketoprofen complex and S-ketoprofen complex In another word,it demonstrates that these two ionic liquids have a higher selectivity,which is coherent with the experimental results.RDG analysis shows that the interaction between R-ketoprofen and[Bmim][L-Ser]and[Bmim][L-Trp]is stronger than that of S-ketoprofen and[Bmim][L-Ser]and[Bmim][L-Trp],which is due to the strong hydrogen bond and more van der Waals interactions.Therefore the[Bmim][L-Ser]and[Bmim][L-Trp]has a recognition effect on R-ketoprofen.4.The regeneration process design of extractant rectification:Aspen Plus process simulation software was used to simulate the distillation process of extractant diethyl D-tartrate and organic solvent 1,2-dichloroethane.The parameters of the distillation process were optimized to determine the optimal number of stages,feed position and reflux ratio.