Studies On Chromatographic Enantioseparation Of 2-Thiohydantoin And Dihydrobenzofuranacetic Acid Derivatives

It is well-known that different enantiomers exhibit different properties of pharmacology,pharmacokinetics and toxicology.In pharmaceutical industry,preparation of high optical purity chiral drugs can not only avoid the side effects and metabolic risk from the invalid enantiomorphism isomers,but also can lower the dosage of chrial drugs.Therefore,quality control studies become more and more important for the chiral drugs and their drag-like derivatives or intermediates.Currently,our country is at the critical stage of drug discovery and urgently need quality control technology for the new chiral drugs with novel scaffold.Recently,chiral separation based on chromatograph has become the most important method for quality control of chiral drugs.In our studies,two chiral drug derivative and intermediate have been investigated for their enantioseperation using CSP.As a five-membered heterocyclic compounds,2-thiohydantoin possessed a variety of properties and have been widely used in life sciences,agriculture and synthetic chemistry.This series of compounds have antibacterial and antitumor activities according to the literature report.Recently,scientists found that 2-thiohydatoin derivative Nec-1 belongs to cell necrosis suppressor which could inhibit RIP1 kinase.There is a chiral center in its structure,and the activity of the R isomer is significantly higher than that of the S isomer.Therefore,the establishment of chiral separation method for 2-thiohydantoin compounds using chromatographic method is very important for the quality control.GPR40 belongs to G protein-coupled receptor and mainly distributed in pancreatic β cells,gut K and L cells.It can be activated by free long chain fatty acids by increasing intracellular Ca2+ concentration for promoting insulin release and has been considered as a new drug target for the treatment of type II diabetes.There are many different structures of GPR 40 agonists and 2-dihydrobenzofuranacetic acid derivatives are one of the most active scaffold.Due to the chiral center in its structure,it is necessary to establish a method for enantioseperation of these compounds.In this paper,eight 2-thiohydantoin compounds and three dihydrobenzofuranacetic acid derivatives were enantiomeric separated on Chiralpak IA column and Chiralpak IC column.The separation conditions of the chiral compounds were investigated systematically under the normal phase system.The effects of the structure,concentration and column temperature of the alcohol modifier on the chiral separation were studied and then investigated the mechanism of enantioseparation.In our studies,we also observed the phenomenon of solvent type induced and temperature induced elution order reversal.The mechanism of chiral separation includes entropy-driven and enthalpy-driven process.In addition,capillary electrophoresis method was used as enantioseparation method for dihydrobenzofuran ethyl acetate and this work provides a new and simple method for the quality control on related chiral drugs and their intermediates.