Chiral Stationary Phases Based On Optically Active Polymers: Synthesis And Their Chiral Resolution Performance

Chirality is one of intrinsic properties of the nature.For a natural chiral compound, the enantiomers are usually different in quantity,in some cases a single isomer exists exclusively.Drug action is the result of pharmacological and pharmacokinetic processes,by which it enters,interacts and leaves the body.There is a broad range of examples where the stereoisomers of drugs show differences in terms of their bioavailability,distribution,metabolic and excretion behavior and where stereochemical parameters have a fundamental significance in their action and disposition in biological systems.This exquisite stereoselectivity which can occur in many of the metabolic routes of a given drug or xenobiotic has to be carefully consid ered when its development is envisaged or its safety is evaluated.Chiral technologies include both asymmetric synthesis and optical resolution of racemates,which is very important to the development of chiral drugs.Optical resolution,especially,the high-performance liquid chromatography(HPLC) enantioseparation based on chiral stationary phase(CSP)is most easy and low-cost process for developing of chiral drugs.Therefore,in recent decades more and more attention has been paid to the investigation on new chiral materials for CSPs,the structure-property relationship and the chiral resolution technology with high efficiency.In this present work,a new type of N-phenylacrylamide derivatives has been developed,in which a chiral oxazoline moiety substitutes at ortho-position of phenyl group(denoted as OPAMs).The corresponding pre-polymers were obtained by the radical polymerizations of OPAMs in the presence of(3-mercaptopropyl)trimethoxysilane (MPS).The poly(OPAM)-based CSPs have been prepared by the coupling reaction between the pre-polymers and macropore silica gel,and their resolution performance has been examined under the inverse HPLC conditions.This study covers mainly the following parts:1.The synthesis of optically active pre-polymers and corresponding CSPs.By changing polymerization conditions,such as the monomer concentration,MPS concentration,and the content of Y(OTf)₃ in reaction media,a series of pre-polymers with different molecule weights and specific rotations have been synthesized.The corresponding polymer-bonded CSPs were prepared by "grafting to" method,and their structures were characterized by elemental analysis(EA),thermogravimetry analysis(TGA),and FT-IR.2.The evaluation of chiral resolution ability.The chiral resolution ability was examined under the reverse phase chromatography conditions towards nine racemates including phenylalanine,aspartic acid,valine,serine,alanine,proline,lysine,malic acid,and mandelic acid.The results showed that racemic aspartic acid,valine,serine and alanine could be separated by these CSPs,and poly(PhOPAM)-based column exhibits a moderate resolution performance.The relationship between the structure of CSPs and optical resolution has been elucidated in some extent.The effects of flow rate,organic addition content were also studied.The optimum operation parameters for the effective separation of enantiomer covered the followings:flow rate=1ml/min, H₂O eluent.3.The chiral separation performance of poly(OPAM)-bonded CSPs under a chiral ligand exchange chromatography(CLEC)mode.The effects of pH of the mobile phase and the concentration of the center ion Cu²⁺were studied.The optimum operation parameters for the effective separation of enantiomer covered the followings:flow rate=1ml/min,pH=7.0,Cu(Oac)₂-H₂O eluent with[Cu²⁺]of 0.1mmol/L.In addition,the elution order of enantiomers has been determined by comparison of the chromatogram of optically pure isomers.