Study On The Synthesis Of Octadentate Tricyclic Complexes Of Lanthanide Ion Tb³⁺

Tb(Ⅲ)complex plays an important role in fluorescence analysis.It shows great stability,strong fluorescence intensity,large extinction coefficient and long fluorescence lifetime in the bioassay based on time-resolved fluorescence.In this paper,the synthesis of a Tb(Ⅲ)octadentate three membered macrocyclic complex was optimized.Its organic ligand is 2-hydroxy-m-benzenedicarbonamide derivative.As a bifunctional group,it can not only enhance the emission of characteristic light of Tb3+,but also covalently connect with biological substances such as protein.It is an excellent fluorescent immunoprobe and fluorescent marker.However,the reported research route is too long,the experimental technology is complex,and the economic factors limit its large-scale production,restrict its application in the field of fluorescence analysis,so we are committed to solve this series of problems in the research.Through literature research and experiments,the original research route has been improved,mainly in the following four aspects:(1)In this work,the starting material for the preparation of 2-hydroxy-m-benzenedicarbonamide derivative was changed from 3-methylsalicylic acid to 2,6-dimethylphenol,and then the active amide A was obtained by processing of methylation,benzyl oxidation,chlorination and acylation reaction.It is found that the yield of amide A can be effectively increased by using dimethyl sulfate as methylation reagent and acyl chloride as acylation reagent.(2)In the synthesis process optimization of symmetrical amines,the protective group Ts of aziridine was replaced by Cbz,and chloroethylamine hydrochloride was used as raw material.Subsequently,compound B was obtained by cyclization,Cbz protection,ring opening with ethylenediamine and Pd/C catalytic hydrogenation.This strategy circumvented the operation of long-time reflux and the employment of ion exchange resin with strong basicity,and reduced the steps of synthesis procedure.(3)In the original route of asymmetric amines,tertiary amines were prepared firstly,and then asymmetric amines were obtained by reduction ammonization and ring opening reaction with lysine aldehyde.Initially,our research on the synthesis of tertiary amine was not satisfactory until tertiary amine was replaced by ethylenediamine.From this,single reduction ammonization was achieved and ring was opened subsequently to furnish the target product.(4)The previous studies involved a complicated system in the cyclization procedure,a time-consuming after treatment and four steps to the aim product after cyclization.In this work,only two steps were needed to afford aim product after cyclization,which is the removal of methyl group and chelation reaction.And at the same time,the difficulties of crude product purification for the macrocyclic compound was resolved.Based on above-mentioned transformation,a new synthesis route has been accomplished for the target product.Through a series of process modifications,the fluorescent complex Tb-GlutLysBH(2,2)IAM was obtained through 27 steps.The method developed here is a general,convenient and economical process,which laid a foundation for large-scale production.