Chrial Derivatives Preparation And Application Of D₀/D₈ PPZ-Pro

Chirality is one of the common features of the universe.Many enantiomers of the enantiomeric drugs have different physiological activities,and in most cases,only one drug enantiomer has significant pharmacological activity,and the other enantiomer has no pharmacological biological activity or toxicity.Amine compounds are important physiologically active substances.Chiral amine compounds present in the human body play an important physiological role.Therefore,the establishment of chiral amine compounds'analytical method is of great significance for chiral drugs and chiral metabolomics research.Currently,the combination of Isotope Coded Derivatization(ICD)and Liquid Chromatography-Mass Spectrometry(LC-MS)is applied to the analysis of chiral amine compounds.However,there are few isotope-labeled chiral derivatization reagents.Therefore,this paper develops a new isotope-labeled chiral derivatization reagent and uses LC-MS to establish a method for the separation and analysis of chiral amine compounds,which is applied to actual sample analysis.The analytical methods established in this paper will provide effective and reliable analytical testing tools for new drug development,metabolomics research and the discovery of disease biomarker.The main research contents are as follows:1.Synthesis of 1-(5-fluoro-2,4-dinitrobenzene by reaction of 1,5-difluoro-2,4-dinitrophenyl with methylpiperazine and methylpiperazine-d8 Base)4-methylpiperazine)(d0-PPZ)and d8-PPZ.Synthesis of(S)-l-(5-(4-methylpiperazin-1-yl)-2,4-dinitrophenyl)pyrrolidine by reaction of L-valine with do-PPZ and d8-PPZ,respectively 2-carboxylic acid(d0-PPZ-Pro)and d8-PPZ-Pro.The structure was characterized by nuclear magnetic,mass spectrometry and the like.2.This chapter studies the influence of derivatization reaction temperature and time on the yield of derivatization reaction,establishing the optimal derivatization reaction conditions of d0-Pro-PPZ and amine.The optimal chromatographic separation conditions are established by optimizing the mobile phase composition and ratio.Six chiral amine compounds used in this experiment(phenethylamine,naphthylethylamine,1-aminoindan,phenylalanine methyl ester hydrochloride,valine methyl ester hydrochloride,phenylglycine methyl ester salt Acid salt)are completely separated under this chromatographic condition(resolution:2.1-3.8).3.1-Amino indan is a metabolite of Parkinson's therapeutic drug.In order to detect 1-aminoindan in body fluids,this paper utilizes LC-MS/MS and establishes an analytical method for 1-aminoindan.The effects of Collision-Induced Dissociation(CID)of different energies on specific m/z ionic strength are investigated.When the CID is 17 eV,there is the characteristic fragment peak m/z=289.2(or 297.2).The 1-aminoindan is in 10 nmol/L to 100 nmol/L,and the concentration has a good linear relationship with the peak area.The lowest detection line is 50 fmol.The established analytical method is applied to 1-aminoindan analysis in actual samples(saliva).