Synthesis And Process Optimization Of New Spiro-drug Lead Compounds Containing Quinoline Moiety Via 1,3-dipole Cycloaddition Reaction

Quinoline compounds,which have usually been found in many drug molecules and natural products,are an important class of heterocyclic compounds.They also show a variety of bioactivities and pharmacological activities,such as malaria,anticancer,antivirus,antitumor,and sterilization,etc.Meanwhile,spiro compounds represent an important class of naturally occurring compounds characterized highly pronounced biological properties.In this dissertation,by using multicomponent reaction"one pot method",some novel spiro-compounds containing quinoline moiety were synthesized successfully through 1,3-dipolar cycloaddition reaction.The work of this thesis is mainly carried out from the following three parts:1. First,the progress and application of quinoline derivatives in new drug research are introduced.Secondly,the research progress of 1,3-dipole cycloaddition reaction and multi-component reaction is reviewed.2.42 new quinoline derivatives were prepared by[3+2]cycloaddition of?E?-3-?2-phenoxyquinoline-3-group?-1-phenylacetone-2-ene-1-keto/?E?-3-??2-phenox yquinolin-3-yl?methylene?-1-phenylpyrrolidine-2,5-dione with azomethine ylides generated in-situ from isatin and N-methyl glycine.The effects of reaction temperature,reaction time and reaction solvent on cyclization were investigated.In addition,comparing with the different substituent group in benzene ring,the results show that the electronic effect of substituents has little to do with yield,and the cycloadducts were isolated in modest yields and only one isomer was isolated in each reaction.3. Fourteen new spiro-compounds with quinoline moiety were synthesized by one-pot method of the dipoles formed by in-situ reaction of hydrin,o-phenylenediamine,L-proline and the newly synthesized dipolarophiles containing quinoline rings.At the same time,the optimal reaction conditions were determined:refluxed in methanol for 3h at the boiling temperature.The structure of the target product was confirmed by two-dimensional spectrogram and the possible reaction mechanism was proposed.The structures of 56 new compounds prepared in this paper were verified by¹HNMR,¹³CNMR and MS.At the same time,two single crystals were cultured,and the spatial configuration of the target product was determined by X-ray diffraction analysis of the single crystal.