Synthesis,Antitumor Activity of 2-amino-Pyrrole/pyridine Derivatives and 2-alkylthio-4-aminoquinazolines

Author:Liu Jin

Supervisor:lin jun


Degree Year:2018





2-Aminopyrrole/pyridine represents privileged heterocyclic motifs exist in numerous biologically active natural products,important synthetic compounds and organic functional materials.As so,it is very important for the development of novel,highly efficient,concise and environmentally benign methods for the preparation diverse 2-aminopyrrole/pyridine derivatives.This thesis is based on the diversity oriented synthesis(DOS)and green chemistry strategy,five types of heterocyclic derivatives containing 2-aminopyrrole/pyridine motifs were constructed by the reaction of heterocyclic ketene aminals(HKAs)and 1,1-enediamines(EDAMs).With the same strategy,a series of 2-alkylthio-4-aminoquinazolines with inhibition of cell division cycle 25B phosphatase(CDC25B)and antitumor activity were synthesized.This dissertation is composed of six chapters.In Chapters 1,a mini review about the methods to synthesis of 2-aminopyrrole/pyridine derivatives and the reaction that based on building blocks(HKAs)were presented.Diversity-oriented synthesis and green chemistry strategy were described.the research thought,the main content and research methods were introduced.In Chapters 2,an efficient synthetic strategy to construct 2-aminopyrrole derivatives was developed via cascade reaction of Morita-Baylis-Hillman(MBH)acetates with heterocyclic ketene aminals(HKAs)/1,1-enediamines(EDAMs).13 fully subsituted pyrrole derivatives and 25 pyrrolo[1,2-a]pyrimidine derivatives were synthesized with a yield of 73-91%(Scheme 1).Scheme 1 Synthesis of pyrrolo[1,2-a]pyrimidines and fully subsituted pyrrolesIn Chapters 3,the Michael addition/cyclization reaction of HKAs and N-substitut-ed maleimide under catalyst-free condition was studied.34 highly substituted bicyclic pyrrolidinone derivatives were synthesized with a yield of 20-96%(Scheme 2).Scheme 2 Synthesis of bicyclic pyrrolidinone derivativesIn Chapters 4,the regioselective acylations and intramolecular annulations of HKAs with methacrylic anhydride or crotonic anhydride under neutral conditions was studied.30 substituted bicyclic 2-pyridones derivatives were synthesized with a yield of 83-95%(Scheme 3).Scheme 3 Synthesis of bicyclic 2-pyridones derivativesIn Chapters 5,the nucleophilic substitution/cyclization reaction of EDAMs and 4-chloro-3-formaldehyde coumarin was studied.31 2-amino-1-nitro-5H-chromeno[3,4-c]pyridin-5-one derivatives were synthesized with a yield of 72-93%(Scheme 4).Scheme 4 Synthesis of 2-amino-l-nitro-5H-chromeno[3,4-c]pyridin-5-one derivativesIn Chapters 6,we have developed an environmentally benign protocol for the synthesis of fluorinated 2-alkylthio-4-aminoquinazolines,under microwave irradiation conditions,using basic alumina as solid support as well as base catalysts.29 compounds were synthesized with a yield of 60-92%.Most target compounds exhibited excellent inhibitory activity against CDC25B as well as good antitumour activity.Scheme 5 Synthesis of fluorinated 2-alkylthio-4-aminoquinazoline derivativesIn conclusion,based on the background and significance of target compound research as well as the diversity oriented synthesis and green chemistry strategy,six series of 162 novel heterocyclic compounds were synthesized and characterized by spectroscopic data.The plausible reaction mechanism was proposed,and the reaction conditions were optimized and improved.This thesis provides some alternative ways for the synthesis of highly substituted 2-aminopyrrole/pyridine and 2-alkylthio-4-aminoquinazoline derivatives.In addition,some target compounds exhibited different inhibitory effects against tumor cell lines.