Imidazolium Chloride Catalyzed Transamidation,Double-growth Metal Halide Exchange Synthesis Of Aromatic Heterocyclic Multiple Substitutions And Synthesis Of Aromatic Heterocyclic Polysubstituted Compounds TRK Targeting Inhibitor Loxo-101

Synthesis of amide bond and benzimidazole derivatives catalyzed by imidazolium chloride,double Grignard metal halogen exchange and the synthesis of TRK targeted inhibitor loxo-101,three parts above consists of this thesis.Part ?: Amide bond and benzimidazole are essential components of organic function compounds for drugs,which gives the great significance to the construction of these two fragments.Many literatures on the construction of amide bond and the synthesis of benzimidazole derivatives are available now,and a few efficient ones have been applied to industrial production practice.A simple method as we provide to construct amide bond and benzimidazole hydrochloride as a promoter which runs with low cost and high yield.Part ?: Based on the study of Grignard exchange reactions available,the selective bromine-metal exchange reactions on bromine substituted heteroaromatic compounds with acidic protons at non-low temperature have been studied in this paper.Combination i-PrMgCl and n-BuLi not only solves the intermolecular quenching problem when alkyl lithium is used as halogen-lithium exchange reagent alone,also exhibits good selectivity.Part ? :Tumors are now seen as a financial burden on every developing and developed country,with the increasing number of aged population in china,the incidence of tumor rises dramatically.Among those put threat to human lives,lung cancer is one of the malignant tumors whose incidence rate rises fastest.Therefore,it is particularly important to enhance the drug research on lung cancer treatment as well as the drug resistance showed by tumors.Loxo101 lung cancer inhibitor by loxo Oncology and Bayer joint research is designed to treat a variety of locally advanced or metastatic solid tumors in adults and children,which exhibits good activity and no clear selectivity to cancers.For patients with NTRK fusion,the effective rat-e is up to 76%.It has been reported loxo-101 is mainly synthesized by using 5-chloro-3-nitro-pyrazolo [1,5-a] pyrimidine as parent nucleus and 2-(2,5-difluorophenyl)-pyrrolidine and 3-hydroxypyrrolidine as branched chains,respectively.Compared with the present synthesis methods of loxo101 available on literatures,this study aims to devise a superior route of loxo101 with much more feasibility to meet industrial demand.Pyrazole [1,5-a] pyrimidine was synthesized from 2-aminopyrazole in one step,and then the parent nucleus 5-chloro-3-nitro-pyrazole [1,5-a] pyrimidine was obtained by nitration and chlorination of phosphorus oxychloride.1-Bromo-2,5-difluorobenzene with pyrrolidine borate proceeded with Suzuki coupling,chiral 2-(2,5-difluorophenyl)-pyrrolidine was obtained by hydrogenation and chiral resolution,and chiral 3-hydroxypyrrolidine was purchased from the market.loxo-101 was obtained via Buchwald-Hartwig coupling after amidation of these three intermediates.In synthesis of the branched chain 2-(2,5-difluorophenyl)-pyrrolidine,the fact that hydrogenation of 2-(2,5-difluorophenyl)-pyrrole requires both high temperature and pressure to proceed was found,which led us to drop the idea of hydrogenation of 2-(2,5-difluorophenyl)-pyrrole.Other schemes are applied to approach this instead.The progress of targeted inhibitors of non-small cell lung cancer(NSCLC)domestically and abroad in recent years is reviewed in this study.