Study On The Synthesis Of Pyridazinespirobenzosultam

Benzosultams have an important pharmacodynamic functional group sulfonamide group,which plays an important role in medicinal chemistry.Studies have found that these compounds have multiple biological activities such as anti-virus,anti-cancer,anti-microbial,anti-malaria and anti-leukemia,and are widely used in the fields of medicine and agriculture.Pyridazines have a variety of biological activities such as antibacterial,insecticidal,weeding,plant growth regulation and anti-virus.They are often used in agricultural fields as environmentally friendly pesticides.The Diels-Alder reaction is the most efficient and convenient way to construct six-membered cyclic compounds.It has been successfully applied to the synthetic route of natural products such as cyclooxygenin and paclitaxel.In view of the potential biological activity of benzosultams and pyridazines,designing and synthesizing new structure containing pyridazines and benzosultam motif,and testing their antibacterial and antiviral activities have become new research hotspots in this field.The main content of this thesis includes the following aspects:（1）3-substituted benzisothiazole 1,1-dioxide was synthesized by Grignard reaction when o-benzoylsulfonimide was used as raw material.A series ofα-haloacylhydrazone compounds with different substituents were synthesized by chlorination condensation reaction which substituted acetophenone was used as substrate.（2）3-substituted benzoisothiazole 1,1-dioxide andα-haloacylhydrazone were used as substrates to obtain pyridazinobenzosulfonylactam by inverse electron demand Diels-Alder reaction.（3）The Diels-Alder reaction was optimized in terms of solvent,base type,reaction temperature and time,and the optimum reaction conditions were obtained.（4）By studying the effect of substituents in the substrate on the reaction,it was found that the reaction was greatly affected by steric hindrance and electronic effect,and the highest yield reached 93.4%.（5）The gram-scale reaction was explored and the yield did not change significantly,which indicated that the reaction has good applicability.（6）The structures of the compounds were characterized by ¹H NMR,¹³C NMR and HRMS.The configuration of the products was determined by X-ray single crystal diffraction.The regioselectivity of the reaction was analyzed by density functional theory calculation and frontier orbital theory.（7）The antimicrobial activity of new pyridazinespirobenzosultam compounds was investigated.The results showed that different substituents had different effects on the antimicrobial activity of pyridazinespirobenzosultam compounds.When the substituents were electron-donating groups,the antimicrobial activity of the compounds was enhanced.In this thesis,a series of pyridazinespirobenzosultam compounds were synthesized which 3-substituted benzoisothiazoles 1,1-dioxides andα-haloacylhydrazone were used substrates by invers electronic demand Diels-Alder reaction.This method has the advantages of high regional selectivity,mild reaction conditions and wide range of substrates,which provides a methodical basis for the synthesis of pyridazinespirobenzosultam compounds.The inhibitory activity of pyridazinespirobenzosultam compounds against Salmonella paratyphi B was studied,which provided important reference value for further discovery of these compounds with better biological activity.