Synthesis Of Pyrimido [1,2-b] Indazole Derivatives

BackgroundThe Hu-FBPase controls the central sugar dysplasia substrate cycle of C3 compounds are the key step in the merged into glucose,a large number of studies have shown that FBPase designed for targets of hypoglycemic drugs is feasible in theory.And because from the AMP is Hu-FBPase the endogenous inhibitor,the design AMP analogues is a hotspot of research Hu-FBPase inhibitors.At present,the synthesis methods of Hu-FBPase inhibitors are basically piecewise and step by step synthesis,especially the construction of core skeleton often requires multi-step transformation.On the other hand,in order to fully study the structure-activity relationship of Hu-FBPase inhibitors,multiple paths are often required to achieve the introduction of different groups.In this paper,based on reasonable design and virtual screening,a new type of Hu-FBPase inhibitor rigid tricyclic pyrimido[1,2-b]indazoles was found,and a synthetic methodology was proposed to construct the core skeleton of pyrimido[1,2-b]indazole derivatives,laying a reliable foundation for the rapid construction of compound libraries by subsequent specific modification.ObjectiveTo establish a synthetic methodology for the construction of pyrimido[1,2-b]indazoles derivatives,and to synthesize a series of pyrimido[1,2-b]indazole compounds by extending different substrates.MethodUsing triethylamine,3-aminoindazole and benzaldehyde as template substrates,the conditions of constructing pyrimido[1,2-b]indazole,including the optimal reaction conditions of iodine,oxidant,solvent and temperature,were studied.Subsequently,the applicability of triethylamine as a C2 synthon to the synthesis of pyrimido[1,2-b]indazoles in 3-aminoindazole derivatives and aldehyde was investigated under optimal reaction conditions,and the application range of benzaldehyde and 3-aminoindazole substrates was studied.At the same time,the chemical structure of the target product was confirmed according to the NMR spectrum and mass spectrum data,and the structure of the compound was confirmed by X-ray single crystal diffraction.Results and ConclusionsUsing simple and easily available aromatic aldehydes,3-aminoindazole and triethylamine as raw materials,cheap and readily available NH₄I as the medium and chlorobenzene as the solvent,the selective control of pyrimidine cyclization was achieved without the use of metal catalysts and peroxides,and the yield was up to 95%.In particular,4-arylpyrimido[1,2-b]indazole derivatives were synthesized from cheap,stable and low-toxicity triethylamine by C-N bond cleavage as C2 synthon.A total of 32 derivatives of pyrimido[1,2-b]indazoles were synthesized,including 18 compounds with different groups on the pyrimidine ring and 14 compounds with different electron donor,electron acceptor and halogen substituents on the indazole ring.In addition,the synthesized4-arylpyrimido[1,2-b]indazole derivatives introduced a large number of functional groups and reaction sites that can be further specifically modified,laying a solid foundation for the subsequent discovery of new Hu-FBPase inhibitors through precise regulation.It is predicted that this research will have good applications in organic chemistry,pharmaceutical chemistry and material science.