Synthesis Process Study Of Polysubstituted Pyrrole,Furan And Isoxazoline As Drug Skeleton

The preparation and production of five-membered heterocyclic drugs is a major research content in the field of pharmaceutical engineering.Five-membered heterocyclic skeletons such as furan,pyrrole,thiophene,and isoxazole exist as important functional structures in various drug molecules.Therefore,construction of these heterocyclic skeletons is often a key step in the synthesis and preparation of such drug molecules.This paper investigates the innovative preparation process of 2-amino-3-cyanofuran derivatives and 2-amino-3-cyanopyrrole derivatives,which are important drug intermediates.And a series of 3,5-diaryl-4,5-dihydroisoxazole derivatives with potential drug activity were designed and synthesized.Part I:A novel synthetic route of ethyl 5-amino-4-cyano-3-aryl-1H-pyrrole-2-carboxylates,as important synthetic precursors of pyrrole drugs,was studied.This effective route was as follows:2-benzylidenemalononitriles(1 mmol,1.0 equiv),ethyl glycinate hydrochloride(2.5 mmol,2.5 equiv),and iodine(0.2 mmol,0.2 equiv)in DMF(5.0 mL)at 120℃ for 20 h under air.Finally,twenty ethyl 5-amino-4-cyano-3-aryl-1H-pyrrole-2-carboxylate were obtained under the optimizing reaction conditions.All target products were characterized by NMR,HR-MS,and IR.In addition,a single crystal was cultured and its structure was determined by single crystal X-ray diffraction.This synthesis route obtains the advantages of cheap and readily available raw materials,mild reaction,simple steps,excellent yield,easy post-treatment,and transition-metal-freePart II:A novel synthesis route of 2-amino-3-cyanofuran,an important intermediate in drug synthesis,was realized.First,1,1-dicyanocyclopropane was synthesized from benzylidene propionitrile and acetophenone pyridinium salts.After that,21 desired products were synthesized in 55-81%yield by using 1,1-dicyanocyclopropanes as reaction material in the presence of DBU as the promoter and DMF as the solvent at 120℃ for 8-12 hours.All products were determined by HR-MS,1H NMR,13C NMR,and IR.Single crystal structures of six desired products were confirmed by X-ray diffraction method.This process gets the advantages of cheap and easy-to-obtain raw materials,mild reaction,simple post-treatment,and transition-metal-free.Part III:A series of 3,5-diaryl-4,5-dihydroisoxazole derivatives with potential drug activity were designed and the optimal synthetic route was developed.Firstly,a series of substituted 1,1-dicyanocyclopropanes were synthesized from the corresponding substituted 2-benzylidenemalononitriles and acetophenone pyridinium salts.Then,ten 3,5-diary1-4,5-dihydroisoxazole derivatives with different substituents were successfully synthesized from 1,1-dicyanocyclopropane and hydroxylamine hydrochloride by controlling the reaction temperature at 40℃ or 80 ℃.All 3,5-diaryl-4,5-dihydroisoxazole derivatives were characterized by IR,NMR,and HR-MS.In addition,two single crystals were successfully cultured and its structure was determined by single crystal X-ray diffraction.