Synthesis Of Fused 1,5-benzothiazepines And Multiple Ester Groups-substituted 1,5-benzodiazepines Via Tandem Reaction

1,5-benzazepine derivatives(sulfur nitrogens,diazepines)which have unique biological and pharmacological activity are a class of compounds fused with a benzene ring and a seven-membered heterocyclic ring.They play an prominent role in antispasmodic,anti-anxiety,antibacterial,anti-inflammatory and antiviral.1,5-benzothiazepines and 1,5-benzodiazepines which are the core structure of many commercial drugs have been used in the treatment of cardiovascular and central nervous system disorders,cancer,AIDS and other diseases.Studies have shown that the introduction of polycyclic structures or the active group ester will make them have a variety of different physiological and pharmacological activities.In modern organic chemistry,the formation of complex molecules from simple and widely available substrates in an inexpensive and environmentally friendly manner is a difficult task.The tandem reaction one-pot synthesis method has the advantages of high atom economy,energy saving and consumption reduction,which meets the requirements of green chemistry.In view of this,two green and efficient tandem reactions were developed for the one-pot synthesis of polycyclic fused1,5-benzodiazepine compounds and multiple ester groups-substituted1,5-benzodiazepine compounds in this paper.The specific research work is as follows.1.A synthetic method of indene/naphthalene ring polycyclic fused1,5-benzothiazepines catalyzed by green Lewis acid Ce Cl₃ has been developed via tandem reaction one-pot synthesis.With substituted o-aminothiophenol,substituted1-indene/naphthone and ethyl glyoxylate(2-formyl thiazole,2-formyl pyridine)as raw materials,36 novel 2-position ester or aryl substituted indene/naphthalene ring fused 1,5-benzothiazepines that have not been reported in literature were obtained via three-component tandem reaction with Ce Cl₃ as acidic catalyst in ethanol at room temperature.32 kinds of target compounds are imine configuration and 4 kinds of them are enamine configuration in yield of 76-89%.The conditions of the three-component tandem reaction were optimized and screened and a reasonable catalytic synthesis mechanism was proposed.The obtained target compounds were all analyzed by ¹H NMR,¹³ C NMR,IR,MS and elemental analysis.Combined with the X-ray single crystal diffraction results of compound 5bca and 5acb crystals,the correctness of the target product structure was confirmed.The theoretical research calculation of the imine or enamine configuration of the target compound was carried out.The synthesis method abandons the traditional and inefficient step-by-step synthesis of 1,5-benzothiazepine compounds and has the advantages of novel method,environmental protection process,simple operation and high atom economy.2.A synthesis method of 1,5-benzodiazepine compounds substituted by multiple ester groups and having an exocyclic double bond(Z configuration)has been developed via one-pot and tandem reaction.With substituted 1,2-phenylenediamine,diethyl 1,3-acetone dicarboxylate,2,3-dicarbonyl compounds(2,3-butanedione,ethyl pyruvate,ethyl benzoylformate)as the raw material,18 novel 1,5-benzodiazepines substituted by multiple ester groups and having an exocyclic double bond which is Z configuration were obtained via one-pot tandem reaction with PTSA as acidic catalyst in ethanol at room temperature.The reaction didn't require isolation of intermediates and underwent nucleophilic addition,elimination of dehydration,intramolecular hydrogen transfer and cyclization.The experimental process was screened and optimized and a reasonable catalytic reaction mechanism was proposed.All target compounds were characterized by ¹H NMR,¹³C NMR,IR,MS and elemental analysis.The X-ray single crystal diffraction analysis and Gaussian calcultion of compound Vda proved the correctness of the structure of the target compound.The tandem reaction method has green process,mild conditions,short reaction time which provides an efficient and simple synthetic route for 1,5-benzodiazepine compounds and the highest yield can reach 86%.