Design And Synthesis Of Pyrimidine-fused Heterocyclic Scaffolds

The dissertation is divided into three chapters.In Chapter One,the application of privileged structures and pyrimidine-fused heterocyclic scaffolds in drug design were summarized.Discovery of lead compound was the beginning and key step in drug design. Design and synthesis of structurally diverse libraries based on privileged structures were an efficient way to discover lead compounds.Pyrimidine and pyrimidine-fused heterocyclic compounds have been widely employed in design of privileged structures in medicinal chemistry.Moreover,benzothiazepine and isoquinoline derivatives are well-known to exhibit diverse biological activities. Bischler-Napieralski reaction was an efficient method to synthesize nitrogen containing heterocyclic compounds and has been used to prepare benzothiazepine derivatives.The aim and significance of the dissertation were to design and synthesize pyrimido[4,5-b][1,4]benzothiazepine and pyrimido[5,4-c]isoquinoline scaffolds with potential applications in drug discovery.In Chapter Two,an efficient methodology to access to libraries of pyrimido[4,5-b][1,4]benzothiazepine scaffold via Bischler-Napieralski reaction was firstly developed.Four 5-amino-4,6-bisphenylthiopyrimidins were prepared by thiophenol substitution of the commercially available 5-amino-4,6-dichloro-pyrimidine. Then the precursors were treated with eight carboxylic acids or their derivatives under the catalysis of PPA/POCl₃ to lead to twenty pyrimido[4,5-b][1,4]benzothiazepine derivatives with 30%-98%yields.The results shown that the cyclization is suitable for various substrates.The isolation and characterization of intermediates supported that the cyclization may be mechanistically similar to the Bischler-Napieralski reaction.In addition,the selective oxidation of 4-arylthio groups to the corresponding sulfoxide compound with 75%-77%yields,which were converted to corresponding 4-n-butylamino-substituted pyrimido[4,5-b][1,4]benzothiazepines via nucleophilic substitution with 80%-90%yields.The above results provided an efficient methodology to access structurally diverse libraries of pyrimido[4,5-b][1,4]benzothiazepines.Finally,it was proved that the cyclization is unsuitable to prepare 8 or 9-membered heterocycles.To expand the scope of applications,an efficient strategies to access to structurally diverse libraries of pyrimido[5,4-c]isoquinolines via sulfur monoxide extrusion reaction were developed in Chapter Three.The scope of the sulfur extrusion reaction of pyrimido[4,5-b][1,4]benzothiazepines was investigated.The pyrimidobenzothiazepine sulfoxides were subjected to the thermal sulfur monoxide extrusion reaction,but no sulfur extrusions were observed for sulfide and sulfone analogues.Then the selective sequential oxidation of 4-arylthiopyrimido[4,5-b][1,4]benzothiazepines were investigated. 4-Arylsulfonylpyrimido[4,5-b][1,4]benzothiazepine sulfoxides were prepared with 52%-60%yields.The nucleophilic substitution of side-chain sulfone by n-butylamine afforded 4-aminopyrimido[4,5-b][1,4]benzothiazepine sulfoxides with 85%-92%yields,which were converted to the final 4-aminopyrimido[5,4-c]isoquinolines via thermal sulfur monoxide extrusion with high yields(80%-92%).The above results provided an efficient methodology to prepare libraries of pyrimido[5,4-c]isoquinoline with more diversities. Moreover,three approaches to access structurally diverse libraries of pyrimido[5,4-c]isoquinolines were developed.In the first,a one-pot procedure to prepare pyrimido[5,4-c]isoquinolines by combining the nucleophilic replacement and sulfoxide extrusion was explored.Various nucleophiles were readily introduced via the displacement of the 4-arylsulfonyl groups thereby generating additional structural diversification,but the reactions involving weak nucleophiles were more difficult.In the second, 4-arylsulfonylpyrimido[4,5-b][1,4]benzothiazepine sulfoxides were treated with ring sulfoxide extrusion and eventual nucleophilic substitution of the side-chain sulfone group to the desired pyrimido[5,4-c]isoquinolines.The efficiency to prepare 6-arylpyrimido[5,4-c]isoquinolines with a weak nucleophiles substituent at the 4-position was improved.Twenty-eight 6-arylpyrimido[5,4-c]isoquinolines were prepared via the above two approaches.In the third,a 4-step procedure, pyrimido[4,5-b][1,4]benzothiazepines were first carefully oxidized to the side-chain sulfoxide analogs followed by its substitution by a nucleophile to provide 4-substituted pyrimido[4,5-b][1,4]benzothiazepines,then oxidized again to the ring sulfoxides followed by sulfoxide extrusion to give the desired pyrimido[5,4-c]isoquinolines.The last two steps of the transformation could be carried out in a continuous operation without purification of the ring sulfoxide analogs to afford thirteen pyrimidoisoquinolines.This procedure expands the synthesis to 6-alkylpyrimido[5,4-c]isoquinolines.The three approaches complement not only to each other,but also to previously reported procedures to generate pyrimido[5,4-c]isoquinoline libraries with high structural diversity of pharmaceutically interests.