The Synthesis Of Pyrimido[4,5-b][1,4]Benzodiazepines And Analogues

Priviledged structures represent a class of molecules capable of binding to multiple receptors with high affinity. Design and synthesis of structurally diverse libraries based on privileged structures were an efficient way to discover lead compounds. As a structural component of key biomolecules, pyrimidine moiety has been widely employed in design of privileged structures in medicinal chemistry. Benzodiazepines were first coined as the privileged substructure by Evans et al. in 1988. These compounds show a variety of biological effects predominately ascribed to their actions in the central nervous system.In Chapter One, the application of pyrimidine-fused heterocycles and benzodiazepines in drug design were reviewed. The Bischler-Napieralski-cyclization reactions in organic synthesis and our efforts to develop synthetic methods to prepare pyrimidine-fused heterocyclic scaffolds were summarized.Benzodiazepines were first coined as the privileged substructure by Evans et al. in 1988. These compounds show a variety of biological effects predominately ascribed to their actions in the central nervous system. Bischler-Napieralski-cyclization reaction was an efficient method in synthesis of benzodiazepine and has been used to prepare nitrogen containing heterocyclic compounds. The aim and significance of the dissertation were to design and synthesize pyrimidine-fused heterocycles scaffolds via Bischler-Napieralski-type cyclization reaction.In Chapter Two, an efficient method was developed for the construction of novel heterocyclic scaffolds 2-chloro-pyrimido[4,5-b][1,4]benzodiazepines, via a Bischler-Napieralski-type cyclization reaction. The resulting compounds are suitable for further manipulations, such as nucleophilic substitution reactions of the 2-chloro group to yield products with more diversity. Therefore, this new reaction is applicable to the preparation of large libraries of novel scaffolds that are of interest in drug discovery.The starting pyrimidines 5-amino-4-(N-alkylphenylamino)-2-chloropyrimidins were readily prepared from commercially available 2,4-dichloro-5-nitropyrimidine in high yields. The cyclization reactions of 5-amino-4-(N-alkylphenylamino)-2-chloropyrimidins with various acids were investigated and these reactions proceeded smoothly to yield products in the presence of excess amount of phosphorus oxychloride. The desired cyclization products were obtained in moderate to high yields.In Chapter Three, an efficient method was developed for the construction of novel heterocyclic scaffolds 2-chloro-pyrimido[4,5-b][1,4]thienodiazepines, via a Bischler-Napieralski-type cyclization reaction.In this chapter, The key precursor N-methylthiophen-2-amine was prepared by five steps from commercially available thiophene. The cyclization reactions with aromatic acids gave low yields. Then we obtained the desired cyclization products according to fractional step-one-pot process.