Synthesis Of Novel 8,9-dihydro-5H-pyrimido[4,5-e][1,4]Diazepin-7(6H)-ones

The thesis deals with the preparation of pyrimido[4,5-e][1,4]diazepin-7(6H)-ones . It is divided into two chapters.In the first chapter, the biological activity and synthesis methods of pyrimido [4,5-e][1,4] diazepines were summarized, On the basis of the preliminary work in our laboratory, we introduced the purpose and significance of the experiment.The pyrimidine moiety was widely incorporated in the design of privileged structures in medicinal chemistry. Pyrimido[4,5-e][1,4]diazepines have been reported to exhibit a variety of biological activities. Multiple drugs on the market contain the skeleton of pyrimidine .According to reports, Pyrimido[4,5-e][1,4]diazepines contain the biological activity of NK1 receptor antagonist,cysteine protease inhibitors,Raf kinase inhibitor and anticonvulsant. Recently, seven synthetic methods of Pyrimido[4,5-e][1,4]diazepines were reported in the literature. while, we were only able to find one method for the synthesis of pyrimido[4,5-e][1,4]diazepin-8(9H)-one derivatives which were prepared by condensation of 2-cyano-5-((4-methoxyphenyl amino)methyl)-4-(neopentylamino) pyrimidine with chloroacetyl chloride. In recent years, a variety of pyrimidine molecular scaffolds were constructed for their privileged structure in our laboratory and we also built a compound library.In the second chapter, experimental design and synthesis work of pyrimido[4,5-e][1,4]diazepin-7(6H)-ones were introduced。4, 6-dihydroxy-pyrimidine are starting materials. after vilsmeier-hack reaction, amino acid ester substituted, aldehyde reduction, chlorination and other operations we got the precursor for cyclization , and successfully optimized cyclization conditions. Then we studyed on the relevant cyclization conditions via 21 different amines,experimental results showed that various amines in the reaction have a very good yield 57% -99%. 5 amino acid ethyl esters were also studied from 4,6 - dichloro -5 - formyl pyrimidine. Via substitution, reduction, chlorination we got cyclization precursors, the target compounds were obtained in cyclization via n-butylamine with yield of 55% -88%, the experimental results indicated that the route adapted to different amino acids. The reaction principles are as follows: (1) For aliphatic amines, the reaction temperature was increased as increasing the size of the aliphatic group .cyclization of aliphatic amines is easier than aromatic amines. (2) For aromatic amines, the reaction proceeded faster when aromatic amines with an electron-donating group compared to those with an electron-withdrawing group. When an ortho substituent is present in the aromatic amine, the reaction was slower than the corresponding meta and para substituted analogs , however, little effect on the yield. (3) For amino acid esters, the cyclization reactions involving phenylalanine ethyl ester required higher temperature to be completed compared to phenylglycine ethyl ester and glycine ethyl ester Similarly, reactions with larger groups also required higher temperature for completionThe chloro atom on the 8, 9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H) is highly reactive towards a nucleophile, such as an amine, alcohol, thiol, in addition to Suzuki coupling reaction ,which further increases the structural diversity of this novel scaffold. The above results provided an efficient methodology to prepare libraries of novel 8, 9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7(6H)...