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

The dissertation deals with the preparation of 6,7-dihydro-5H-pyrimido [4,5-e][1,4]diazepin-8(9H)-one via intramolecular lactamization as the key reaction step. It is divided into two chapters.In Chapter One, we summarized the biological activity and synthetic methods of pyrimidine fused diazepin-ones and their analogues. Pyrimidine and diazepin-ones are hybrided by two privileged structures, pyrimidine and diazepine. The bicyclic pyrimido[4,5-e][1,4]diazepines were reported to exhibit a variety of biological activities. For example, some derivatives are known as tachykinin receptor antagonists, anticonvulsant agents, cysteine protease inhibitors and raf kinase inhibitors.Despite interesting biological activities, the synthetic methods for pyrimido[4,5-e][1,4]diazepines are limited in the literature, we were only able to find one method for the synthesis of pyrimido[4,5-e][1,4]diazepin-8(9H)-one derivative prepared by a intramolecular coupling reaction of 2-(((4-amino-6-(methoxy carbonyl)pyrimidin-5-yl)methyl)(methyl)amino)acetic acid.In chapter two, practical methodology was developed for the synthesis of 6,7-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-8(9H)-one derivatives. This synthetic strategy is based on intramolecular cyclization of amino acid ester substituted 4-aminopyrimidines to construct the pyrimido[4,5-e][1,4]diazepine core. However, under the ring closing conditions of sodium ethoxide, the desired results could not be achieved. In view of this, we modified the route, Finally, nucleophilic substitution of chloromethylpyrimidine by various racemic amino acid esters provided 13 cyclization precursors in high overall yields.In the cyclization step, we explored sodium hydride/tetrahydrofuran and room temperature for the cyclization conditions and then achieved the desired cyclization product with moderate yield. The successful route is as follows: Reduction of the formyl group in compound 4-amino-6-chloropyrimidine-carbaldehyde with NaBH4 in MeOH furnished the corresponding alcohol derivatives (4-amino-6-Chloropyrimidin -5yl)methanol in 92% yields. Compound (4-amino-6-Chloropyrimidin-5yl)methanol was treated with SOCl2 to lead to chloromethylpyrimidine 6-chloro-5-(chloromethyl) pyrimidin-4-amine. Nucleophilic substitution of compound 6-chloro-5-(chloromethyl) pyrimidin-4-amine by various racemic amino acid esters provided the cyclization precursors in high overall yields. Treatment of cyclization precursors with NaH in THF resulted the ring closure product .With the current condition 13 pyrimido[4,5-e][1,4]diazepin-8(9H)-ones were produced in moderate to high yields. As expected, the ring closure reaction proceeded slower when the size of the R1 and R2 group was increased. The cyclization reaction tolerates various groups in the amino acid esters, such as alkyl, aromatic, hydrogen and hydroxyethyl groups.