Design And Synthesis Of Pyridobenzodiazepine Library With Multiple Diversification Points

Benzodiazepines, as an important"privileged structure"have attracted considerable attention in the field of the pharmacology and organic synthesis. This dissertation involves the synthesis of pyridobenzodiazepines.In Chapter One, the biological activities and synthetic methodologies of the benzodiazepine compounds are summarized. Generally speaking, there are two methods widely used in literatures: the cyclization of the substituted benzene derivatives, and rearrangement of the proper cyclic precursors. According to the reaction types of the syntheses of benzodiazepine from the substituted benzenes, three methods are employed: the condensation of the carbonyl and amide groups, crossing couplings of the amide and halogen groups, and intramolecular cyclization reaction. However, no example is reported as far as we have known for the synthesis of pyridobenzodiazepine in the Bischler-Napeiralski or Pictet-Spengler type cyclization method, while it has been extensively investigated in the synthesis of tricyclic benzodiazepine compounds.Pyridobenzodiazepine, an important privileged structure, is widely found in the inhibitors of HIV-1 receptor, muscarinic receptor, vasopressin V2 receptor and agents to modulate activities of the central nervous system. The synthetic strategies to pyridobenzodiazepines are generally relied on the preparation of the key lactam ring systems and subsequently functionalization of the heterocyclic scaffold to introduce other substituents with various carbon-derived substituents at the 6-position of the central heterocycle core. In this dissertation, we have employed intramolecular cyclization reaction to build up the C6-substituted Pyridobenzodiazepines library.In Chapter Two, we have investigated the experimental conditions for the syntheses of pyridobenzodiazepine compounds. The method is featured by the facile synthetic route, mild condition, commercially available starting materials and high yield etc. Significantly, the new method was exemplified by the preparation of a novel 41-member pyrido[2,3-b][1,4]benzodiazepine library.It has demonstrated that the target compounds could be obtained in moderate yields with various carboxylic acids such as, aromatic aliphatic and heterocyclic acids etc. This reaction appears to be sensitive to the electronic effects. An electron-donating group on the aromatic acid tends to accelerate the reaction in higher yields, while an electron-withdrawing groups leads to prolong the reaction time in lower yields. No obvious influence is observed on the effects of the substitution position as far as we have investigated. This reaction is also sensitive to the steric effects of the aliphatic acids because the presence of a bulky group slows the reactions, resulting in prolonging the reaction time. Moreover, current strategy shows that it leads to the lower yield for the heterocyclic acids, comparing with the benzoic acid.When a substituent group, either electron-donating or electron-withdrawing groups, is attached to the pyridine-2,3-diamine at the para-position, the reaction goes well (46%~96%). The electron-donating groups lead to the fast reaction in higher yield, on the contrary, the electron-withdrawing groups lead to slow the reaction in a lower yield. However, it is not legible to make a definite conclusion on the electron effect. When it is substituted at the meta-position, two isomers are obtained. And the reaction is slower when substituted at the orth-position.To expand the scope of the synthesis, 5 pyrido[4,3-b][1,4]benzodiazepine compounds were prepared. Given that numerous anilines and carboxylic acids are readily available the method demonstrated could be readily adopted to prepare large pyridobenzodiazepine libraries. The current strategy should complement existing methodologies to enable rapid exploration of biological activities for this class of heterocycles.In Chapter Three, we explored the feasibility for the synthesis of pyridine-fused 5,6-dihydrobenzodiazepines by using the Pictet-Spengler reaction. Experimental results have shown that only one reaction condition (a mixtuer of 4-nitrobenzaldehyde and N2-methyl-N2-m-tolylpyridine-2,3-diamine (in the ratio of 1:1.5 equiv.) with excessive TFA under reflux) could give the desired products. And the rest reaction conditions of diamines and corresponding aldehydes led to the imine products. It is worth noting that pyridine-fused 5,6-dihydrobenzodiazepines could be catalytically reduced from pyridobenzodiazepin compounds.