Green Synthesis And Structure Characterization Of 4(3H)-Quinazolinones

Quinazolinones are a class of important organic compounds, which widely exist in natural products. For example, natural products febrifugine, isofebrifuzine and neodichroine were found in natural plant Dichroa febrifuga; natural products vasicinone and deoxyvasicinone were found in Adhatoda vasica; natural product luotonin A was found in the natural plant Peganum nigellastrum Bunge, etc. Quinazolinones have a wide range of pharmacological activities, such as anticancer, antibacterial, antifungal, antimalarial, antitubercular, antivirus, anticonvulsant, central nervous system depressant, cholinesterase inhibition, opioid receptor antagonist, anti Parkinson’s, anti histaminic, anti-inflammatory, hypolipidemic, antihypertensive, anti hyperglycemic, etc. In this paper, we have studied the synthesis of 2-substituted and 2,3-bisubstituted quinazolinones and comprehensively analyzed the structure of quinazolinones.The paper is divided into four parts:Chapter 1 is the first part, mainly review quinazolinones in the following three aspects:(1) natural occurrence of quinazolinone derivatives;(2) the extensively pharmacological activities of quinazolinones;(3) various synthetic methods of quinazolinones.The second part is chapter 2. We mainly studied the reaction of anthranilamide and benzyl bromide catalyzed by copper to synthesize the 2-substituted-4(3H)-quinazolinones and 2,3-bisubstituted quinazolinones. We eventually discovered the optimal condition through studying the influencing factors: copper catalyst, base, solvent, temperature and time.(1) The optimal condition in the reaction between anthranilamide and benzyl bromide catalyzed by Copper are: CuBr(0.02eq), K2CO3(1.0eq), DMSO, 120℃, 24 h. And under the conditions the yield of 2-phenyl-4(3H)-quinazolinone is 97%.(2) We have studied the scope of the reaction under this optimal condition. we have researched the reaction between a sort of anthranilamides and benzyl bromide derivatives. The results indicate that this synthetic method is common adapted to the reaction of anthranilamides and benzyl bromide derivatives.(3) A mechanism for the reaction of anthranilamide and benzyl bromide catalyzed by CuBr is proposed. Firstly, in the presence of K2CO3, anthranilamide and benzyl bromide react via SN2 nucleophilic substitution to yield the intermediate 2-(benzylamino)benzamide. Secondly, the intermediate is oxidated to give the intermediate imines catalyzed by CuBr. Thirdly, the imines intermediate produces the dihydroquinazolinone through intramolecular addition. At last, the dihydroquinazolinone is oxidated again to yield the target product quinazolinone.Chapter 3 is the third part, we mainly investigated the reaction of anthranilamide and aromatic aldehyde. Since the reaction does not need any other catalyst and addictives, the reaction system is very simple. We mainly studied other factors affected the reaction such as solvent, temperature and time. And we eventually discovered the optimal condition.(1) The optimal condition in the reaction between anthranilamide and benzaldehyde: DMSO, 120 ℃, 24 h. And under the conditions the yield of 2-phenyl-4(3H)-quinazolinone is 97%.(2) We have studied the scope of the reaction under this optimal condition. To begin with, we have researched the reaction between anthranilamide and aromatic aldehyde derivatives. Then we studied the reaction between benzaldehyde and a sort of anthranilamides as well. The results indicate that this synthetic method is extensively adapted to the reaction between anthranilamides and aldehyde derivatives.(3) We have proposed a mechanism for the reaction between anthranilamide and benzaldehyde: to begin with, anthranilamide and benzaldehyde react to the condensed intermediate 2-phenyl-1,2-dihydrogen-4(3H)-quinazolinone. Then, the intermediate dehydrogenize a molecule of H2 to yield the target molecule 2-phenyl-4(3H)-quinazolinone in the presence of air.Chapter 4 is the fourth part. To the best of our knowledge, there is no deep study on the structural analysis of quinazolinones, including NMR and IR analysis. By studying on the structure analysis, we find that the chemical shift of proton on amido group sharply move to the low field(δH > 10 ppm) because of the influence of carbonyl and aromatic heterocyclic system. This is the characteristic analytical data of 1H-NMR in quinazolinones. The chemical shift in 4-quaternary carbon atom is about 160 ppm, which is the characteristic analytical data of 13C-NMR in quinazolinones. Amid N-H stretching vibration(?N-H ≈ 3400 cm-1) and amide C=O stretching vibration(?C=O ≈ 1650 cm-1) are the characteristic analytical data of IR in quinazolinones.In conclusion, two kinds of synthetic methods of quinazolinones were studied in the thesis. Both of the methods are novel, and the operation is simple. More importantly, the two methods coincide with the principle of green chemistry, so it has some promising applications in the industrial production. And study on the structural analysis of quinazolinones is beneficial to the identification of quinazolinones in the future.