- N3-Alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides
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Dimethylformamide dimethylacetal (DMFDMA) is widely used as a source of electrophilic one-carbon units at the formate oxidation level; however, electrophilic methylation with this reagent is previously unreported. Reaction of anthranilamide with DMFDMA at 150 °C for short periods gives mainly quinazolin-4-one. However, prolonged reaction with dimethylformamide di(primary-alkyl)acetals leads to subsequent alkylation at N3. 3-Substituted anthranilamides give 8-substituted 3-alkylquinazolin-4-ones. Condensation of anthranilamides with dimethylacetamide dimethylacetal provides 2,3-dimethylquinazolin-4-ones. In these reactions, the source of the N 3-alkyl group is the O-alkyl group of the orthoamides. By contrast, reaction with the more sterically crowded dimethylformamide di(isopropyl)acetal diverts the alkylation to the oxygen, giving 4-isopropoxyquinazolines, along with N3-methylquinazolin-4-ones where the methyl is derived from N-Me of the orthoamides. Reaction of anthranilamide with the highly sterically demanding dimethylformamide di(t-butyl)acetal gives largely quinazolin-4-one, whereas dimethylformamide di(neopentyl)acetal forms a mixture of quinazolin-4-one and N3-methylquinazolin-4-one. The observations are rationalised in terms of formation of intermediate cationic electrophiles (alkoxymethylidene-N,N-dimethylammonium) by thermal elimination of the corresponding alkoxide from the orthoamides. These are the first observations of orthoamides as direct alkylating agents.
- Nathubhai, Amit,Patterson, Richard,Woodman, Timothy J.,Sharp, Harriet E. C.,Chui, Miranda T. Y.,Chung, Hugo H. K.,Lau, Stephanie W. S.,Zheng, Jun,Lloyd, Matthew D.,Thompson, Andrew S.,Threadgill, Michael D.
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p. 6089 - 6099
(2011/10/08)
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- Quinazolinone compounds
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Phosphate derivatives are disclosed of quinazolinone compounds having structural formula (I) or a pharmaceutically acceptable salt thereof, wherein X' represent hydroxyl, alkyl, alkoxy, or O-Z where Z is a phosphate or phosphate derivative; Y' represents
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- Resistance-modifying agents. 5.1 Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP)
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Clinical studies concerning the role of poly(ADP-ribose) polymerase (PARP) in the repair of drug- and radiation-induced DNA damage have been impeded by the poor solubility, lack of potency, and limited specificity of currently available inhibitors. A seri
- Griffin, Roger J.,Srinivasan, Sheila,Bowman, Karen
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p. 5247 - 5256
(2007/10/03)
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