Study on the Novel Fluorine-18 Radiolabeling Methodologies and the Synthesis of 4(3H)-Quinazolinones

Author:Cheng Ran

Supervisor:zhao kang


Degree Year:2017





In this thesis,we focused on the fluorine-18 radiolabeling methodologies and synthesis of 4(3H)-quinazolinones.Totally,we have developed two novel fluorine-18 radiolabeling methods and two efficient green reactions of 4(3H)-quinazolinones.(1)A novel method for the convenient access to the first radiolabeling of[18F]4-fluoroisoquinolines has been developed,which is enabled by a silver-mediated amination of alkynes and radiofluorination of resulted phenyl(isoquinoline)-iodonium salts.The selectivity and applicability of the reaction were also studied.The presented method not only realizes the radiolabeling of 4-fluoroquinoline with pharmacological activity,but also makes up for the deficiency of the[18F]isoquinoline synthesis.(2)Based on our previous work on the[18F]trifluoromethylthiolation,we developed a Cu-mediated[18F]trifluoromethylthiolation of the a-position of the carbonyl compounds for the first time with easy available precursors,difluorocarbene reagents,sulfur and[18F]fluoride.Mechanistic insight into SCF3 Formation with control experiments and DFT calculations provides a reasonable process and encourages us to revise the mechanism we postulated in our previous work.This method will also be helpful for the development of pharmaceuticals with trifluoromethylthiolate group.(3)We have reported a new one-pot strategy for the synthesis of biological and pharmacological N-alkoxyl,N-H,N-alkyl and N-aryl4(3H)-quinazolinones starting from 2-aminobenzamides and various aldehydes.The process involves a cyclocondensation reaction catalyzed by p-toluenesulfonic acid followed by oxidative dehydrogenation using phenyliodine diacetate as the oxidant.Advantages of this method including mild reaction conditions,simple work-up procedures and functional groups tolerance provide a new research idea and theoretical basis for the development of heterocyclic chemistry and hypervalent iodine chemistry(4)Based on our previous research on 4(3H)-quinazolinones,we developed a rapid construction of the 4(3H)-quinazolinones through a novel one-pot AcOH-promoted cyclocondensation elimination process without the participation of either an oxidant or a heavy-metal catalyst.The method has proven to apply to a broad scope of substrates and to afford the desired 4(3H)-quinazolinones including the natural product pegamine in satisfactory to excellent yields.Realizing the goal of "green chemistry".