Rhodium And Palladium-catalyzed Synthesis Of Uracil Derivatives

Uracil is a base unique to RNA and is one of the four bases that make up RNA,which is equivalent to thymine(T)in DNA.Replaces thymine in DNA during DNA transcription,pairing with adenine.Thymine is obtained by methylation of uracil.Because of this important role of pyrimidine,many similar drugs have been developed.The most classic drug is the discovery of metabolic antagonist,such as 5-fluorouracil,which play an important role in the development of tumor drugs.In this project,the structural modification and synthesis of antitumor drugs based on uracil as the basic mother nucleus was performed.This project first constructed two new methods for synthesizing uracil derivatives.The first method is to form a new aziridine ring-opening product with the uracil substrate and sulfamate compounds with the participation of high-valent iodine.The reaction conditions were optimized,including rhodium catalyst,high-valent iodine,reaction time,temperature,solvent,etc.In the second method,a new type of uracil derivative was synthesized by Suzuki coupling reaction using uracils and substituted phenylboronic acids(or esters)with palladium catalyst.Reaction conditions of above reaction were optimized,including palladium catalyst,reaction time,temperature and bases.Using rhodium as a catalyst,the optimum reaction conditions are as following:To solution of uracils and sulfamate compounds in dichloromethane,added rhodium dipolyacetate(0.03 equivalents),iodobenzenediacetic acid(1.5 equivalents)or iodoylbenzene(1.5 equivalents),and magnesium oxide(4 equivalents).The mixtue was recated at room temperature for 2 hours.For palladium as a catalyst,[1,1’-bis(diphenylphosphino)ferrocene]palladium dichloride,bistriphenylphosphine palladium dichloride,and tetrakis(triphenylphosphine)palladium showed catalytic effect to the Suzuki coupling reaction of iodine or chlorine and boric acid(ester)compounds.The optimum reaction conditions are as following:ethylene glycol dimethyl ether as solvent,tetrakis(triphenylphosphine)palladium(0.02 eq),sodium hydroxide(1.5 eq)reacted at 80 ℃ for 16h.In this project,67 compounds were obtained through the above methods,of which 27 were new uracil derivatives,and two synthetic methods for synthesizing new uracil derivatives using rhodium or palladium as catalysts were obtained.The research laid a certain foundation for the discovery of new uracil antitumor drugs.