Study On The Synthesis Of Six Member Heterocyclic Guanidines Of Pyrimidinone

This dissertation is divided into three parts.The main task of the first part:(1) Design and explore a solution phase synthetic route for six member heterocyclic guanidines of pyrimidine.A series of guanidines are synthesized.(2) According to the solution phase synthetic route,the solid phase synthetic route of six member heterocyclic guanidines is designed and the route is verified by experiment.(3) Among the first part,raw material Pbf-NH₂(2,2,4,6,7-pentamethyl dihydrobenzofuran-5-sulfonyl amine) is used for synthesis of some simple biguanides. The second part of the job is to study the Michael addition reaction of amines to activated alkenes promoted by Zn/NH₄Cl system or solvent free and no catalyst condition.We studied the synthesis method of quinolinnone and indole heterocycles containing guanidine group under Pbf mediated thiourea guanylating transformation condition in the third part.The first part of the thesis include four chapters.(1) The first chapter introduces the basic characteristics of the guanidine compounds and the major uses of the guanidine in some fields.The pharmacological activities of natural and synthetic compounds containing guanidine are emphasized.This chapter also summarizes varies of routes for preparing guanidines.Particularly,the methods for preparation of five and six member heterocyclic guanidines are emphasized.Considering the literatures and their pharmacological activities reported in recent years,the main idea of the thesis is formed.(2) The second chapter is the core of this thesis.The synthetic route is designed and executed.The starting material 1,3,5-trimethylphenol,the pbf-NH₂ is synthesized,through the three-step reactions by the starting material 1,3,5-trimethylphenol.Then the triphosgene is used through two-step reactions, Pbf-NCS(2,2,4,6,7- pentamethyldihydrobenzofuran-5- sulfonyl isothiocynate) is obtained,and then Pbf-NCS reacted with primary amines to give Pbf activated thioureas.Subsequently,the Pbf activated thioureas reacted with N-alkylβamino acid esters to form the intermediate guanidines.The guanidine precursors are deprotected by THA/H₂O and through intramolecular cyclization to generate pyrimidin-4-ones, including 1-alkyl-2-alkylamino-5-alkyl- primidin-4-ones,1-alkyl-2-alkylamino-6-alkyl-primidin-4-ones,and 1-alkyl-2-alkylamino-5-alkyl- primidin 4-ones,and the structure of the products are analyzed.(3) In accordance with the solution phase synthetic method,the third chapter is developed.N-Fmoc,βamino acids are connected with Hydroxymethyl-resin and through.De-protection N-alkylation reaction.Then the resin-bound compounds reacted with Pbf-activated thioureas bearing substitutions,in the presence of Mukaiyama reagent or I₂.Finally the resin-bound product is cleaved in TFA/H₂O with spontaneous cyclization to give the desired final product.(4) In the fourth chapter,Pbf-NH₂ is converted to Pbf-NC(SMe)₂,and then reacted with primary or secondary amines,the Pbf protected S-methylisothiourea is obtained.Then Pbf protected S-Methylisothiourea is treated with alkylguandines.Finally Pbf is cleaved by TFA/H₂O,to obtain the target molecules,including 1-alkyl-5-alkyl-biguanides,and 1,1-dialkyl-5-alkyl- biguanides.The chapter five also is the second part of the thesis.In this chapter,Zn/NH₄Cl system,and no catalyst and solvent free condition is studied for Michael addition of amines withα,βunsaturated olefins.Some kinds ofβamino derivatives are synthesized,such asβamino acid esters,nitriles,amides,and ketones.Among these compounds,N-alkylβamino acid esters are used as starting material for chapter two.In the third part,we studied the synthesis method of quinolinnone and indole heterocycles containing guanidine group under Pbf mediated thiourea guanylating transformation condition.