Studies On The Synthesis Of Several Intermediates For Constructing N-Heterocyclic Drugs

Guanidines are a group of important nitrogen-containing compounds, which havegood biological activity and have been widely used in many fields such as medicine,pesticide and fine chemicals. In particular, aromatic guanidines have attracted moreand more attention owing to their ability of fungicide, anti-microbial, and molecularrecognition. However, there are some limitations in the synthesis of such aromaticguanidines, such as rare materials, high pollution to environment or slashing reactionconditions. For example, the highly toxic cyanamide was used in the preparation ofImatinib, a drug to treat CML, which increased the poison on human body. Therefore，we plan to develop a new method for synthesis of the key imatinib intermediateapplying the traditional Ullmann reaction system rather than to using cyanamide. Thisdissertation contains three chapters.In the first chapter, main characters, applications and preparations of aromaticguanidines were outlined. While Imatinib drug and its synthetic routes were brieflyreviewed.In the second chapter, the progress of copper-catalyzed Ullmann reaction wassummarized. Then the copper-catalyzed reaction of 2-iodo-1-methyl-4-nitrobenzenewith guanidine hydrochloride was examined. Through optimization of reactionconditions such as solvent, base, catalyst and ligand, we found that this couplingreaction can be effectively catalyzed by CuI. The coupling reactions of other arylhalides were also tested and giving coresponding products. All guanidines have beencharacterized by IR,¹H NMR,¹³C NMR and HR-MS.In addition to the copper-catalyzed coupling reaction between aryl halides andguanidine hydrochloride, some monosubstituted guanidine derivative were obtainedby base-mediated nucleophilic reaction. Moreover, an unexpected dimethylaminoderivative was gained, on which a new method for synthesis of dimethylaminocompounds was developed. The advantages of this method are simple operationd andrapid reaction rate. All products have been characterized by IR,¹H NMR,¹³C NMRand HR-MS. Some compounds were also determined by X-ray diffraction techniques.