Preparation And Derivatization Of Halopyrazolo [1,5-a] Pyrimidine

The synthesis of pyrazolo[1,5-a]pyrimidine derivatives plays an important role in pharmacological activities and biological products.Drugs such as anti-anxiety drugs Ocinaplon,sleeping drugs Zaleplon and Inplon,fungicides Pyrazophos,biological products such as KDR kinase inhibitors,precursors of fused tricyclic inhibitors,and a serotonin 5-HT₆receptor newly developed by Roche,all contain the parent structure of pyrazolo[1,5-a]pyrimidine.There are few reports on the construction of pyrazolo[1,5-a]pyrimidine.Although some achievements have been made,the reaction conditions and synthesis methods are harsh,the toxicity of the halogenation reaction is high,and the utilization rate of atoms is low,which does not meet the requirements of green chemistry.There are few reports on the C-S coupling of pyrazolo[1,5-a]pyrimidine.Among the existing synthesis methods,the product selectivity is not high and the substrate is relatively single.In order to solve the above problems,a series of pyrazolo[1,5-a]pyrimidine rings with different substituents were synthesized by using a highly efficient and easy to operate method with pyrazolo[1,5-a]pyrimidine as the backbone.NIS was used as iodine source to carry out selective single/double iodination reaction,and the reaction conditions were green and pollution-free.Secondly,the coupling reaction of C-S/Se is studied,which can selectively replace monosulfur/selenoether,water as solvent,and the reaction time is short.The work content of this thesis is as follows:Part one:I₂-catalyzed cyclization ofβ-ketonitrile with 1H-pyrazol-5-amine.In this thesis,a simple and efficient method was used to synthesize pyrazolo[1,5-a]pyrimidine using I₂ as catalyst,1H-pyrazo-5-amine andβ-ketonitrile as substrates.In the substrate suitability study,a series of pyrazolo[1,5-a]pyrimidine were synthesized in good to excellent yields.This method has the advantages of simple and mild reaction conditions,a wide range of substrates,and the ability to amplify the reaction on a gram scale.Part two:Halogenation of pyrazolo[1,5-a]Pyrimidines with NXS.This chapter developed a method for the halogenation of pyrazolo[1,5-a]pyrimidine,using NXS（X=I,Br,Cl）as the halogenating agent,the reaction process is green and efficient.Firstly,changing the ratio of pyrazolo[1,5-a]pyrimidines to NIS and the type of solvent,selective monoiodination and diiodination of pyrazolo[1,5-a]pyrimidine were performed with good selectivity and good to excellent yields.Secondly,in the reaction of pyrazolo[1,5-a]pyrimidine with NBS and NCS,a series of dibrominated and dichlorinated products were formed in moderate to good yields.This method is characterized by a wide range of substrates,good functional group tolerance,and the ability to synthesize at gram level.This work provides an efficient method for the construction of structurally diverse halo pyrazolo[1,5-a]pyrimidine derivatives.Part three:Selective C-S（Se）coupling of pyrazolo[1,5-a]pyrimidine.This chapter reports a simple method for the synthesis of monoaryl thioether pyrazolo[1,5-a]pyrimidine,using monoiodo pyrazolo[1,5-a]pyrimidine as the substrate,sulfonyl hydrazide as the sulfur source,and water as the solvent.Under the catalysis of phase transfer catalyst PEG-400,a series of monosubstituted aryl thioethers are synthesized in a short time with good yield.Characteristic of high selectivity.Furthermore,the conditions are suitable for the coupling reaction of C-Se for the synthesis of arylse-substituted pyrazolo[1,5-a]pyrimidine.This research provides an efficient and convenient method for the construction of pyrazolo[1,5-a]pyrimidine and its derivatives.Its mild reaction conditions,excellent yield and high selectivity greatly broaden the applied range of pyrazolo[1,5-a]pyrimidine compounds.