Synthesis Of Important Intermediates And Derivatives Of Posaconazole

As a representative of the second-generation triazole antifungal drugs,posaconazole has the advantages of high efficiency,low toxic side effects and broad antibacterial spectrum.The synthesis and development of posaconazole intermediates and derivatives have become hot topics in current research.Based on the existing literature,N,N-bis(2-hydroxyethyl)-4nitroaniline,N,N-bis(chloroethyl)-4nitroaniline and key intermediate of posaconazole 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine was synthesized by nucleophilic substitution reaction using 4-chloronitrobenzene and diethanolamine,dichlorosulfoxide and p-methoxyaniline as main raw materials.Conversion of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine to 1-4(methoxyphenyl)-4-(4-aminobenzene)piperazine by nitro reduction.The optimization of the synthesis process conditions of each step was carried out to make the reaction conditions relatively mild and the yield of each step product was obviously improved.Based on the important intermediate posaconazole,1-4(methoxyphenyl)-4-(4-aminophenyl)piperazine,it was structurally modified by acylation and other reactions to obtain five posaconazole semicarbazide derivativesand three posaconazole amide derivatives.The structure was confirmed by LC-MS and 1H NMR.Eight posaconazole derivatives have not been reported in the literature.