Research Towards The Improved Synthesis Of Raltegravire Intermediate

The potassium salte of Raltegravir is observed to inhibit RNA integrase enzyme activity,thus HIV is suppressed in the integration process,resulting in,delaying the onest of AIDS.So far,Raltegravir,as the first RNA integrase inhibitor,have been applied to prevent and treat HIV diagnosis,as well as prevent and delay AIDS.Thisarticleultimatelycompoundthetargetproducts,N-（（4-Fluorophenyl）methyl）-1,6-dihydro-5-hydroxy-1-methyl-2-（1-methyl-1-（（（5-methyl-1,3,4-oxadiazol-2-yl）carbonyl）amino）ethyl）-6-oxo-4-pyrimid inecarboxamide,which is the critical intermediate of Raltegravir.K⁺.Cyclization reacting is an important part of this article,this paper includes the following two chapters:The first chapter summarized advances of AIDS and anti-AIDS drugs.We introduced the pharmacology and pharmacokinetics of Raltegravir,and all the synthetic routes for the midbody.Afterwards,we analyzed advantages and disadvantages of each route.And then,we chooesd optimal route and promoted it.We have mainly studied the synthetic process of Raltegravir·K⁺.2-Methylalanine,as the original material,react with benzyl chloroformate,we obtained the compound 9,and the yield of this reaction is 92%;the compound 9 reacted with sopropyl chlorocarbonate and produced a lively intermediates.Subsequently,the lively intermediates turn into compound10 with the action of ammonia,the yield of this reaction is 96%;the compound 10 dehydrated and turn into compound 3 in the protection of N₂,the yield of this reaction is 95%;Compound 4 could be obtained by the compound 3 and hydroxylamine hydrochloride,the yield of this reaction is91%;The compound 4 was separated and purificated,and reacted with dimethyl acetylenedicarboxylate,the reaction obtained compound 5 and the yield is 97%;The compound 6 was synthesized by the compound 5 in dimethyl tetrahydrofuran with 1,10-phenanthroline and copper chloride as catalyst and inert gases as protection,the reaction occurred at the reflux condition for 12 hour,and eliminated a molecular methanol,the yield is61%.We have conducted a series of investigation for solvent、PH、reaction temperature、reantion time in each reaction,and selected the best condition.We have screened the catalyst and ligand in the reaction of compound 6.Ultimately,the total recovery is 52%.Compared with the orignal process,the improved route was more simple,cheaper and harmfulless.We have shortened the reaction time for 12 hour,reduced the reaction temperature for 50℃,improved the yield of 9%.This study simplified the reaction with the accessible raw materials,and reduced the pollution to environment.It more accord with green pharmaceutical development.