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1、摘要甲酰胺等原料一次性加入反应釜中,经“一锅”两步反应直接合成瑞戈菲尼。中间产物不经分离纯化，收率高，三废少，操作简单。用N■咪卩坐甲酰胺基，苯氧拨甲酰胺基或氯甲酰胺基代替异氧酸基，得到相似的反应结果。关键词：3-<-4-硝基苯酚，瑞戈菲尼，合成，“一锅”法反应，工艺优化AbstractRegorafenibisanovelmulti-kinaseinhibitor,itcaninhibitmanykindsofenzymeswhichcanpromotethegrowthofcancercells,therebyinhibitingtumorcellproliferationandtu
2、morangiogenesis.Regorafenibhasplayedaverygoodeffectinthetreatmentofmetastaticcolorectalcancerandgastrointestinalstromaltumors.Therefore,theexplorationofitssynthesisprocessandapplicationshavebecomethefocusofchemists.Inthisthesis,wehavedevelopedanew,simpleandefficientsyntheticprocessofregorafenib,i
3、nordertosimplifymanipulation,improveyieldoftheproductanddecreasewastes.l.Thesynthesisoftheimportantintermediate3-fluoro-4-aminophenolwasdesignedandcarriedout.Fromthecheapandmarketavailable4-fluoroaniline,the3-fluorophenolwassynthesizedatfirst,whichwastransformedtothe3-fluoro-4-aminophcnolbynitrat
4、ionandcatalytichydrogcnation.2.Thereactionof3-fluoro-4-aminophenolwith4-chloro-3-(trifluoromethyl)phenylisocyanategavel-(4-chloro-3・(trifluoromethyl)phenyl)-3-(2-fluoro-4-hydroxyphenyl)urea,whichreactedthenwith4-chloro・N-methyl-2-pyridineWiththismethod,the1-(4-chloro-3-(trifluoromethyl)phenyl)-3-
5、(2-fluoro-4-hydroxyphcnyl)urcacanbeobtainedinhighyieldandgoodpurityatroomhitemperature.Intheprocessoffbnningregorafenibbyreactingoftheintermediatewith4-chloro-N-methyl-2-pyridinecarboxamide,onedonotneedtoregardthecompetitionissuesbetweenaminoandhydroxygroups.Therefore,itgreatlysimplifiedtheexperi
6、mentalprocedures-Afteroptimizingthereactionconditions,asimple,efficientandindustrialapplicablesyntheticprocesswasrealized.2.Anew“one・pof'two-stepreactionmethodwasdevelopedforthesynthesisofregorafenibonthebasisoftheabovestudies.Put3-fluoro-4-aminophenol,4-chloro・3・(trifluoromethyl)phenylisocyanate
7、and4-chloro-N-methyl-2-pyridinecarboxamidealltogetherintothereactor,thetwo-stepreactionstookplacesuccessivelytogivethefinalproductdirectelywithoutisolationoftheintermediate.SimilarresultswereobtainedwhileusingtheN-imid
