2015.4张霁博士—叠缩方法绿色化工艺化学

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1、GreeningtheProcessChemistrybyTelescoping叠缩方法绿色化工艺化学Dr.JiZhang(张霁博士)HECPharma(东阳光药业)ISPEChinaAnnualSpringConference2015Beijing,ChinaProcessofMidazolambyTelescoping合成工艺实例叠缩工艺Telescopingprocess(Telescopedortelescopicprocess)是直接将未经纯化后处理的粗产物投入下一步反应，经过数步免除纯化过程（用符号[]表示）后才经分离纯

2、化而获取高纯度的产物。Thecrudeproductwasdirectlytreatedintothenextreactionwithoutpurification,aprocessthateliminatingpurificationsteps(indicatedbysymbol[]represents)andfinallyisolationandpurificationtoobtainahighpurityproduct.A+BIIP1x叠缩工艺和一锅法反应(Telescopingandone-potreaction数步反应的

3、简化;强调反应的简单性，避开一些中间体的分离即把多步反应按顺序或纯化;者一次性投料在一个反应器工艺过程的简捷和快速途里得到所需的产物，而不牵径涉到后处理纯化过程simplifythenumberofEmphasizessimplicitystepsThemulti-stepreactionAvoidseparationsofsomeVSsequenceoraone-potinaintermediatesreactor,withoutinvolvingSimpleandfastwayforpost-treatment

4、purificationprocessprocess叠缩工艺一锅法反应(Telescopingprocess)（One-potreaction）叠缩工艺和一锅法反应(TelescopingandOne-potreaction)1理想的工艺路线设计应使所有中间体无需经过柱层析纯化Idealprocessshouldbedesignedsothatallintermediatewithoutpurificationbycolumnchromatography2叠缩工艺就是将多步工艺过程免经过溶解、过滤、打浆和重结晶等经典操除柱层析纯化的

5、理想状态作就能达到纯化目的IdeallytelescopedprocessistoBydissolution,filtration,andre-crystallizationremovethemulti-steppurifiedoperationsachievethepurposeofpurificationbycolumnchromatography3放大生产时也多采用打浆、盐等方式以获取最好产率和纯度usere-slurry,saltformationandotherwaystogetthebestyieldandpurity叠

6、缩工艺的实例分析(Casestudy1)叠缩工艺的实例分析(Casestudy1)最后工艺特点:用氢溴酸取代盐酸用于重氮盐和肼的制备，没有分离肼的氢溴酸盐，直接用于哒嗪酮的制备，直接从水中析出高纯度高产率水溶性差的产品Zhang,J.Morton,H.E.;Ji,J.TetrahedronLett.2006,47,8733-8735Org.Proc.Res.Dev.2006,10,512-5177叠缩工艺和工艺的绿色化Telescopingandgreeningprocess1产品质量及工艺的稳定性Qualityofproducta

7、ndprocessstability2增加产率、减少损失、减少劳动时间Increaseyields,reducelosses,reducinglabortime3显著降低运作成本Significantlyreduceoperatingcosts提高工艺操作人员的安全保护4Improvethesafetyforoperators5提高运行和环境安全ImprovetheenvironmentZhang,J.;Cue,B.W.GreenTechniquesforOrganicSynthesisandMedicinalChemistryJo

8、hnWiley&Sons,2012:631叠缩工艺的实例分析(Casestudy2)ONO2OOt-BuONa+OOEt7OMe8OMeOMeOO1)Ra-Ni/H2EtOC2OEtO2CO2)NaBH(OAC)3NONO2H9rac