化学药实用工艺研究Practical_Process_Research_and_Development—冯鑫2017.8.21

PracticalProcessResearchandDevelopment,冯鑫XinFeng2017/8/21,Content：,1：RouteSelection2:ReagentSelection3:SolventSelection4:RunningReaction5:Optimizingthereactionbyminimizingimpurities6:ToolsforPurifyingtheproduct,1RouteSlection,AHealth,SAFETY,andEnvironmentalassessmentisacriticalcriterioninourprocessdevelopment.Itsgottobedealtwith,anditsnottakenlightly.Ifproblemsareinsurmountable,orIfthereisdangertotheenvironment,asynthesiswillbereplaced.”,1-1:AnalyzingWasteStreams(FirstPrinciple),Itisfarbettertopreventwaste,notjustreducingwaste.,Routeswithfewerstepsrequiresmallerquantitiesofstartingmaterials,solvents,andreagents,andrequirelesslabor.,1-2:AtomEconomyAtomeconomyisnottheprimaryconsiderationformanufacturinginthepharmaceuticalindustry,1-3:LessHazardousChemicalsyntheses,1-4:ReduceuseofProtectinggroupsTheroutewiththefeweststepsmaybethegreenestandcheapestandthefewestopportunitiesforerrors.-difficult!,1-5:CatalysisWithcatalyticreactionsinvolvingexpensivecatalystscost-efficientroutewillrecyclethecatalysts.,1-6:DirectIsolationsDirectisolationminimizeconsumptionofRM,energy,timeandlabor.AnditisveryconvenientbothforplantandKilo-lab.Filtration/crystallization/recrystallization/slurryisthefavorite.,Example,Biotransformations,Biotransformationsprovideexcitingopportunitiesforchangingsyntheticroutes.Previouslyfermentationswereconsideredforcomplexmoleculessuchasantibiotics.Biocatalystshavebeendevelopedforsyntheticpurposesanditwasusuallyassociatedwithenzymes:transaminases,Example,Example:,Guidelinesfordevelopingbiocatalyticprocesss,Costestimates,Cost=rawmaterial+manufacturing+wastedisposal,2ReagentSelection,Someidealcharacteristicsofreagents,2-1Strongbases,Kot-Buisamoderatelystrongbase,anditsuseonscalecanbehamperedbyitslowsolubilityinorganicsolvent.,Characteristicsofsomeaminesusefulforscale-up,2-4Oxidations,Oxidationsareoftentroublesomeforscale-upThehighlyreactivityreagentscanleadtohazardousoperationsWastedisposalcostscanbehighiftoxicbyproductsandalargeamountwasteareproduced.So.Thepreferredapproachistodesigncatalyzedoxidationswithbulkoxidantsthatareinexpensive,readilyavailable,lesshazardousandnon-toxic.Suchas:H2O2inconcentrationsnogreaterthan30%,NaClO2,NaClO,NMO,Oxone.,Example,2-5Reductions,Caution!.H2generated.BH3.THF/NaBH4/BF3.Et2OwithNaBH4/RedAl/H2withPd,3SolventSelection,Solventscanhavehugeimpactsonprocessingcost,environment.Manygreenchemistryprinciplesarereflectedinusingsolvents,suchasminimizingwaste/minimizingenergytorecyclesolvents.Solventsmaybeclassifiedintoseveralgroupsasbellow:1:Protic,orhydrogenbond-donatingsolvents,suchasH2O,EtOH,AcOH2:Hydrogenbond-acceptingsolvents,suchasH2O,TEA,EA,Acetone,DMF3:Polaraproticsolvents,suchasDMSO,DMF,DMAC4:Chlorocarbonsolvents,suchasDCM,CHCl35:Fluorocarbonsolvents,suchashexafluoroisopropanol6:Hydrocarbonsolvents,suchasheptanes,toluene,3-1Usingazeotropestoselectsolvents,Manyorganicsolventsformazeotropeswithwater,andazeotropingoutwatercanpromotethereaction,sometimesitwasusedfordrying.Azeotropicremovalofvolatilecomponentscandriverections,3-2Solventsubstitutions,Anumberofchemicalshavebeenusedasinexpensive,greensolvents,suchas2-methyl-tetrahydrofuran,DME,1,3-propanediol.Usedforkindsofreaction,suchasorganometallicreaction,extraction,PTCreaction.Thesesolventsweredemonstratedascommercialavailability.,3-3Solventfreereaction,Insolvent-free(neat)reaction,asmallexcessofliquidreagentmayfunctionassolvent.Theproductareoftennon-crystalline.Quenchingsuchreactionsmayproducehightemperatures.Alwaysincreasedthereactionratebutdecreasedthework-upprocess.,Example:,Perspective,4RunningReaction,Asynthesisisnotthesameasaprocess.ProcesschemistryisnotmerelysyntheticchemistryDetailsoftheoperationscanbeveryimportant.,4-1Safety,Safetyisalwaysthefirstpriority.Accidentsincurgreatcost!Eachreactionshouldbeconsideredforpossiblehazards,includingreactionexotherms,gasevolution,andthesafetyofhandlingreagents,solvents,andproducts.CHA,HAZOPAnalysis.Safetyissuesshouldnotbetakenforgranted.Reviewsafetyregularly.,4-2Selectingthereactionscale,Itwasdeterminedby:theamountofchemicalsavailablehowexpensivethecomponentsareThesizeofavailableequipmentHowrobustoftheprocess,4-3ProcessDescription,Nonspecificdescripsionfoundinchemistryexperimentalprocedures,Stepbystepprocedureforsettingupandrunningreaction,4-5In-processcontrols,IPCsinclude:Simplephysicalguidelines,suchasreachingacolorendpoint/reachingandmaintainingcriticaltemperature/PHvalues./HPLCorUPLCorGCanalysis.In-processassayconsiderationsinclude:1:obtainingarepresentativesample2:preparethesampleforaccurateanalysis3:conductingtheassay4:analyzingthedataforreproducibilityandaccuracy,4-6Workup-Queching,Safetyistheforemostconsiderationinquenchingareaction,4-6Workup-Extraction,Emulsionsformedcandelayprocessingandleadtoproductlosses.BreakEmulsions:RaisethetemperatureslightlyIncreasetheionicstrengthofaqueousphasebyaddingbrineAdjustthePHvaluesslightlyFilteroffsmallparticlesIncreasedtheamountofsolventAddingsmallamountofamorepolarsolvent,e.g.2-10%MeOH.Gentleragitation,5Optimizingthereactionbyminimizingimpurities,SafetyisalsothefirstpriorityImprovetheyieldImprovethequalityImprovetheproductivityonscaleReducethecostReducethewaste,5-1Benefitsofheterogeneousprocessing,Heterogeneousprocesscanbebeneficialifbyproductsprecipitateastheyformoriftheproductcrystallizesasitforms.,5-2DecreasesideproductsbyDecreasingdegradationofstartingmaterials,5-3Additionsequence,Durationofadditionandthetimebetweenaddition,90%decreasedto57%duetothececompositionofmeldrumacidathightemperature.,Additionsequence,5-4Temperaturecontrolsmalltemperaturechangescangreatlyaffectbyproductformation,5-5Minimizingimpuritiesformedduringwor