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化学药实用工艺研究Practical-Process-Research-and-Development—冯鑫2017.8.21PPT课件

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化学药实用工艺研究Practical-Process-Research-and-Development—冯鑫2017.8.21PPT课件PracticalProcessResearchandDevelopment冯鑫XinFeng2017/8/21Content:1:RouteSelection2:ReagentSelection3:SolventSelection4:RunningReaction5:Optimizingthereactionbyminimizingimpurities6:ToolsforPurifyingtheproduct1RouteSlectionAHealth,SAFETY,andEnvironmentalassessme...

化学药实用工艺研究Practical-Process-Research-and-Development—冯鑫2017.8.21PPT课件
PracticalProcessResearchandDevelopment冯鑫XinFeng2017/8/21Content:1:RouteSelection2:ReagentSelection3:SolventSelection4:RunningReaction5:Optimizingthereactionbyminimizingimpurities6:ToolsforPurifyingtheproduct1RouteSlectionAHealth,SAFETY,andEnvironmentalassessmentisacriticalcriterioninourprocessdevelopment....It’sgottobedealtwith,andit’snottakenlightly.Ifproblemsareinsurmountable,orIfthereisdangertotheenvironment,asynthesiswillbereplaced.”1-1:AnalyzingWasteStreams(FirstPrinciple)Itisfarbettertopreventwaste,notjustreducingwaste.Routeswithfewerstepsrequiresmallerquantitiesofstartingmaterials,solvents,andreagents,andrequirelesslabor.1-2:AtomEconomyAtomeconomyisnottheprimaryconsiderationformanufacturinginthepharmaceuticalindustry1-3:LessHazardousChemicalsyntheses1-4:ReduceuseofProtectinggroupsTheroutewiththefeweststepsmaybethegreenestandcheapestandthefewestopportunitiesforerrors.-----difficult!!!!!1-5:CatalysisWithcatalyticreactionsinvolvingexpensivecatalystscost-efficientroutewillrecyclethecatalysts.1-6:DirectIsolationsDirectisolationminimizeconsumptionofRM,energy,timeandlabor.AnditisveryconvenientbothforplantandKilo-lab.Filtration/crystallization/recrystallization/slurryisthefavorite.ExampleBiotransformationsBiotransformationsprovideexcitingopportunitiesforchangingsyntheticroutes.Previouslyfermentationswereconsideredforcomplexmoleculessuchasantibiotics.Biocatalystshavebeendevelopedforsyntheticpurposesanditwasusuallyassociatedwithenzymes:transaminasesExampleExample:GuidelinesfordevelopingbiocatalyticprocesssQuickesttoeffectChangeExample1ScreenmediumDissolvesubstrateinDMF,DMSO,oracetone2ModifystartingmaterialChangeBocforbenzyl3ScreenbiocatalystsHigh-throughputCostestimatesCost=rawmaterial+manufacturing+wastedisposal2ReagentSelectionSomeidealcharacteristicsofreagentscharacteristicCommentsorexamplesSpecificforthedesiredsynthetictransformationIsolationiseasierfromhigh-yieldingreactionSafe:posednochemicalreactionhazardLiabilityincreaseswithscaleNoshippingrestrictionsCH3LiinEt2ONopurchasingrestrictionsTimeisrequiredtoobtainlicenses,thechemicalcouldbeusedtomakeillegaldrugsNon-toxicPPEistime-consuming,cumbersome,inconvenientIfhighlytoxic,non-volatileDimethylsulfatemaybepreferredoverCH3IReadilyavailablefrommultiplevendorsOnevendormayholdupsupplyorraisecostInexpensive,withconsistentqualitybatchtobatchInexpensive,high-qualityreagentslowerthecostofgoodsStable,goodshelf-lifeGreaterflexibilityinschedulingmanufacturingReadilygeneratedandusedifshortshelf-lifeGreaterflexibilityinschedulingoperationsFacilitateswork-upandisolationofpureproduct,orhasnoeffectonwork-upoftheproductIncreasedproductivityProducesnon-toxicbyproductLowerdisposalcostCatalytic,andreadilyrecoveredandreusedLowerthecostofgoodsRequiresnospecializedequipmentorfacilitiesHydrogenationfacility2-1StrongbasesKot-Buisamoderatelystrongbase,anditsuseonscalecanbehamperedbyitslowsolubilityinorganicsolvent.Characteristicsofsomeaminesusefulforscale-upCompoundpKaComments3-dimethylaminopropylamine~11UsedtoremoveexcessRCOClTEA10.75HClsaltinsolubleinMeCNDIPEA10.4HClsaltinsolubleinMeCN4-methylmorpholine10.08PeptidecouplingImidazole7.0Peptidecoupling/silylation2,6-lutidine6.65sulfationDMAP9.7Acylation/catalyst2-4OxidationsOxidationsareoftentroublesomeforscale-upThehighlyreactivityreagentscanleadtohazardousoperationsWastedisposalcostscanbehighiftoxicbyproductsandalargeamountwasteareproduced.So……..Thepreferredapproachistodesigncatalyzedoxidationswithbulkoxidantsthatareinexpensive,readilyavailable,lesshazardousandnon-toxic.Suchas:H2O2inconcentrationsnogreaterthan30%,NaClO2,NaClO,NMO,Oxone……..Example…2-5ReductionsCaution!!!!......H2generated.BH3.THF/NaBH4/BF3.Et2OwithNaBH4/RedAl/H2withPd3SolventSelectionSolventscanhavehugeimpactsonprocessingcost,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………3-1UsingazeotropestoselectsolventsManyorganicsolventsformazeotropeswithwater,andazeotropingoutwatercanpromotethereaction,sometimesitwasusedfordrying.Azeotropicremovalofvolatilecomponentscandriverections3-2SolventsubstitutionsAnumberofchemicalshavebeenusedasinexpensive,greensolvents,suchas2-methyl-tetrahydrofuran,DME,1,3-propanediol.Usedforkindsofreaction,suchasorganometallicreaction,extraction,PTCreaction.Thesesolventsweredemonstratedascommercialavailability.3-3SolventfreereactionInsolvent-free(neat)reaction,asmallexcessofliquidreagentmayfunctionassolvent.Theproductareoftennon-crystalline.Quenchingsuchreactionsmayproducehightemperatures.Alwaysincreasedthereactionratebutdecreasedthework-upprocess.Example:PerspectiveAspectCommentSafetyAvoidsolventsthataretoxicorhighlyflammablePromotehigh-yieldingreactionsCompatiblewithdesiredchemistryCanisolateproductingoodyieldConvenientIsolateproductfromreactionsolventH2O-miscibilityAzeotropingability,controlamountofH2OpresentduringreactionsCostandrecoverabilityLowerthecostEnvironmentalEasyforrecycle,friendlyLong-termavailabilityManyvendorsWaterassolventGreen,butwastewatertreatmentmaybehighNeatreactionSelectedapplication,butlimitedheatcapacitycanmaketemperaturecontroldifficult.4RunningReactionAsynthesisisnotthesameasaprocess…..ProcesschemistryisnotmerelysyntheticchemistryDetailsoftheoperationscanbeveryimportant.4-1SafetySafetyisalwaysthefirstpriority…..Accidentsincurgreatcost!!!!!Eachreactionshouldbeconsideredforpossiblehazards,includingreactionexotherms,gasevolution,andthesafetyofhandlingreagents,solvents,andproducts.CHA,HAZOPAnalysis…..Safetyissuesshouldnotbetakenforgranted.Reviewsafetyregularly.4-2SelectingthereactionscaleItwasdeterminedby:theamountofchemicalsavailablehowexpensivethecomponentsareThesizeofavailableequipmentHowrobustoftheprocess4-3Process DescriptionNonspecificdescripsionfoundinchemistryexperimentalproceduresStepbystepprocedureforsettingupandrunningreaction4-5In-processcontrolsIPCsinclude:Simplephysicalguidelines,suchasreachingacolorendpoint/reachingandmaintainingcriticaltemperature/PHvalues…../HPLCorUPLCorGCanalysis.In-processassayconsiderationsinclude:1:obtainingarepresentativesample2:preparethesampleforaccurateanalysis3:conductingtheassay4:analyzingthedataforreproducibilityandaccuracy4-6Workup-QuechingSafetyistheforemostconsiderationinquenchingareaction4-6Workup-ExtractionEmulsionsformedcandelayprocessingandleadtoproductlosses.BreakEmulsions:RaisethetemperatureslightlyIncreasetheionicstrengthofaqueousphasebyaddingbrineAdjustthePHvaluesslightlyFilteroffsmallparticlesIncreasedtheamountofsolventAddingsmallamountofamorepolarsolvent,e.g.2-10%MeOH.Gentleragitation5OptimizingthereactionbyminimizingimpuritiesSafetyisalsothefirstpriorityImprovetheyieldImprovethequalityImprovetheproductivityonscaleReducethecostReducethewaste5-1BenefitsofheterogeneousprocessingHeterogeneousprocesscanbebeneficialifbyproductsprecipitateastheyformoriftheproductcrystallizesasitforms.5-2DecreasesideproductsbyDecreasingdegradationofstartingmaterials5-3Additionsequence,Durationofadditionandthetimebetweenaddition90%decreasedto57%duetothececompositionofmeldrumacidathightemperature.Additionsequence5-4Temperaturecontrolsmalltemperaturechangescangreatlyaffectbyproductformation5-5MinimizingimpuritiesformedduringworkupAttheendofthereaction,generatingastablereactionmixtureisnecessarytopreventformationofsignificantamountsofimpuritiesduringsubsequentprocessing,especiallyonscale6ToolsforPurifyingtheproductPurificationBycolumnchromatography(API,earlyphase)Crystallization(favorite!!!!)Purificationbyreslurrying
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