左乙拉西坦合成工艺优化研究

233010。L-、、、。L-48．0%。。OptimizationofsynthesisofLevetiracetamWANGHong-huWEIYa-fengCHENWen-jieBengbuBBCAMedicineScience＆DevelopmentCo．Ltd．BengbuAnhui233010ChinaAbstractAimToexploretheoptimizationedsyntheticrouteforLevetiracetam．MethodsLevetiracetamwaspreparedfromL-methio-nineviareduction-dethiomethylationesterificationammonolysisamidationandintramolecularcyclocondensaionreaction．ResultsTheoverallyieldwas48．0%calculatedfromL-methionine．ConclusionThereactionyieldwashihgernostrictreactionconditionssimpli-fiedrouteandmoresutabletobeindustrilialized．Keywordslevetiracetamsynthesisoptimization。1～3。UCB、、、、。。42-α-±-α--2--1-R+-α-、。、、5。6～8L-40%。。。L-。2。211。1·186·AnhuiMedicalandPharmaceuticalJournal2011Jun15622．1L-20091022Bchi5101H400．13MHzBruckAM-400PerkinElmer-34l589nm。2．22．2．1S-ⅡL-50g336mmoL4LT-1500g。75～80℃4h。1%8-CHCl32×1000mlCHCl33×1200ml。32．0g98．9%95．0%273～275℃。2．2．2S-ⅢS-25．76g230mmol150ml－10℃37．0ml5h400mlpH=5．5～6．065℃。36．8g99．2%HPLC95．2%148～149℃。1HNMRppm1．02tJ=7．5Hz3H、1．94m2H、3．82s3H、4．00tJ=6．2Hz1H。2．2．3S-2-ⅣS-18．44g120mmol40ml12．12g120mmolHCl450ml。100ml12．0g。100ml5℃2h10ml10h。9．6g78．0%。1HNMRppm1．02tJ=7．2Hz3H、1．95m2H、4．02m1H。2．2．4S-2-2--1-ⅠS-2-9．16g89．8mmol100mlKOH13．44g240mmol1．0g。－5℃16ml31．25g207mmolCH2Cl26hKOH4．0g3h25ml9．34g68．0%116～117℃。C=1。1HNMRppm0．95tJ=7．5Hz3H、1．70m1H、2．04mJ=3．0Hz2H、2．44m1H、3．45m2H、4．44qJ=5．5Hz1H、5．52s1H、6．33s1H。IRKBr3385cm－1NH1676cm－1C=O1618cm－1C=O。33．1S-L-。500gNaBH4/NiCl2·6H2O、W-2T-150gL-75-80℃4hS-T-195．0%W-292．0%NaBH4/NiCl2·6H2O89．5%。3．2S-5。。6PH。99．2%。3．3。。10%V/V。。。2．2．33。3315℃。5℃。。4L-T-1L-95．0%。S-99．2%。10%。5℃3%。L-48．0%。1Kasteleijn-NolstTrenitDGAMarescauxCStodieckSetal．Pho-tosensitiveepilepsyamodeltostudytheeffectsofatlliepiLepticdrugs．EvaluationofthepiracetamanaloguJ．Eveti-racetamEpi-lepsyRes1996253225－30．2．J．201088429－31．·286·AnhuiMedicalandPharmaceuticalJournal2011Jun15611121．2．210029。ZealongaSD4h20h、、、。AP＜0．05AP＜0．05P＞0．05。1h。Erig-eronbreviscapusVanthand-mazz。berviscapineBre1。23。4。。11．1。。0．9%。TTC。。。1．2ACS-HI。JA-1203。DHG-9053A。。1．3SD250～350g。SCXK2009－012。[e-mail]1．4SPSS16．0。LSD。22．12．1．1Zealonga55cm0．285mm20mm。2．1．26～840A1h、B、C、2h、4h、D、E584mg·kg－110ml·kg－1。10%350mg·kg－1ip。0。、Y20mm1．5cm。。4h4。2．22．2．1。4h24h。14021～331～3。10。。2．2．224h3．≤4J．2010191678－80．4SuneesJMarmonVDifferdingEetal．2-Oxo-1-pyrrolidingderiv-ativesprocessforpreparingthemandtheirusesP．WO0164637A12001－09－07．5AtesCSurteesJBurteauA-Cetal．OxopyrrolidineCompoundspreparationofsaidcompoundsandtheiruseinthemanufacturingoflevetiracetamandanaloguesP．WO03014080A22003－02－20．6．J．2004289413－7．7．J．200535227－8．8．J．20071611860－4．2010－12－21·386·AnhuiMedicalandPharmaceuticalJournal2011Jun156