盐酸托莫西汀.docx
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盐酸托莫西汀.docx
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盐酸托莫西汀
∙Atomoxetinehydrochloride,Tomoxetinehydrochloride,LY-1396--药物合成数据库
∙发布时间:
2004-10-25来源:
本站整理
【药物名称】
Atomoxetinehydrochloride,Tomoxetinehydrochloride,LY-139602[(+)-isomer],LY-135252(racemate),LY-139603,Strattera
【化学名】
(R)-(-)-N-Methyl-gamma-(2-methylphenoxy)benzenepropanaminehydrochloride;(R)-(-)-N-Methyl-3-phenyl-3-(2-methylphenoxy)propylaminehydrochloride
【CAS登记号】
82248-59-7,83015-26-3(freebase)
【结构式】
【分子式】
C17-H21-N-O.Cl-H
【分子量】
291.8198
【原研厂家】
Lilly(Originator)
【作用类别】
Antidepressants,AttentionDeficitHyperactivityDisorder(ADHD),Treatmentof,Autism,Treatmentof,MoodDisorders,Treatmentof,PSYCHOPHARMACOLOGICDRUGS,NorepinephrineReuptakeInhibitors
【研发状态】
Launched-2003
【合成情况】
〖来源〗
TetrahedronLett
〖合成路线〗
〖标题〗
AnewchemoenzymaticenantioselectivesynthesisofR-(-)-tomoxetine,(R)-fluoxetineand(S)-fluoxetine
〖合成方法〗
Anewsynthesisfortomoxetinehydrochloridehasbeenreported:
Thereductionofbenzoylaceticacidethylester(I)withBaker'syeastandglucoseinwater,ortheenzymatichydrolysisof3-acetoxy-3-phenylpropionicacidethylester(II),gives(-)-3-hydroxy-3-phenylpropionicacidethylester(III),whichbyreactionwithmethylamineyieldsthecorrespondingamide(IV).Thereductionof(IV)withLiAlH4inetheraffords(-)-3-hydroxy-N-methyl-3-phenylpropylamine(V),whichisprotectedwithdi-tert-butyldicarbonatetotheamide(VI).Thecondensationof(VI)witho-cresol(VII)bymeansoftriphenylphosphineanddiethylazodicarboxylate(DEAD)inetheryieldstheprotectedfinalproduct(VIII),whichisfinallydeprotectedwithdryHClinmethanol.
〖作者〗
Dike,S.Y.;Kumar,A.;Ner,D.H.
〖参考〗
Dike,S.Y.;Kumar,A.;Ner,D.H.;AnewchemoenzymaticenantioselectivesynthesisofR-(-)-tomoxetine,(R)-fluoxetineand(S)-fluoxetine.TetrahedronLett1991,32,16,1901
〖出处〗
TetrahedronLett1991,32,(16):
1901
〖备注〗
Anewsynthesisfortomoxetinehydrochloridehasbeenreported:
Thereductionofbenzoylaceticacidethylester(I)withBaker'syeastandglucoseinwater,ortheenzymatichydrolysisof3-acetoxy-3-phenylpropionicacidethylester(II),gives(-)-3-hydroxy-3-phenylpropionicacidethylester(III),whichbyreactionwithmethylamineyieldsthecorrespondingamide(IV).Thereductionof(IV)withLiAlH4inetheraffords(-)-3-hydroxy-N-methyl-3-phenylpropylamine(V),whichisprotectedwithdi-tert-butyldicarbonatetotheamide(VI).Thecondensationof(VI)witho-cresol(VII)bymeansoftriphenylphosphineanddiethylazodicarboxylate(DEAD)inetheryieldstheprotectedfinalproduct(VIII),whichisfinallydeprotectedwithdryHClinmethanol.
〖来源〗
DrugsFut
〖合成路线〗
〖标题〗
Tomoxetinehydrochloride
〖合成方法〗
N,N-Dimethyl3-phenyl-3-(o-tolyloxy)propylamine(I)isallowedtoreactwithphenylchloroformate(II)inrefluxingtoluenetogivephenylmethyl[3-(o-tolyloxy)-3-phenylpropyl]carbamate(III),whichishydrolyzedwithNaOHinrefluxingpropyleneglycol-water.TheracemicproductisthentreatedwithL-mandelicacidandNa2CO3inwatertoyieldthecorresponding(-)-mandelatesaltasaprecipitate,whichisfinallytreatedwithNa2CO3,extractedwithetherandacidifiedwithHCl(I).
〖作者〗
Casta馿r,J.;Prous,J.
〖参考〗
Casta馿r,J.;Prous,J.;Tomoxetinehydrochloride.DrugsFut1986,11,2,134
〖出处〗
DrugsFut1986,11,
(2):
134
〖备注〗
Synthesisof090043:
N,N-Dimethyl3-phenyl-3-(o-tolyloxy)propylamine(I)isallowedtoreactwithphenylchloroformate(II)inrefluxingtoluenetogivephenylmethyl[3-(o-tolyloxy)-3-phenylpropyl]carbamate(III),whichishydrolyzedwithNaOHinrefluxingpropyleneglycol-water.TheracemicproductisthentreatedwithL-mandelicacidandNa2CO3inwatertoyieldthecorresponding(-)-mandelatesaltasaprecipitate,whichisfinallytreatedwithNa2CO3,extractedwithetherandacidifiedwithHCl(I).(Scheme09004302a)DescriptionMp.166-8?
[alpha]20,D=-37.6?
[alpha]25,365=-181.3?
〖来源〗
JChemSoc-PerkinsTransI
〖合成路线〗
〖标题〗
Chemoenzymaticsynthesisofthenon-tricyclicantidepressantsfluoxetine,tomoxetineandnisoxetine
〖合成方法〗
Anewsynthesisoftomoxetinehasbeendescribed:
Thereductionofomega-chloropropiophenone(I)withNaBH4inethanolgives3-chloro-1-phenyl-1-propanol(II),whichistreatedwithbutyricanhydrideandpyridineindichloromethanetoyieldthecorrespondingracemicester(III).Theopticalresolutionof(III)withimmobilizedlipaseBfromCandidaantarctica(CALB)affordsamixtureofunreacted(S)-esterand(R)-alcohol(IV)thatareseparatedbycolumnchromatography.Condensationofth(R)-alcohol(IV)with2-methylphenol(V)bymeansofPPh3anddiethylazodicarboxylate(DEAD)inTHFgivesthecorrespondingether(VI),whichisfinallytreatedwithmethylamineinrefluxingethanol.
〖作者〗
Anthonsen,T.;Ho,B.H.;Liu,H.L.
〖参考〗
Anthonsen,T.;Ho,B.H.;Liu,H.L.;Chemoenzymaticsynthesisofthenon-tricyclicantidepressantsfluoxetine,tomoxetineandnisoxetine.JChemSoc-PerkinsTransI2000,11,11,1767
〖出处〗
JChemSoc-PerkinsTransI2000,11,(11):
1767
〖备注〗
〖来源〗
TetrahedronLett
〖合成路线〗
〖标题〗
Pd-catalyzedkineticresolutionofbenzylicalcohols:
Apracticalsynthesisof(R)-tomoxetineand(S)-fluoxetinehydrochlorides
〖合成方法〗
Thereductionof3-hydroxy-3-phenylpropionicacidethylester(I)withLiAlH4inTHFgives1-phenylpropane-1,3-diol(II),whichistreatedwithTs-ClandTEAindichloromethanetoyieldthemonotosylate(III).Theopticalresolutionof(III)bymeansof(Pd(OAc)2,(-)-sparteineandO2inhottolueneyieldsamixtureofthedesired(S)-1-phenyl-3-(tosyloxy)-1-propanol(IV)andthepropiophenone(V)thatisseparatedbycolumnchromatography.Thereactionof(IV)withmethylamineinhotTHFaffordsthechiralsecondaryamine(VI),whichisfinallycondensedwith2-methylphenol(VII)bymeansofPPh3andDEADinethylethertoprovidethetarget(R)-tomoxetine.
〖作者〗
Ali,I.S.;Sudalai,A.
〖参考〗
Ali,I.S.;Sudalai,A.;Pd-catalyzedkineticresolutionofbenzylicalcohols:
Apracticalsynthesisof(R)-tomoxetineand(S)-fluoxetinehydrochlorides.TetrahedronLett2002,43,31,5435
〖出处〗
TetrahedronLett2002,43,(31):
5435
〖备注〗
〖来源〗
JOrgChem
〖合成路线〗
〖标题〗
Asymmetricsynthesisofbothenantiomersoftomoxetineandfluoxetine.Selectivereductionof2,3-epoxycinnamylalcoholwithRed-Al
〖合成方法〗
Theasymmetricepoxidationof(E)-3-phenyl-2-propen-1-ol(I)bymeansoftitaniumtetraisopropoxide,(+)-diethyltartrate(+)-(DET)andtBu-OOHindichloromethanegivesthechiralepoxide(II),whichisopenedbymeansofbis(2-methoxyethoxy)aluminumhydride(Red-Al)inDMEtoyieldthechiraldiol(III).Theregioselectivereactionof(III)withMs-ClandTEAinethyletheraffordstheprimarymesylate(IV),whichiscondensedwith2-methylphenol(V)bymeansofPPh3andDEADinethylethertoprovidetheadduct(VI).Finallythiscompoundistreatedwithmethylamineinhotaq.THFtogiverisetothetarget(R)-tomoxetine.
〖作者〗
Gao,Y.;Sharpless,K.B.
〖参考〗
Gao,Y.;Sharpless,K.B.;Asymmetricsynthesisofbothenantiomersoftomoxetineandfluoxetine.Selectivereductionof2,3-epoxycinnamylalcoholwithRed-Al.JOrgChem1988,53,17,4081
〖出处〗
JOrgChem1988,53,(17):
4081
〖备注〗
〖来源〗
JAmChemSoc
〖合成路线〗
〖标题〗
Catalyticasymmetricepoxidationandkineticresolution:
Modifiedproceduresincludinginsituderivatization
〖合成方法〗
Theasymmetricepoxidationof(E)-3-phenyl-2-propen-1-ol(I)bymeansoftitaniumtetraisopropoxide,(+)-diethyltartrate(+)-(DET)andtBu-OOHindichloromethanegivesthechiralepoxide(II),whichisopenedbymeansofbis(2-methoxyethoxy)aluminumhydride(Red-Al)inDMEtoyieldthechiraldiol(III).Theregioselectivereactionof(III)withMs-ClandTEAinethyletheraffordstheprimarymesylate(IV),whichiscondensedwith2-methylphenol(V)bymeansofPPh3andDEADinethylethertoprovidetheadduct(VI).Finallythiscompoundistreatedwithmethylamineinhotaq.THFtogiverisetothetarget(R)-tomoxetine.
〖作者〗
Gao,Y.;etal.
〖参考〗
Gao,Y.;etal.;Catalyticasymmetricepoxidationandkineticresolution:
Modifiedproceduresincludinginsituderivatization.JAmChemSoc1987,109,19,5765
〖出处〗
JAmChemSoc1987,109,(19):
5765
〖备注〗
〖来源〗
EP0052492
〖合成路线〗
〖标题〗
3-Aryl-3-phenylpropylamines
〖合成方法〗
N,N-Dimethyl3-phenyl-3-(o-tolyloxy)propylamine(I)isallowedtoreactwithphenylchloroformate(II)inrefluxingtoluenetogivephenylmethyl[3-(o-tolyloxy)-3-phenylpropyl]carbamate(III),whichishydrolyzedwithNaOHinrefluxingpropyleneglycol-water.TheracemicproductisthentreatedwithL-mandelicacidandNa2CO3inwatertoyieldthecorresponding(-)-mandelatesaltasaprecipitate,whichisfinallytreatedwithNa2CO3,extractedwithetherandacidifiedwithHCl(I).
〖作者〗
Foster,B.J.;Lavagnino,E.R.(EliLillyandCompany)
〖参考〗
Foster,B.J.;Lavagnino,E.R.(EliLillyandCompany);3-Aryl-3-phenylpropylamines.EP0052492
〖出处〗
EP0052492,,():
〖备注〗
Synthesisof090043:
N,N-Dimethyl3-phenyl-3-(o-tolyloxy)propylamine(I)isallowedtoreactwithphenylchloroformate(II)inrefluxingtoluenetogivephenylmethyl[3-(o-tolyloxy)-3-phenylpropyl]carbamate(III),whichishydrolyzedwithNaOHinrefluxingpropyleneglycol-water.TheracemicproductisthentreatedwithL-mandelicacidandNa2CO3inwatertoyieldthecorresponding(-)-mandelatesaltasaprecipitate,whichisfinallytreatedwithNa2CO3,extractedwithetherandacidifiedwithHCl(I).(Scheme09004302a)DescriptionMp.166-8?
[alpha]20,D=-37.6?
[alpha]25,365=-181.3?
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