盐酸托莫西汀.docx

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?