SummaryCrossaldolreactionoftricarbonyl(eta6-benzaldehyde)chromium (I)withparaldehyde(II)bymeansofpolystyreneboundsulfonic acidcatalystandpolystyrenesupporteddi(3,5-bis(trifluoromethy l)phenyl)proplinolcatalystinacetonitrile/H2Ogivestheadduct (III),whichuponphotolysisinEt2Oaffords3(R)-hydroxy-3-pheny lpropanal(IV).Condensationofaldehyde(IV)withmethylamine(V )inthepresenceofNa2SO4inTHF,followedbyreductionwithNa BH(OAc)3provides3-(methylamino)-1-phenyl-1(R)-propanol(VI)(2) .Thiscompoundisalternativelypreparedbyreductionof3-(meth ylamino)-1-phenyl-1-propanonehydrochloride(VII)withKBH4inTH Fat66°Cyields3-(methylamino)-1-phenyl-1-propanolhydrochlori de(VIII),whichupontreatmentwithNaHCO3inCH2Cl2/H2Oandsub sequentchiralresolutionbymeansofL-mandelicacidinacetone (1).Otherwise,hydroborationofN-methyl-3-phenyl-2-propenamine (IX)with(Ipc)2BHinDME,followedbyoxidationbymeansofH2O2 andKOHyieldsdesired(R)-alcohol(VI)(3).Condensationofalc ohol(VI)withortho-halotoluenes(Xa-c)inEtOAcat77°C(1)or witho-fluorotoluene(Xd)inEtOAcat77°C,optionallyusingKO HinDMSOat130°C(1,3)providesatomoxetinefreebase(XI),wh ichisfinallytreatedwithHClinacetonetoaffordatomoxetine hydrochloride(1,3).SummarySynthesisofakeyintermediatetoat omoxetinehydrochloride:Mannichreactionofacetophenone(I)wit hmethylaminehydrochloride(II)and(HCHO)ninthepresenceofp -TsOHinEtOHat110°Cgives3-(methylamino)-1-phenyl-1-propanon ehydrochloride(III)(1),whichuponenantioselectivereduction bymeansofH2,[Rh((R,R)-BenzP((COD)]SbF6,ZnCl2andCs2CO3in MeOH(1)orenzymaticreductionbymeansofcarbonylreductase(d erivedfromEscherichiacoliTM1908),isopropanoldehydrogenasea ndNADP+ini-PrOH(2)furnishes3-(methylamino)-1-phenylpropan-1 (R)-ol(IV),akeyintermediatetoatomoxetinehydrochloride(1,2 ).Alternativesynthesisofintermediate(III):Iodinationof3-c hloropropiophenone(V)withNaIinacetonegives3-iodopropiophen one(VI),whichuponcouplingwithmethylamine(VII)inTHFyield ssecondaryamine(VIII),whichupontreatmentwithHClinEtOHg enerates3-(methylamino)-1-phenyl-1-propanonehydrochloride(III) (2).SummaryAlternativesynthesisofintermediate(II):Enantios electiveReformatskyreactionofbenzaldehyde(X)withethyliodo acetate(XI)bymeansofMe2ZnandPh3POinthepresenceofcatal yst(G)inEt2O/toluenefurnishesethyl3(S)-hydroxy-3-phenylprop anoate(II)(3).Preparationofcatalyst(G):Esterificationof( S)-indoline-2-carboxylicacid(XII)withMeOHinthepresenceof SOCl2,followedbyN-protectionwithBoc2OusingEt3Nprovidesth ecorrespondingcarbamate(XIII).Reactionofmethylesterderiva tive(XIII)withphenylmagnesiumbromide(XIV)inEt2Oat0°Cle adstotertiaryalcohol(XV),whoseBocmoietyisdeprotectedin thepresenceofTFAinCH2Cl2toafford[2(S)-indolinyl]-diphenyl methanol(G)(3).SummarySynthesisofatomoxetinefreebase(XIII ):Asymmetrichydrocyanationreactionofbenzaldehyde(I)withHC NinthepresenceofPrunusarmeniacahydroxynitrilelyase(ParsH NL)ini-Pr2Ogives(R)-mandelonitrile(II),whichisprotecteda sthecorrespondingsilylether(III)usingTBDMSClinthepresen ceofimidazoleandDMAPinCH2Cl2.Treatmentofnitrile(III)wi thDIBALinCH2Cl2providesthealdehyde(IV),whichuponWittig olefinationwithmethyltriphenylphosphoniumiodide(V)inthepre senceofLiHMDSinTHFyieldstheolefin(VI).Hydroboration-oxid ationreactionofterminalalkene(VI)withBH3·Me2SinTHFthen NaOHandH2O2affordsalcohol(VII),whichisconvertedtotheco rrespondingmesylate(VIII)usingMsClandEt3NinCH2Cl2.Conden sationofmesylate(VIII)withmethylamine(IX)inTHFat65°Cg ivesrisetothesecondaryamine(X),fromwhichtheTBDMSgroup isremovedbymeansofTBAFinTHFtoobtainthecorresponding(S )-alcohol(IX).Finally,Mitsunobureactionofaminoalcohol(XI) withortho-cresol(XII)bymeansofDIADandPPh3inTHFfurnish estheatomoxetinefreebase(XIII)(1).SummarySynthesisofatom oxetine:Mannichreactionofacetophenone(I)withN,O-dimethylhy droxylamine(II)andformaldehydeinthepresenceofHClini-PrO Hgivessubstitutedaminoketone(III),whichuponenantioselecti vereductionwithH2inthepresenceofRuCl2((S)-DMSEGPHOS)((S)- DAIPEN)andNaOMeinMeOHaffords(R)-alcohol(IV).Subsequenthy drogenolysisofmethoxyamine(IV)overRaney-NiinMeOHat50°C provides3-(methylamino)-1-phenylpropan-1(R)-ol(V)(1),whicht hencoupleswith1-fluoro-2-methylbenzene(VIa)(1,2)inthepres enceoft-BuOKinDMSOat60°C(1),orKOH,NaOMe,NaOEtorNaOH at100°C(2)tofurnishatomoxetine(VII)(1,2).Also,asymmetr icreductionof3-(methylamino)-1-phenylpropan-1-one(VIII)with (S)-BINAPinacetonitrileor(S)-BINAP-RuinTHFyieldsthecorre sponding(R)-alcohol(V),whichuponMitsunobureactionwitho-cr esol(VIb)inthepresenceofBu3PandADDPinTHFat60°CorPh 3andDEADintolueneat120°Caffordsthetargetatomoxetine(V II)(3).SummaryThecondensationofacetophenone(I)withN-benzy l-N-methylamine(II)andparaformaldehydeinaq.HClgives3-(N-b enzyl-N-methylamino)-1-phenyl-1-propanone(III),whichisreduced bymeansofNaBH4inmethanoltoyieldthealcohol(IV).Therea ctionof(IV)withSOCl2inchloroformaffordsthecorresponding chloroderivative(V),whichiscondensedwitho-cresol(VI)bym eansofK2CO3inDMSOtoprovidetheether(VII).Theopticalres olutionoftheracemicether(VII)bymeansof(S)-(+)-mandelica cidinrefluxingisopropanolyieldsthe(R)-enantiomer(VIII),w hichiscondensedwithphenylchloroformate(IX)andNaOHinhot toluenetoaffortdthedebenzylatedphenylcarbamate(X).Finally thiscompoundistreatedwithKOHinDMSOat100oCtoobtainth efreebaseofthetitlecompound(XI)(1).SummaryCondensationo f3-(methylamino)-1-phenylpropanol(I)with2-fluorotoluene(II) bymeansoftBuOKinDMAC,followedbyatreatmentwithoxalicac idgivesN-[3-(2-methylphenoxy)-3-phenyllpropyl]-N-methylamineox alate(III)asaracemicmixture,whichuponchiralresolutionby meansof(+)-mandelicacidprovidesatomoxetineL-mandelate(IV) .Finally,thisaminesaltistreatedwithNaOHtofurnishatomox etinefreebase(V)(1).SummaryReductionof3''-chloropropiopheno ne(I)withNaBH4inEtOH(1)orLiAlH4(2)gives3-chloro-1-phen yl-1-propanol(II)(1,2),whichisesterifiedwith(n-PrCO)2Oin thepresenceofpyridineinCH2Cl2toyieldtheracemicpropionat eester(III).Opticalresolutionofintermediate(III)withimmo bilizedlipaseBfromCandidaantarctica(CALB)affordsamixture of(R)-alcohol(IV)andunreacted(S)-ester,thatareseparated bycolumnchromatography(1).Alternatively,thedesired(R)-alco hol(IV)hasbeenobtainedbyesterificationoftheracemicinter mediate(II)with(ClCH2CO)2Ointhepresenceofpyridine,follow edbyenzymatichydrolysisoftheracemicester(IX)usinglipase SAM-2(2).Mitsunobucouplingof(R)-alcohol(IV)witho-cresol (V)usingPPh3andDEAD(1,2)inTHF(1)producesthecorrespondi ngether(VI),whichisthencondensedwithmethylamine(VII)(1, 2)inrefluxingEtOH(1),optionallyinthepresenceofNaI(2), toprovidetomoxetine(VIII)(1,2).Finally,treatmentofthefre ebase(VIII)withHClfurnishesthetargettomoxetinehydrochlor ide.SummaryMannichreactionofacetophenone(I)withdimethylami ne(II)andHCHOini-PrOHat80°Caffordsbeta-(dimethylamino)p ropiophenonehydrochloride(III),whichuponreductionwithNaBH4 inthepresenceofaqueousNaOH,followedbytreatmentwithHCl ini-Pr2Ofurnishes3-(dimethylamino)-1-phenyl-1-propanolhydroch loride(IV).Chlorinationofalcohol(IV)bymeansofSOCl2into luene/triethylorthoformategivesthecorrespondingchloroderiva tive(V),whichthencoupleswitho-cresol(VI)inthepresenceo fNaOHintoluene/H2OorDMSOat90°CtoyieldN,N-dimethyl-3-(o -tolyloxy)-3-phenylpropylamine(VII)(1).N-Demethylationofinte rmediate(VII)usingPhOCOClinrefluxingtolueneproducesphenyl N-methyl-3-(o-tolyloxy)-3-phenylpropyl]carbamate(VIII)(1,2),w hichishydrolyzedwithKOHinrefluxingtolueneorNaOHinreflu xingpropyleneglycol/H2Otoyieldracemicatomoxetine(IX)(1,2). Resolutionofracemate(IX)with(S)-(+)-mandelicacidinH2Oor EtOAc,tolueneat70°C,toluene/MTBE,acetonitrile,toluene/MeO H,orEtOAcandsubsequenttreatmentoftheresultantfreebasew ithHClinH2O,EtOAc,BuOAc/H2OorBuOAc/tolueneoracetonitrile /i-Pr2Ofurnishesthedesiredatomoxetinehydrochloride(1-4,6,7) .Alternativesynthesisofintermediate(IX):Condensationofeno ne(X)withmethylamine(XI)inEtOH,i-PrOH,MeOH,THF,acetone ,EtOAcortolueneaffords(2E)-3-(methylamino)-1-phenylprop-2-en -1-one(XII),whoseketogroupisreducedtosecondaryalcohol(X III)bymeansofNaBH4inTHF,KBH4inEtOHorLiAlH4inMeOH.Re ductionofalpha,beta-unsaturatedamine(XIII)withH2overPd/C inEtOHorEtOAc,H2overRaney-NiinEtOHorH2overPd(OH)2/C inTHFgivesasecondaryamine(XIV).Thiscompoundisalternativ elyproducedbyreductionofketone(XV)(obtainedbyhydrogenoly sisofenone(XII)usingPd/CinAcOHorEtOH,Raney-NiinEtOHo rPd(OH)2/CinMeOH)withKBH4inEtOH,NaBH4inTHForLiHinTH ForEtOH(5).Alternatively,directcondensationofacrylophenon e(X)withmethylamine(XI)inthepresenceofNaBH4inEtOHaffo rdsalcohol(XIV)(7).Etherificationofsecondaryalcohol(XIV) witho-fluorotoluene(XVIa)(1-5,6,7)oro-chlorotoluene(XVIb)( 5)inthepresenceofKOHintoluene,triethyleneglycoldimethyl etherorDMSOat100°C,NaOHinDMFat100°C,K2CO3inDMFor DMAat100°CorNa2CO3inDMAat100°Cgivesracemicatomoxetin e(IX)(1-7).SummaryThebiocatalyticreductionof3-oxo-3-phenyl propionitrile(I)employingbaker''syeastorCurvularialunatapr ovides3(R)-hydroxy-3-phenylpropionitrile(IIa),whichisfurther reducedusingBH3·Et2SinTHFtoyield(R)-3-hydroxy-3-phenylpro pylamine(III).Acylationofamine(III)withethylchloroformate (IVa)inthepresenceofK2CO3inCH2Cl2(1,2)orwithmethylch loroformate(IVb)inthepresenceofNaHCO3inTHF(3)affordsth ecorrespondingcarbamates(Va)(1,2)or(Vb)(3),respectively. Subsequentreductionofcarbamates(Va)(1,2)or(Vb)(3)withLi AlH4inrefluxingTHFprovidestheN-methylamine(VI)(1,2,3),w hichuponcondensationwitheither2-chlorotoluene(VIIa)(1,2)or2-fluorotoluene(VIIb)(3)bymeansofNaHinDMSOproduces(R)-tomoxetine(VIII)(1,2,3).Thefreebase(VIII)isfinallyconvertedtothetitle(R)-tomoxetinehydrochloridebytreatmentwithHCl.Intermediate(III)hasalsobeenobtainedbyadifferentstrategy:Condensationofbenzaldehyde(IX)withacetonitrile(X)inthepresenceoft-BuOK,BuLiorNaOMeinTHFat-65°Cto0°Cprovidesracemic3-hydroxy-3-phenylpropionitrile(IIb).Reductionofnitrile(IIb)withBH3·Me2SorLiAlH4inrefluxingTHF,orbycatalytichydrogenationoverRaney-NiinNH3/EtOHat90°Caffordstheracemicaminoalcohol(XI),whichisthenresolvedwith(S)-(+)-mandelicacidtoyieldtherequired(R)-enantiomer(III)(3).他达那非 |
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