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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