合成路线:A new enantioselective synthesis of (S)-fluoxetine has been reported:Reduction of 3-furaldehyde (I) under Wolff-Kishner conditions provided the desired 3-methylene-2,3-dihydrofuran (II) along with minor amounts of 3-methylfuran (III),which were used in the next step without previous separation.The asymmetric carbonyl-ene reaction of (II) with benzaldehyde (IV) using (S)-1,1'-binaphthol and titanium isopropoxide furnished the target (S)-2-(3-furyl)-1-phenylethanol (V).Condensation of the sodium alkoxide of (V) with 4-fluorobenzotrifluoride (VI) gave rise to ether (VII).Carboxylic acid (VIII) was then obtained by oxidative cleavage of the furan derivative (VII) with RuCl3/NaIO4.Coupling of acid (VIII) with methylamine gave amide (IX).Finally,amide reduction employing borane in THF yielded the title compound.
合成路线:Reduction of 3-furaldehyde (I) under Wolff-Kishner conditions provided the desired 3-methylene-2,3-dihydrofuran (II) along with minor amounts of 3-methylfuran (III),which were used in the next step without previous separation.The asymmetric carbonyl-ene reaction of (II) with benzaldehyde (IV) using (R)-1,1'-binaphthol and titanium isopropoxide furnished the target (R)-2-(3-furyl)-1-phenylethanol (V).Condensation of the sodium alkoxide of (V) with 4-fluorobenzotrifluoride (VI) gave rise to ether (VII).Carboxylic acid (VIII) was then obtained by oxidative cleavage of the furan derivative (VII) with RuCl3/NaIO4.Coupling of acid (VIII) with methylamine gave amide (IX).Finally,amide reduction employing borane in THF yielded the title compound.
参考文献标题:Enantioselective synthesis of (S)- and (R)-fluoxetine hydrochloride
文献作者:Miles,W.H.; et al.
参考来源:Tetrahedron 2001,57(50),9925
合成路线:The reduction of 3-hydroxy-3-phenylpropionic acid ethyl ester (I) with LiAlH4 in THF gives 1-phenylpropane-1,3-diol (II),which is treated with Ts-Cl and TEA in dichloromethane to yield the monotosylate (III).The optical resolution of (III) by means of (Pd(OAc)2,(-)-sparteine and O2 in hot toluene yields a mixture of the desired (S)-1-phenyl-3-(tosyloxy)-1-propanol (IV) and the propiophenone (V) that is separated by column chromatography.The reaction of (IV) with methylamine in hot THF affords the chiral secondary amine (VI),which is finally condensed with 2-methylphenol (VII) by means of PPh3 and DEAD in ethyl ether to provide the target (R)-tomoxetine.
合成路线:The asymmetric epoxidation of (E)-3-phenyl-2-propen-1-ol (I) by means of titanium tetraisopropoxide,(+)-diethyl tartrate (+)-(DET) and tBu-OOH in dichloromethane gives the chiral epoxide (II) (1),which is opened by means of bis(2-methoxyethoxy)aluminum hydride (Red-Al) in DME to yield the chiral diol (III).The regioselective reaction of (III) with Ms-Cl and TEA in ethyl ether affords the primary mesylate (IV),which is treated with methylamine in hot THF to afford the secondary amine (V).Finally this compound is condensed with 4-(trifluoromethyl)chlorobenzene (VI) by means of NaH in dimethylacetamide to give rise to the target (S)-fluoxetine.
参考文献标题:Pd-catalyzed kinetic resolution of benzylic alcohols: A practical synthesis of (R)-tomoxetine and (S)-fluoxetine hydrochlorides
文献作者:Ali,I.S.; Sudalai,A.
参考来源:Tetrahedron Lett 2002,43(31),5435
合成路线:The asymmetric epoxidation of (E)-3-phenyl-2-propen-1-ol (I) by means of titanium tetraisopropoxide,(+)-diethyl tartrate (+)-(DET) and tBu-OOH in dichloromethane gives the chiral epoxide (II),which is opened by means of bis(2-methoxyethoxy)aluminum hydride (Red-Al) in DME to yield the chiral diol (III).The regioselective reaction of (III) with Ms-Cl and TEA in ethyl ether affords the primary mesylate (IV),which is condensed with 2-methylphenol (V) by means of PPh3 and DEAD in ethyl ether to provide the adduct (VI).Finally this compound is treated with methylamine in hot aq.THF to give rise to the target (R)-tomoxetine.
合成路线:The reduction of 3-hydroxy-3-phenylpropionic acid ethyl ester (I) with LiAlH4 in THF gives 1-phenylpropane-1,3-diol (II),which is treated with Ts-Cl and TEA in dichloromethane to yield the monotosylate (III).The optical resolution of (III) by means of (Pd(OAc)2,(-)-sparteine and O2 in hot toluene yields a mixture of the desired (S)-1-phenyl-3-(tosyloxy)-1-propanol (IV) and the propiophenone (V) that is separated by column chromatography.The reaction of (IV) with methylamine in hot THF affords the chiral secondary amine (VI),which is finally condensed with 4-(trifluoromethyl)chlorobenzene (VII) by means of NaH in hot dimethylacetamide to provide the target (S)-fluoxetine.
参考文献标题:Asymmetric synthesis of both enantiomers of tomoxetine and fluoxetine.Selective reduction of 2,3-epoxycinnamyl alcohol with Red-Al
文献作者:Gao,Y.; Sharpless,K.B.
参考来源:J Org Chem 1988,53(17),4081
合成路线:The asymmetric epoxidation of (E)-3-phenyl-2-propen-1-ol (I) by means of titanium tetraisopropoxide,(+)-diethyl tartrate (+)-(DET) and tBu-OOH in dichloromethane gives the chiral epoxide (II),which is opened by means of bis(2-methoxyethoxy)aluminum hydride (Red-Al) in DME to yield the chiral diol (III).The regioselective reaction of (III) with Ms-Cl and TEA in ethyl ether affords the primary mesylate (IV),which is condensed with 2-methylphenol (V) by means of PPh3 and DEAD in ethyl ether to provide the adduct (VI).Finally this compound is treated with methylamine in hot aq.THF to give rise to the target (R)-tomoxetine.
合成路线:The reduction of 3-hydroxy-3-phenylpropionic acid ethyl ester (I) with LiAlH4 in THF gives 1-phenylpropane-1,3-diol (II),which is treated with Ts-Cl and TEA in dichloromethane to yield the monotosylate (III).The optical resolution of (III) by means of (Pd(OAc)2,(-)-sparteine and O2 in hot toluene yields a mixture of the desired (S)-1-phenyl-3-(tosyloxy)-1-propanol (IV) and the propiophenone (V) that is separated by column chromatography.The reaction of (IV) with methylamine in hot THF affords the chiral secondary amine (VI),which is finally condensed with 4-(trifluoromethyl)chlorobenzene (VII) by means of NaH in hot dimethylacetamide to provide the target (S)-fluoxetine.
参考文献标题:Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization
文献作者:Gao,Y.; et al.
参考来源:J Am Chem Soc 1987,109(19),5765
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