- 【化学名】(1S)-3-(Methylamino)-1-phenyl-1-propanol
- 【CAS登记号】114133-37-8
- 【结构式】
- 【分子式】C10H15NO
- 【分子量】165.2372
- 【来源】Aldrich; D&O Chemicals, Inc.; Hangzhou Coben Chemical Co., Ltd.; SpeedChem Company
- 【合成情况】
- 〖目标产物〗Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera
- 〖合成路线〗
- 〖合成方法〗A new synthesis for tomoxetine hydrochloride has been reported: The reduction of benzoylacetic acid ethyl ester (I) with Baker's yeast and glucose in water, or the enzymatic hydrolysis of 3-acetoxy-3-phenylpropionic acid ethyl ester (II), gives (-)-3-hydroxy-3-phenylpropionic acid ethyl ester (III), which by reaction with methylamine yields the corresponding amide (IV). The reduction of (IV) with LiAlH4 in ether affords (-)-3-hydroxy-N-methyl-3-phenylpropylamine (V), which is protected with di-tert-butyldicarbonate to the amide (VI). The condensation of (VI) with o-cresol (VII) by means of triphenylphosphine and diethylazodicarboxylate (DEAD) in ether yields the protected final product (VIII), which is finally deprotected with dry HCl in methanol.
- 〖参考〗Dike, S.Y.; Kumar, A.; Ner, D.H.; A new chemoenzymatic enantioselective synthesis of R-(-)-tomoxetine, (R)-fluoxetine and (S)-fluoxetine. Tetrahedron Lett 1991, 32, 16, 1901
- 〖目标产物〗Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera
- 〖合成路线〗
- 〖合成方法〗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.
- 〖参考〗Ali, I.S.; Sudalai, A.; Pd-catalyzed kinetic resolution of benzylic alcohols: A practical synthesis of (R)-tomoxetine and (S)-fluoxetine hydrochlorides. Tetrahedron Lett 2002, 43, 31, 5435
- 〖目标产物〗(S)-Fluoxetine
- 〖合成路线〗
- 〖合成方法〗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〗Gao, Y.; Sharpless, K.B.; Asymmetric synthesis of both enantiomers of tomoxetine and fluoxetine. Selective reduction of 2,3-epoxycinnamyl alcohol with Red-Al. J Org Chem 1988, 53, 17, 4081
- 〖目标产物〗(S)-Fluoxetine
- 〖合成路线〗
- 〖合成方法〗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〗Gao, Y.; et al.; Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization. J Am Chem Soc 1987, 109, 19, 5765
- 〖目标产物〗(S)-Fluoxetine
- 〖合成路线〗
- 〖合成方法〗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〗Ali, I.S.; Sudalai, A.; Pd-catalyzed kinetic resolution of benzylic alcohols: A practical synthesis of (R)-tomoxetine and (S)-fluoxetine hydrochlorides. Tetrahedron Lett 2002, 43, 31, 5435
- 〖目标产物〗(R)-Fluoxetine
- 〖合成路线〗
- 〖合成方法〗The esterification of 3-benzoylpropionic acid (I) with methanol and sulfuric acid gives the corresponding methyl ester (II), which is regioselectively reduced with (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] in THF, yielding the chiral lactone (III). Ring opening of (III) with ammonia in methanol affords the chiral butyramide (IV), which is treated with iodobenzene diacetate (IBA) in acetonitrile to provide the cyclic carbamate (V). The methylation of (V) with NaH and methyl iodide in DMF gives the expected N-methyl derivative (VI), which is hydrolyzed with NaOH in refluxing ethanol to yield the chiral 3-(methylamino)-1(S)-phenyl-1-propanol (VII). Finally, this compound is condensed with 4-(trifluoromethyl)chlorobenzene (VIII) by means of NaH in DMSO. The intermediate propanol (VII) can also be obtained directly from (V), by reductive cleavage of the carbamate ring with borane/dimethyl sulfide complex in THF.
- 〖参考〗Senanayake, C.H.; Hilborn, J.W.; Jurgens, A.R. (Sepracor Inc.); Fluoxetine process from benzoylpropionic acid. WO 9967196
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