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盐酸托莫西汀盐酸托莫西汀 , Atomoxetine hydrochloride, Tomoxetine hydrochloride, 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】 Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera 【化学名】 (R)-(-)-N-Methyl-gamm...
盐酸托莫西汀
盐酸托莫西汀 , Atomoxetine hydrochloride, Tomoxetine hydrochloride, 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】 Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera 【化学名】 (R)-(-)-N-Methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride; (R)-(-)-N-Methyl-3-phenyl-3-(2-methylphenoxy)propylamine hydrochloride 【CAS登记号】 82248-59-7, 83015-26-3 (free base) 【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, Attention Deficit Hyperactivity Disorder (ADHD), Treatment of, Autism, Treatment of, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Norepinephrine Reuptake Inhibitors 【研发状态】 Launched-2003 【合成情况】 〖来源〗 Tetrahedron Lett 〖合成路线〗 〖标题〗 A new chemoenzymatic enantioselective synthesis of R-(-)-tomoxetine, (R)-fluoxetine and (S)-fluoxetine 〖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. 〖作者〗 Dike, S.Y.; Kumar, A.; Ner, D.H. 〖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 〖出处〗 Tetrahedron Lett1991,32,(16):1901 〖备注〗 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. 〖来源〗 Drugs Fut 〖合成路线〗 〖标题〗 Tomoxetine hydrochloride 〖合成方法〗 N,N-Dimethyl 3-phenyl-3-(o-tolyloxy)propylamine (I) is allowed to react with phenyl chloroformate (II) in refluxing toluene to give phenyl methyl [3-(o-tolyloxy)-3-phenylpropyl]carbamate (III), which is hydrolyzed with NaOH in refluxing propyleneglycol - water. The racemic product is then treated with L-mandelic acid and Na2CO3 in water to yield the corresponding (-)-mandelate salt as a precipitate, which is finally treated with Na2CO3, extracted with ether and acidified with HCl (I). 〖作者〗 Casta馿r, J.; Prous, J. 〖参考〗 Casta馿r, J.; Prous, J.; Tomoxetine hydrochloride. Drugs Fut 1986, 11, 2, 134 〖出处〗 Drugs Fut1986,11,(2):134 〖备注〗 Synthesis of 090043: N,N-Dimethyl 3-phenyl-3-(o-tolyloxy)propylamine (I) is allowed to react with phenyl chloroformate (II) in refluxing toluene to give phenyl methyl [3-(o-tolyloxy)-3-phenylpropyl]carbamate (III), which is hydrolyzed with NaOH in refluxing propyleneglycol- water. The racemic product is then treated with L- mandelic acid and Na2CO3 in water to yield the corresponding (-)-mandelate salt as a precipitate, which is finally treated with Na2CO3, extracted with ether and acidified with HCl (I). (Scheme 09004302a) Description Mp. 166-8? [alpha]20,D= -37.6? [alpha]25,365= -181.3? 〖来源〗 J Chem Soc - Perkins Trans I 〖合成路线〗 〖标题〗 Chemoenzymatic synthesis of the non-tricyclic antidepressants fluoxetine, tomoxetine and nisoxetine 〖合成方法〗 A new synthesis of tomoxetine has been described: The reduction of omega-chloropropiophenone (I) with NaBH4 in ethanol gives 3-chloro-1-phenyl-1-propanol (II), which is treated with butyric anhydride and pyridine in dichloromethane to yield the corresponding racemic ester (III). The optical resolution of (III) with immobilized lipase B from Candida antarctica (CALB) affords a mixture of unreacted (S)-ester and (R)-alcohol (IV) that are separated by column chromatography. Condensation of th (R)-alcohol (IV) with 2-methylphenol (V) by means of PPh3 and diethyl azodicarboxylate (DEAD) in THF gives the corresponding ether (VI), which is finally treated with methylamine in refluxing ethanol. 〖作者〗 Anthonsen, T.; Ho, B.H.; Liu, H.L. 〖参考〗 Anthonsen, T.; Ho, B.H.; Liu, H.L.; Chemoenzymatic synthesis of the non-tricyclic antidepressants fluoxetine, tomoxetine and nisoxetine. J Chem Soc - Perkins Trans I 2000, 11, 11, 1767 〖出处〗 J Chem Soc - Perkins Trans I2000,11,(11):1767 〖备注〗 〖来源〗 Tetrahedron Lett 〖合成路线〗 〖标题〗 Pd-catalyzed kinetic resolution of benzylic alcohols: A practical synthesis of (R)-tomoxetine and (S)-fluoxetine hydrochlorides 〖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. 〖作者〗 Ali, I.S.; Sudalai, A. 〖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 〖出处〗 Tetrahedron Lett2002,43,(31):5435 〖备注〗 〖来源〗 J Org Chem 〖合成路线〗 〖标题〗 Asymmetric synthesis of both enantiomers of tomoxetine and fluoxetine. Selective reduction of 2,3-epoxycinnamyl alcohol with Red-Al 〖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), 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. 〖作者〗 Gao, Y.; Sharpless, K.B. 〖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 〖出处〗 J Org Chem1988,53,(17):4081 〖备注〗 〖来源〗 J Am Chem Soc 〖合成路线〗 〖标题〗 Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization 〖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), 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. 〖作者〗 Gao, Y.; et al. 〖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 〖出处〗 J Am Chem Soc1987,109,(19):5765 〖备注〗 〖来源〗 EP 0052492 〖合成路线〗 〖标题〗 3-Aryl-3-phenylpropylamines 〖合成方法〗 N,N-Dimethyl 3-phenyl-3-(o-tolyloxy)propylamine (I) is allowed to react with phenyl chloroformate (II) in refluxing toluene to give phenyl methyl [3-(o-tolyloxy)-3-phenylpropyl]carbamate (III), which is hydrolyzed with NaOH in refluxing propyleneglycol - water. The racemic product is then treated with L-mandelic acid and Na2CO3 in water to yield the corresponding (-)-mandelate salt as a precipitate, which is finally treated with Na2CO3, extracted with ether and acidified with HCl (I). 〖作者〗 Foster, B.J.; Lavagnino, E.R. (Eli Lilly and Company) 〖参考〗 Foster, B.J.; Lavagnino, E.R. (Eli Lilly and Company); 3-Aryl-3-phenylpropylamines. EP 0052492 〖出处〗 EP 0052492,,(): 〖备注〗 Synthesis of 090043: N,N-Dimethyl 3-phenyl-3-(o-tolyloxy)propylamine (I) is allowed to react with phenyl chloroformate (II) in refluxing toluene to give phenyl methyl [3-(o-tolyloxy)-3-phenylpropyl]carbamate (III), which is hydrolyzed with NaOH in refluxing propyleneglycol- water. The racemic product is then treated with L- mandelic acid and Na2CO3 in water to yield the corresponding (-)-mandelate salt as a precipitate, which is finally treated with Na2CO3, extracted with ether and acidified with HCl (I). (Scheme 09004302a) Description Mp. 166-8? [alpha]20,D= -37.6? [alpha]25,365= -181.3?
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