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搜狐彩票大厅:95-48-7,C7H8O,108.1412,o-Cresol

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摘 要:95-48-7,C7H8O,108.1412,o-Cresol
  • 【化學名】o-Cresol
  • 【CAS登記號】95-48-7
  • 【結構式】95-48-7,C7H8O,108.1412,o-Cresol--藥物合成數據庫
  • 【分子式】C7H8O
  • 【分子量】108.1412
  • 【來源】ABCR GmbH & Co.; AccuStandard; Acros Organics; Aldrich; Aldrich Flavors and Fragrances; Alfa Aesar; Atul Limited; Bayer Corporation; Fisher Scientific; Fluka; ICN Biomedical Research Products; Lancaster Synthesis Inc.; Lansdowne Chemicals Plc.; Mallinckrodt Laboratory Chemicals; Nanjing Jingmei Chemical Co., Ltd.; Oakwood Products, Inc.; Organix, Inc.; Pfaltz & Bauer, Inc.; Shanghai Jinshan Xingta Chemical Plant; Shanghai Meishan Chemical Company; Shenyang International Trade Group; Sigma Chemical Company; Spectrum Quality Products, Inc.; TCI; Vihita Chem Private Limited
  • 【合成情況】 
  • 〖目標產物〗Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera
  • 〖合成路線〗
  • 〖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.
  • 〖參考〗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
  • 〖目標產物〗Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera
  • 〖合成路線〗
  • 〖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.
  • 〖參考〗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
  • 〖目標產物〗Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera
  • 〖合成路線〗
  • 〖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.
  • 〖參考〗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
  • 〖目標產物〗Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera
  • 〖合成路線〗
  • 〖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.
  • 〖參考〗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
  • 〖目標產物〗Atomoxetine hydrochloride, Tomoxetine hydrochloride, LY-139602 [(+)-isomer], LY-135252(racemate), LY-139603, Strattera
  • 〖合成路線〗
  • 〖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.
  • 〖參考〗Gao, Y.; et al.; Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization. J Am Chem Soc 1987, 109, 19, 5765
  • 〖目標產物〗HIPDM
  • 〖合成路線〗
  • 〖合成方法〗The 5-methylsalicylaldehyde (I) is prepared by a tin (IV) chloride-catalyzed formylation. Iodination of the aldehyde with ICl in glacial acetic acid gives good yield of 3-methyl-5-iodobenzylaldehyde (III). The iodinated salicylaldehyde is reductively aminated with N,N,N'-trimethylpropane-1,3-diamine and sodium borohydride to give N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine (HIPDM) (III) in excellent yield.
  • 〖參考〗Kung, H.F.; Hostyniak, P.J.; HIPDM. Drugs Fut 1985, 10, 9, 742
  • 〖目標產物〗HIPDM
  • 〖合成路線〗
  • 〖合成方法〗The 5-methylsalicylaldehyde (I) is prepared by a tin (IV) chloride-catalyzed formylation. Iodination of the aldehyde with ICl in glacial acetic acid gives good yield of 3-methyl-5-iodobenzylaldehyde (III). The iodinated salicylaldehyde is reductively aminated with N,N,N'-trimethylpropane-1,3-diamine and sodium borohydride to give N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine (HIPDM) (III) in excellent yield.
  • 〖參考〗Blau, M.; Tramposch, K.M.; Kung, H.F.; Radioiodine-labeled N,N-dimethyl-N'-(2-hydroxy-3-akyl-5-iodobenzyl)-1,3.propanediamines for Brain Perfusion Imaging. J Med Chem 1983, 28, 2, 121-125
 
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