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【结 构 式】

【药物名称】Paroxetine, NNC-20-7051, BRL-29060, FG-7051

【化学名称】(-)-(3S,4R)-3-(1,3-Benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine

【CA登记号】61869-08-7

【 分 子 式 】C19H20FNO3

【 分 子 量 】329.37455

【开发单位】Ferrosan A/S (Originator), GlaxoSmithKline (Licensee)

【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT Reuptake Inhibitors

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

A synthesis of [14C]-paroxetine labeled at the methylenedioxy group has been described: 4-Nitropyrocatechol (I) is cyclized with [14C]-CH2Br2 by means of cesium carbonate in DMSO, giving 3,4-(methylenedioxy)nitrobenzene (III). The reduction of (III) with H2 over Pd/C in ethanol yields the corresponding aniline (IV), which is treated with HNO2, copper nitrite and cuprous oxide to afford the corresponding phenol (V). The condensation of (V) with (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-(phenylsulfonyloxymethyl)piperidine (VI) by means of sodium methoxide in methanol gives [14C]-labeled 1-methylparoxetine (VII), which is finally demethylated with vinyl chloroformate and potassium carbonate in dichloroethane.

参考文献 中间体
【1】 Lawrie, K.W.M.; Rustidge, D.C.; The synthesis of [methylene-14C]paroxetine BRL 29060A. J Label Compd Radiopharm 1993, 33, 8, 777.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10982 4-Nitrocatechol; 4-Nitro-1,2-benzenediol; 1,2-Dihydroxy-4-nitrobenzene 3316-09-4 C6H5NO4 详情 详情
(III) 10983 1,2-(Methylenedioxy)-4-nitrobenzene; 5-Nitro-1,3-benzodioxole 2620-44-2 C7H5NO4 详情 详情
(III) 45030 5-nitro-1,3-benzodioxole C7H5NO4 详情 详情
(IV) 10984 1,3-Benzodioxol-5-amine; 1,3-Benzodioxol-5-ylamine.; 3,4-(Methylenedioxy)aniline 14268-66-7 C7H7NO2 详情 详情
(IV) 45031 1,3-benzodioxol-5-amine; 1,3-benzodioxol-5-ylamine C7H7NO2 详情 详情
(V) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(V) 45032 1,3-benzodioxol-5-ol C7H6O3 详情 详情
(VI) 10986 [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl benzenesulfonate C19H22FNO3S 详情 详情
(VII) 10987 (3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylhexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl ether C20H22FNO3 详情 详情
(VII) 45033 1,3-benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methyl ether; (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylpiperidine C20H22FNO3 详情 详情
(VIII) 10988 (3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)hexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)hexahydro-3-pyridinyl]methyl ether C19H20FNO3 详情 详情
(VIII) 45039 (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)piperidinyl]methyl ether C19H20FNO3 详情 详情

合成路线2

A synthesis of [14C]-paroxetine labeled at the -CH2O- group has been described: 4-(4-Fluorophenyl)-1-methyl-1,2,5,6-tetrahydropyridine (I) is hydroxymethylated with [14C]-formaldehyde (II), yielding 4-(4-fluorophenyl)-1-methyl-1,2,5,6-tetrahydropyridine-3-methanol (III), which is hydrogenated with H2 over Pd/C in ethanol to give 4-(4-fluorophenyl)-1-methylpiperidine-3-methanol (IV) as a mixture of cis- and trans-isomers. The reaction of (IV) with phenylsulfonyl chloride and NaOH in water affords the corresponding sulfonate (V), which is then condensed with 3,4-(methylenedioxy)phenol (VI) by means of NaOH in toluene-4-methyl-2-pentanol, giving 4-(4-fluorophenyl)-1-methyl-3-[3,4-(methylenedioxy)phenoxymethyl]piperi dine (VII). The chromatographic separation of the trans-isomer of (VII), followed by its optical resolution with L-(+)-tartaric acid, affords optically pure (-)-(3S,4R)-N-methylparoxetine (VIII), which is finally demethylated with vinyl chloroformate and dry HCl.

参考文献 中间体
【1】 Willcocks, K.; Rustidge, D.C.; Barnes, R.D.; Tidy, D.J.D.; The synthesis of [14C]-3S,4R-4-(4-fluorophenyl)-3-(3,4-methylenedioxyp henoxymethyl)piperidine hydrochloride (BRL 29060A), and mechanistic studies using carbon-13 labelling. J Label Compd Radiopharm 1993, 33, 8, 783.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV cis+trans) 10991 [4-(4-Fluorophenyl)-1-methyl-3-piperidinyl]methanol C13H18FNO 详情 详情
(V cis+trans) 10992 [4-(4-fluorophenyl)-1-methyl-3-piperidinyl]methyl benzenesulfonate C19H22FNO3S 详情 详情
(IV cis+trans) 45035 [4-(4-fluorophenyl)-1-methyl-3-piperidinyl]methanol C13H18FNO 详情 详情
(V cis+trans) 45036 [4-(4-fluorophenyl)-1-methyl-3-piperidinyl]methyl benzenesulfonate C19H22FNO3S 详情 详情
(I) 10989 4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine C12H14FN 详情 详情
(III) 10990 [4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydro-3-pyridinyl]methanol C13H16FNO 详情 详情
(III) 45034 [4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydro-3-pyridinyl]methanol C13H16FNO 详情 详情
(VI) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(VII) 10994 1,3-Benzodioxol-5-yl [4-(4-fluorophenyl)-1-methyl-3-piperidinyl]methyl ether; 3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylpiperidine C20H22FNO3 详情 详情
(VII) 45037 1,3-benzodioxol-5-yl [4-(4-fluorophenyl)-1-methyl-3-piperidinyl]methyl ether; 3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylpiperidine C20H22FNO3 详情 详情
(VIII) 10987 (3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylhexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl ether C20H22FNO3 详情 详情
(VIII) 45038 (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylpiperidine; 1,3-benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methyl ether C20H22FNO3 详情 详情

合成路线3

By condensation of 4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine (I) with 3,4-methylenedioxyphenol (II) with dicyclohexylcarbodiimide (DCC) at 180 C.

参考文献 中间体
【1】 Christensen, J.A.; Squires, R.F. (Ferrosan A/S); 4-Phenylpiperidine compounds. DE 2404113; ES 422734; FR 2215233; GB 1422263; JP 58174363; US 3912743 .
【2】 Kozak, A.; Shapiro, I. (D-Pharm Ltd.); Lipophilic diesters of chelating agents. JP 2001518458; WO 9916741 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 28828 [4-(4-fluorophenyl)-3-piperidinyl]methanol C12H16FNO 详情 详情
(II) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情

合成路线4

The reaction of 4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (I) with formaldehyde and H2SO4 gives racemic 4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (II), which is submitted to optical resolution with (-)-dibenzoyltartaric acid, yielding the 3(S)-enantiomer (III). The reduction of (III) with H2 over Pd/C in ethanol affords trans-(3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methylpiperidine (IV), which is treated with SOCl2 to provide the corresponding chloromethyl derivative (V). The condensation of (V) with 1,3-benzodioxol-5-ol (VI) by means of NaOMe in methanol furnishes trans-(3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)-1-methylpiperidine (VII) , which is condensed with phenyl chloroformate (VIII) in dichloromethane to afford the phenyl carbamate (IX). Finally, the phenoxycarbonyl group of (IX) is removed by treatment with KOH in refluxing methylcellosolve or in refluxing toluene. Alternatively, the reaction of methylpiperidine (VII) with ethyl chloroformate (X) in toluene gives the ethyl carbamate (XI), which is finally treated with KOH in refluxing ethanol/water in order to eliminate its ethoxycarbonyl group. Alternatively, the reaction of methylpiperidine (VII) with vinyl chloroformate (XII) in dichloromethane gives the vinyl carbamate (XIII), which is finally treated with dry HCl gas in refluxing dichloromethane/methanol in order to eliminate its vinyloxycarbonyl group.

参考文献 中间体
【1】 Lynch, I.R.; Richardson, J.E.; Buxton, P.C.; Curzons, A.D.; Wood-Kaezmar, M.W.; Barnes, R.D. (Ferrosan A/S; SmithKline Beecham plc); Piperidine derivs., their preparation and their use as medicaments. EP 0223403; JP 1987129280; US 4721723 .
【2】 Sato, F.; Amano, T.; Kameo, K.; Tanami, T.; Muto, K.; Ono, N.; Goto, J. (Taisho Pharmaceutical Co., Ltd.); Prostaglandin derivs.. JP 1997286775 .
【3】 Lucas, E. (SmithKline Beecham plc); Process for the preparation of paroxetine and structurally related cpds.. WO 0078753 .
【4】 Christensen, J.A.; Squires, R.F. (Ferrosan A/S); 4-Phenylpiperidine compounds. DE 2404113; ES 422734; FR 2215233; GB 1422263; JP 58174363; US 3912743 .
【5】 Lemmens, J.M.; Peters, T.H.A.; Picha, F. (Synthon BV); Process to produce paroxetine. WO 0266466 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10989 4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydropyridine C12H14FN 详情 详情
(II) 10990 [4-(4-Fluorophenyl)-1-methyl-1,2,3,6-tetrahydro-3-pyridinyl]methanol C13H16FNO 详情 详情
(III) 43486 [(3S)-4-(4-fluorophenyl)-1-methyl-1,2,3,6-tetrahydro-3-pyridinyl]methanol C13H16FNO 详情 详情
(IV) 43487 [(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol 105812-81-5 C13H18FNO 详情 详情
(V) 43488 (3S,4R)-3-(chloromethyl)-4-(4-fluorophenyl)-1-methylpiperidine C13H17ClFN 详情 详情
(VI) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(VII) 10987 (3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylhexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl ether C20H22FNO3 详情 详情
(VIII) 13580 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate 1885-14-9 C7H5ClO2 详情 详情
(IX) 13489 ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate C13H20BrNO3 详情 详情
(X) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(XI) 43490 ethyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate C22H24FNO5 详情 详情
(XII) 28068 1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate 5130-24-5 C3H3ClO2 详情 详情
(XIII) 43491 vinyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate C22H22FNO5 详情 详情

合成路线5

The diastereo- and enantioselective condensation of the protected secondary amine (I) with the nitroalkene (II) by means of BuLi in toluene and in the presence of (-)-sparteine gives the (S,S)-carbamate (III) as a single diastereomer. The hydrolysis of the carbamate (III) with HCl in chloroform yields the aldehyde (IV), which is reduced with NaBH4, affording the alcohol (V). The reduction of the nitro group of (V) with Pd/C and ammonium formate gives the amine (VI), which is protected with Boc2O to provide the carbamate (VII). The reaction of (VII) with MsCl and TEA affords the corresponding mesylate (VIII), which is cyclized by means of potassium tert-butoxide in THF, yielding the protected piperidine (IX). Elimination of the Tips group of (IX) with TBAF affords the carbinol (X), which is treated with MsCl and TEA to give the mesylate (XI). The condensation of (XI) with 1,3-benzodioxol-5-ol (XII) by means of NaH in DMF yields the expected adduct (XIII), which is finally deprotected with TFA to furnish the target chiral compound.

参考文献 中间体
【1】 Johnson, T.A.; et al.; Highly diastereoselective and enantioselective carbon- -carbon bond formations in conjugate additions of lithiated N-boc allylamines to nitroalkenes: Enantioselective synthesis of 3,4- and 3,4,5-substituted piperidines including (-)-paroxetine. J Am Chem Soc 2001, 123, 5, 1004.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 44001 tert-butyl (Z)-3-(4-fluorophenyl)-2-propenyl(phenyl)carbamate C20H22FNO2 详情 详情
(II) 44002 triisopropyl[[(E)-3-nitro-2-propenyl]oxy]silane; (E)-3-nitro-2-propenyl triisopropylsilyl ether C12H25NO3Si 详情 详情
(III) 44003 tert-butyl (Z,3R,4S)-3-(4-fluorophenyl)-5-nitro-4-[[(triisopropylsilyl)oxy]methyl]-1-pentenyl(phenyl)carbamate C32H47FN2O5Si 详情 详情
(IV) 44004 (3R,4S)-3-(4-fluorophenyl)-5-nitro-4-[[(triisopropylsilyl)oxy]methyl]pentanal C21H34FNO4Si 详情 详情
(V) 44005 (3R,4S)-3-(4-fluorophenyl)-5-nitro-4-[[(triisopropylsilyl)oxy]methyl]-1-pentanol C21H36FNO4Si 详情 详情
(VI) 44006 (3R,4S)-5-amino-3-(4-fluorophenyl)-4-[[(triisopropylsilyl)oxy]methyl]-1-pentanol C21H38FNO2Si 详情 详情
(VII) 44007 tert-butyl (2S,3R)-3-(4-fluorophenyl)-5-hydroxy-2-[[(triisopropylsilyl)oxy]methyl]pentylcarbamate C26H46FNO4Si 详情 详情
(VIII) 44008 tert-butyl (2S,3R)-3-(4-fluorophenyl)-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-2-[[(triisopropylsilyl)oxy]methyl]pentylcarbamate C29H52FNO4SSi 详情 详情
(IX) 44009 tert-butyl (3S,4R)-4-(4-fluorophenyl)-3-{[(triisopropylsilyl)oxy]methyl}-1-piperidinecarboxylate C26H44FNO3Si 详情 详情
(X) 44010 tert-butyl (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-piperidinecarboxylate C17H24FNO3 详情 详情
(XI) 44011 tert-butyl (3S,4R)-4-(4-fluorophenyl)-3-({[methyl(dimethylene)-lambda~6~-sulfanyl]oxy}methyl)-1-piperidinecarboxylate C20H30FNO3S 详情 详情
(XII) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(XIII) 44012 tert-butyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate C24H28FNO5 详情 详情

合成路线6

The condensation of 4-fluorobenzaldehyde (I) with ethyl acetoacetate (II) by means of piperidine, followed by a treatment with hot NaOH and esterification with methanol in acid medium, gives 3-(4-fluorophenyl)glutaric acid dimethyl ester (III), which is stereoselectively hydrolyzed with liver esterase in aqueous acetone, yielding the monoester (IV) with a 95% ee. The selective reduction of the ester group of (IV) with LiH and LiBH4 in THF affords the chiral 5-hydroxypentanoic acid (V), which is esterified with dimethyl sulfate in methanol to the corresponding methyl ester (VI). The reaction of (VI) with MsCl and TEA in toluene gives the mesylate (VII), which is cyclized with benzylamine (VIII) and TEA in toluene, affording the chiral piperidone (IX).The reaction of (IX) with dimethyl carbonate (X) and NaH in hot toluene yields the chiral carboxylate (XI), which is reduced at the carboxylate and ketonic groups with LiAlH4 or BH3 in DMSO, providing the chiral piperidine methanol derivative (XII). The reaction of (XII) with MsCl and TEA in toluene yields the mesylate (XIII), which is condensed with the phenol derivative (XIV) by means of NaH in hot DMF, affording the adduct (XV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.

参考文献 中间体
【1】 Yu, M.S.; Lantos, I.; Cacchio, T.; Peng, Z.-Q.; Yu, J.; Asymmetric synthesis of (-)-paroxetine using PLE hydrolysis. Tetrahedron Lett 2000, 41, 30, 5647.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(III) 44013 dimethyl 3-(4-fluorophenyl)pentanedioate C13H15FO4 详情 详情
(IV) 44014 (3S)-3-(4-fluorophenyl)-5-methoxy-5-oxopentanoic acid C12H13FO4 详情 详情
(V) 44015 lithium (3R)-3-(4-fluorophenyl)-5-hydroxypentanoate C11H12FLiO3 详情 详情
(VI) 44016 methyl (3R)-3-(4-fluorophenyl)-5-hydroxypentanoate C12H15FO3 详情 详情
(VII) 44017 methyl (3R)-3-(4-fluorophenyl)-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]pentanoate C15H21FO3S 详情 详情
(VIII) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(IX) 44018 (4R)-1-benzyl-4-(4-fluorophenyl)-2-piperidinone C18H18FNO 详情 详情
(X) 34197 dimethyl carbonate 616-38-6 C3H6O3 详情 详情
(XI) 44019 methyl (3S,4R)-1-benzyl-4-(4-fluorophenyl)-2-oxo-3-piperidinecarboxylate C20H20FNO3 详情 详情
(XII) 44020 [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methanol C19H22FNO 详情 详情
(XIII) 44021 (3S,4R)-1-benzyl-4-(4-fluorophenyl)-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)piperidine C22H28FNOS 详情 详情
(XIV) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(XV) 44022 (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether C26H26FNO3 详情 详情

合成路线7

The reaction of the chiral oxazolopyridinone (I) with benzyl chloroformate and phenylselenium bromide by means of LHMDS in THF gives the intermediate (II), which is treated with O3 and oxygen to yield the unsaturated ester (III). The condensation of (III) with the arylcopper derivative (IV) in THF affords a mixture of cis- and trans-isomers that are separated by chromatography. The desired trans-isomer (V) is reduced with AlCl3 and LiAlH4 in THF, giving the carbinol (VI), which by elimination of the chiral auxiliary with H2 over Pd(OH)2 in ethyl acetate, followed by protection of the piperidine nitrogen with Boc2O, provides the carbamate (VII). The reaction of (VII) with MsCl in pyridine yields the corresponding mesylate (VIII), which is condensed with 1,3-benzodioxol-5-ol (IX) by means of NaH in refluxing THF to furnish the protected intermediate (X). Finally, this compound is deprotected with TFA in dichloromethane.

参考文献 中间体
【1】 Llor, N.; Cantó, M.; Hidalgo, J.; Amat, M.; Luque, J.; Miravitlles, C.; Molins, E.; Orozco, M.; Bosch, J.; Pérez, M.; Synthesis of enatiopure trans-3,4-disubstituted piperidines. An enantiodivergent synthesis of (+)- and (-)-paroxetine. J Org Chem 2000, 65, 10, 3074.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 44023 (3R,8aR)-3-phenylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridin-5-one C13H15NO2 详情 详情
(II) 44024 benzyl (3R,8aR)-5-oxo-3-phenyl-6-(phenylselanyl)hexahydro-5H-[1,3]oxazolo[3,2-a]pyridine-6-carboxylate C27H25NO4Se 详情 详情
(III) 44025 benzyl (3R,8aR)-5-oxo-3-phenyl-2,3,8,8a-tetrahydro-5H-[1,3]oxazolo[3,2-a]pyridine-6-carboxylate C21H19NO4 详情 详情
(IV) 44026 　 C7H4CuFLiN 详情 详情
(V) 44027 benzyl (3R,6S,7R,8aR)-7-(4-fluorophenyl)-5-oxo-3-phenylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridine-6-carboxylate C27H24FNO4 详情 详情
(VI) 44028 ethyl 4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]-3-oxobutanoate C20H24FNO2 详情 详情
(VII) 44010 tert-butyl (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-piperidinecarboxylate C17H24FNO3 详情 详情
(VIII) 44011 tert-butyl (3S,4R)-4-(4-fluorophenyl)-3-({[methyl(dimethylene)-lambda~6~-sulfanyl]oxy}methyl)-1-piperidinecarboxylate C20H30FNO3S 详情 详情
(IX) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(X) 44012 tert-butyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate C24H28FNO5 详情 详情

合成路线8

The hydrogenation of 4-(4-fluorophenyl)-3-(ethoxycarbonyl)-1-methylpyridinium bromide (I) with H2 over PtO2 in toluene/ethanol gives racemic (cis)-4-(4-fluorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester (rac)-(II), which is isomerized with NaOMe in refluxing toluene to yield the trans-isomer (rac)-(III). The reduction of (rac)-(III) with LiAlH4 in toluene/THF affords the hydroxymethyl compound (rac)-(IV), which is submitted to optical resolution with L-(-)-di-p-toluoyltartaric acid to provide the chiral (3S,4R)-(V). Alternatively, the optical resolution of (cis)-(rac)-(II) with D-(+)-di-p-toluoyltartaric acid gives the ester (cis)-(3R,4R)-(VI), which is isomerized with NaOMe in refluxing toluene to yield ester (trans)-(3S,4R)-(VII). Finally, this compound is reduced with LiAlH4 in toluene/THF to afford the previously reported intermediate (3S,4R)-(V). The reaction of (3S,4R)-(V) with benzenesulfonyl chloride (VIII) and dimethylethylamine in toluene gives the corresponding sulfonate (3S,4R)-(IX), which is condensed with 5-hydroxy-1,3-benzodioxole (X) by means of NaOMe in hot DMF to yield the adduct (3S,4R)-(XI). Finally, this compound is demethylated by reaction with phenyl chloroformate (XII) to afford the cyclic carbamate (3S,4R)-(XIII), which is hydrolyzed with KOH in refluxing toluene.

参考文献 中间体
【1】 Borrett, G.T.; Ward, N.; Crowe, D.; Wells, A.S. (GlaxoSmithKline plc); Process for the preparation of paroxetine. WO 0129031 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 56453 4-(4-fluorophenyl)-3-(methoxycarbonyl)-1-methylpyridinium bromide C14H13BrFNO2 详情 详情
(II) 56454 (rac)-methyl (3R,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate C14H18FNO2 详情 详情
(III) 56455 (rac)-methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate C14H18FNO2 详情 详情
(IV) 43487 [(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol 105812-81-5 C13H18FNO 详情 详情
(V) 56458 [(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol C13H18FNO 详情 详情
(VI) 56456 methyl (3R,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate C14H18FNO2 详情 详情
(VII) 56457 methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate C14H18FNO2 详情 详情
(VIII) 14713 benzenesulfonyl chloride 98-09-9 C6H5ClO2S 详情 详情
(IX) 10986 [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl benzenesulfonate C19H22FNO3S 详情 详情
(X) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(XI) 10987 (3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylhexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl ether C20H22FNO3 详情 详情
(XII) 13580 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate 1885-14-9 C7H5ClO2 详情 详情
(XIII) 43489 phenyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate C26H24FNO5 详情 详情

合成路线9

The condensation of 4-fluorocinnamic acid ethyl ester (I) with cyanacetic acid ethyl ester (II) by means of NaOEt in ethanol gives 2-cyano-3-(4-fluorophenyl)glutaric acid diethyl ester (III). Alternatively, glutarate (III) can also be obtained by condensation of 4-fluorobenzaldehyde (V) with cyanacetic ester (II) and acetic acid ethyl ester (VI). The reduction of the cyano group of (III) with H2 over PtO2 in ethanol, followed by cyclization in refluxing toluene, yields 4-(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid ethyl ester (IV) as a mixture of the cis- and trans-isomers. The reaction of the mixture (IV) with EtONa in refluxing toluene causes isomerization of the cis-isomer, affording (rac)-trans-4-(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid ethyl ester (VII), which is reduced with LiAlH4 or borane (NaBH4/BF3) to provide the (rac)-(trans)-hydroxymethylpiperidine (VIII). Finally, this compound is reductively methylated by treatment with formaldehyde and H2 over Pd/C in ethanol to furnish (rac)-(trans)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methylpiperidine (IX), the desired intermediate. Alternatively, the cis/trans mixture 4-(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid ethyl ester (IV) can be methylated first with formaldehyde as before to give 4-(4-fluorophenyl)-1-methyl-6-oxopiperidine-3-carboxylic acid ethyl ester (X), also as a cis/trans mixture. This mixture is treated with EtONa in refluxing toluene to yield (rac)-(trans)-4-(4-fluorophenyl)-1-methyl-6-oxopiperidine-3-carboxylic acid ethyl ester (XI). Finally, this compound is reduced with LiAlH4 in THF/toluene to afford the previously described target intermediate (IX).

参考文献 中间体
【1】 Bosch Rovira, A.; Dalmases Barjoan, P.; Herbera Espinal, M.R.; Carulla Oliver, J.M.; Marquillas Olóndriz, F. (Laboratorios Vita, SA); Process for obtaining (±)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. ES 2121685 .
【2】 Bosch Rovira, A.; Dalmases Barjoan, P.; Herbera Espinal, M.R.; Carulla Oliver, J.M.; Marquillas Olóndriz, F. (Laboratorios Vita, SA); Process for obtaining ethyl (±)-cis/(±)-trans-4-(4-fluorophenyl)-1-methylpiperidine-3-carboxylate. ES 2121684 .
【3】 Bosch Rovira, A.; Dalmases Barjoan, P.; Marquilla Olondriz, F.; Herbera Espinal, M.R.; Carulla Oliver, J.M. (Laboratorios Vita, SA); Ethyl 4-(4-fluorophenyl)-2-piperidinone-5-carboxylate and process for obtaining it. ES 2121682 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 56459 ethyl (E)-3-(4-fluorophenyl)-2-propenoate C11H11FO2 详情 详情
(II) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(III) 56460 diethyl 2-cyano-3-(4-fluorophenyl)pentanedioate C16H18FNO4 详情 详情
(IV) 56461 ethyl 4-(4-fluorophenyl)-6-oxo-3-piperidinecarboxylate C14H16FNO3 详情 详情
(V) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(VI) 17491 ethyl acetate 141-78-6 C4H8O2 详情 详情
(VII) 56462 ethyl (3S,4R)-4-(4-fluorophenyl)-6-oxo-3-piperidinecarboxylate C14H16FNO3 详情 详情
(VIII) 56463 (rac)-[(3S,4R)-4-(4-fluorophenyl)piperidinyl]methanol C12H16FNO 详情 详情
(IX) 43487 [(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol 105812-81-5 C13H18FNO 详情 详情
(X) 56464 ethyl 4-(4-fluorophenyl)-1-methyl-6-oxo-3-piperidinecarboxylate C15H18FNO3 详情 详情
(XI) 56465 ethyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-6-oxo-3-piperidinecarboxylate C15H18FNO3 详情 详情

合成路线10

The condensation of cinnamic nitrile (I) with diethyl malonate (II) by means of K2CO3 and tetrabutylammonium bromide in refluxing acetone or NaOEt in refluxing ethyl acetate gives 2-[2-cyano-1-(4-fluorophenyl)ethyl]malonic acid diethyl ester (III), which is cyclized by reduction of its cyano group with H2 over PtO2 in ethanol/conc. HCl or over Ru/C in ethanol to yield (rac)-(trans)-4-(4-fluorophenyl)-2-oxopiperidine-3-carboxylic acid ethyl ester (IV). Finally, this compound is reduced with NaBH4 in THF to afford (rac)-(trans)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine (V), the target intermediate.

参考文献 中间体
【1】 Dalmases Barjoan, P.; Carulla Oliver, J.M.; Moreno Manas, M.; Perez, M. (Laboratorios Vita, SA); Piperidinone deriv., process for obtaining it and process for using it. ES 2137131 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 56466 (E)-3-(4-fluorophenyl)-2-propenenitrile C9H6FN 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 56467 1-ethyl 3-methyl 2-[2-cyano-1-(4-fluorophenyl)ethyl]malonate C15H16FNO4 详情 详情
(IV) 56468 ethyl (3S,4R)-4-(4-fluorophenyl)-2-oxo-3-piperidinecarboxylate C14H16FNO3 详情 详情
(V) 43487 [(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol 105812-81-5 C13H18FNO 详情 详情

合成路线11

The condensation of 1-(tert-butoxycarbonyl)piperidin-2-one (I) with methyl chloroformate (II) by means of LHMDS in THF gives 1-(tert-butoxycarbonyl)-2-oxopiperidine-3-carboxylic acid methyl ester (III), which is transesterified with the chiral auxiliary (IV) by means of DMAP in refluxing toluene to yield the shielded ester (V). The reaction of (V) with phenylselanyl chloride and NaH in THF/HMPA affords the selenide (VI), which is treated with H2O2 to produce an oxidative deselenation to afford the unsaturated ester (VII). The addition of lithium di(4-fluorophenyl)cuprate (VIII) to the asymmetric olefinic amidoester (VII) leads to the addition product (IX). Finally, the reductive cleavage of the chiral auxiliary by reduction with LiAlH4 in refluxing THF produces the simultaneous reduction of the tert-butoxycarbonyl group to afford the target intermediate, the (3S,4R)-4-(4-fluorophenyl-3-(hydroxymethyl)-1-methylpiperidine (X) (see scheme no. 10786004a, intermediate (V)).

参考文献 中间体
【1】 Cossy, J.; et al.; A short formal synthesis of paroxetine. Diastereoselective cuprate addition to a chiral racemic olefinic amido ester. Tetrahedron Lett 2001, 42, 44, 7805.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 56469 tert-butyl 2-oxo-1-piperidinecarboxylate C10H17NO3 详情 详情
(II) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(III) 56470 1-(tert-butyl) 3-methyl 2-oxo-1,3-piperidinedicarboxylate C12H19NO5 详情 详情
(IV) 56471 N-(3,5-dimethylphenyl)-N-[(2S,3R)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]benzenesulfonamide C24H31NO3S 详情 详情
(V) 56472 1-(tert-butyl) 3-{(2R,3S)-3-[3,5-dimethyl(phenylsulfonyl)anilino]-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl} 2-oxo-1,3-piperidinedicarboxylate C35H46N2O7S 详情 详情
(VI) 56473 1-(tert-butyl) 3-{(2R,3S)-3-[3,5-dimethyl(phenylsulfonyl)anilino]-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl} 2-oxo-3-(phenylselanyl)-1,3-piperidinedicarboxylate C41H50N2O7SSe 详情 详情
(VII) 56474 1-(tert-butyl) 3-{(2R,3S)-3-[3,5-dimethyl(phenylsulfonyl)anilino]-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl} 2-oxo-5,6-dihydro-1,3(2H)-pyridinedicarboxylate C35H44N2O7S 详情 详情
(VIII) 56475 　 C27H25CuF4Li 详情 详情
(IX) 56476 1-(tert-butyl) 3-{(2R,3S)-3-[3,5-dimethyl(phenylsulfonyl)anilino]-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl} (3S,4R)-4-(4-fluorophenyl)-2-oxo-1,3-piperidinedicarboxylate C41H49FN2O7S 详情 详情
(X) 56477 (3R,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methyl-2-piperidinone C13H16FNO2 详情 详情

合成路线12

The reduction of L-pyroglutamic acid (I) with NaBH4 gives the chiral pyrrolidinone (II), which is cyclized with benzaldehyde (III) by means of Ts-OH in refluxing toluene to yield the N,O-acetal (IV). The reaction of (IV) with isobutyl chloroformate (V) and phenylselanyl chloride by means of LiHMDS in THF affords the selenoester (VI), which is treated directly with H2O2 in dichloromethane to provide the unsaturated bicyclic lactam (VII). The diastereoselective reaction of (VII) with lithium di(4-fuorophenyl)cuprate (VIII) gives the all-trans trisubstituted pyrrolidone (IX). The reduction of the carbonyl group (IX) with BH3 in THF that also causes the cleavage of the C-O bond of the oxazolidinone yields the pyrrolidine methanol derivative (X), which is submitted to ring expansion by treatment with MsCl, DCE and TEA to afford the expected trisubstituted 3-chloropiperidine (XI). The dechlorination of (XI) by means of Bu3SnH and AIBN in refluxing toluene provides the trans-1-benzyl-4-(4-fluorophenyl)piperidine-3-carboxylic acid isobutyl ester (XII), which is reduced with LiAlH4 in THF to furnish the carbinol (XIII). The reaction of (XIII) with Ms-Cl and TEA in dichloromethane gives the corresponding mesylate (XIV), which is condensed with 1,3-benzodioxol-5-ol (XV) by means of sodium isopropoxide in refluxing isopropanol to yield the aryl ether (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol to afford the target trans-piperidine derivative.

参考文献 中间体
【1】 Liu, L.T.; Hong, P.-C.; Huang, H.-L.; Chen, S.-F.; Wang, C.-L. J.; Wen, Y.-S.; ASsymetric syntheses of trans-3,4-disubstituted 2-piperidinones and piperidines. Tetrahedron Asymmetry 2001, 12, Suppl. 3, 419-26.
【2】 Cossy, J.; et al.; Ring expansion: Formal total synthesis of (-)-paroxetine. Tetrahedron Lett 2001, 42, 33, 5705.
【3】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12085 (2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid 4042-36-8 C5H7NO3 详情 详情
(II) 56485 (5S)-5-(hydroxymethyl)-2-pyrrolidinone C5H9NO2 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IV) 38561 (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one 103201-79-2 C12H13NO2 详情 详情
(V) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(VI) 56478 isobutyl (3R,7aS)-5-oxo-3-phenyl-6-(phenylselanyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate C23H25NO4Se 详情 详情
(VII) 56479 isobutyl (3R,7aS)-5-oxo-3-phenyl-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate C17H19NO4 详情 详情
(VIII) 56475 　 C27H25CuF4Li 详情 详情
(IX) 56480 isobutyl (3R,6S,7R,7aS)-7-(4-fluorophenyl)-5-oxo-3-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate C23H24FNO4 详情 详情
(X) 56481 isobutyl (3S,4R,5S)-1-benzyl-4-(4-fluorophenyl)-5-(hydroxymethyl)-3-pyrrolidinecarboxylate C23H28FNO3 详情 详情
(XI) 56482 isobutyl (3S,4R,5R)-1-benzyl-5-chloro-4-(4-fluorophenyl)-3-piperidinecarboxylate C23H27ClFNO2 详情 详情
(XII) 56483 isobutyl (3S,4R)-1-benzyl-4-(4-fluorophenyl)-3-piperidinecarboxylate C23H28FNO2 详情 详情
(XIII) 44020 [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methanol C19H22FNO 详情 详情
(XIV) 56484 [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl methanesulfonate C20H24FNO3S 详情 详情
(XV) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(XVI) 44022 (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether C26H26FNO3 详情 详情

合成路线13

The cyclization of 4-fluorocinnamic acid ethyl ester (I) with malonic acid diethyl ester (II) by means of NaOMe or t-Bu-OK in THF or ethyl acetate gives (rac)-(trans)-4-(4-fluorophenyl)2,6-dioxopiperidine-3-carboxylic acid ethyl ester (III), which is reduced with LiAlH4 in THF to yield the piperidine methanol (rac)-(trans)-(IV). The protection of the NH group of (IV) with benzyl chloroformate and Na2CO3 in dichloromethane affords the benzyl carbamate (rac)-(trans)-(V), which is acylated with Ac2O and pyridine to provide the acetoxy compound (rac)-(trans)-(VI). The biological optical resolution of (rac)-(trans)-(VI) by means of Lipase CAL-A in hexane gives an easily separable mixture of the unreacted ester (3R,4S)-(trans)-(VI) and the hydrolyzed carbinol (3S,4R)-(VII). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in ethanol to yield the target intermediate, the (3S,4R)-(trans)-4-(4-fluorophenyl)piperidine-3-methanol (3S,4R)-(trans)-(VIII).

参考文献 中间体
【1】 Ali, F.E.; Thomas, M.R. (Beecham Group PLC); Process for the preparation of aryl-piperidine carbinols. EP 0223334 .
【2】 De Gonzalo, G.; et al.; Enzymatic resolution of trans-4-(4'-fluorophenyl)-3-hydroxymethylpiperidines, key intermediates in the synthesis of (-)-paroxetine. J Org Chem 2001, 66, 26, 8947.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac)-(VI) 56489 (rac)-benzyl (3S,4R)-3-[(acetyloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate C22H24FNO4 详情 详情
(3R,4S)-(VI) 56490 benzyl (3R,4S)-3-[(acetyloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate C22H24FNO4 详情 详情
(I) 56459 ethyl (E)-3-(4-fluorophenyl)-2-propenoate C11H11FO2 详情 详情
(II) 56486 ethyl 3-amino-3-oxopropanoate C5H9NO3 详情 详情
(III) 56487 ethyl (3S,4R)-4-(4-fluorophenyl)-2,6-dioxo-3-piperidinecarboxylate C14H14FNO4 详情 详情
(IV) 56463 (rac)-[(3S,4R)-4-(4-fluorophenyl)piperidinyl]methanol C12H16FNO 详情 详情
(V) 56488 (rac)-benzyl (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-piperidinecarboxylate C20H22FNO3 详情 详情
(VII) 56491 benzyl (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-piperidinecarboxylate C20H22FNO3 详情 详情
(VIII) 56492 [(3S,4R)-4-(4-fluorophenyl)piperidinyl]methanol C12H16FNO 详情 详情

合成路线14

The cyclization of 4-fluoro-alpha-methylstyrene (I) with ethylamine and refluxing aqueous formaldehyde gives (rac)-1-ethyl-3-(hydroxymethyl)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (II), which is submitted to optical resolution by means of (-)-di-O-toluoyltartaric acid to yield (S)-isomer (III) and (R)-isomer (IV). The reduction of (S)-isomer (III) by means of LiAlH4 in THF yields (3S)-trans-1-ethyl-3-(hydroxymethyl)-4-(4-fluorophenyl)piperidine (V), which is condensed with 1,3-benzodioxol-5-ol (VI) by means of benzenesulfonyl chloride and TEA in dichloroethane to afford the aryl ether (VII). Finally, the ethyl group of (VII) is cleaved by means of 1-chloroethyl chloroformate and NaOH in toluene/water, followed by a treatment in refluxing methanol to provide the target paroxetine. The (R)-isomer (IV) can be profited by its reduction with H2 over Pd/C in methanol/AcOH/water to give (3R)-cis-1-ethyl-3-(hydroxymethyl)-4-(4-fluorophenyl)piperidine) (VIII), which is isomerized by means of NaOH in toluene/water and condensed with 1,3-benzodioxol-5-ol (VI) and NaOH in toluene/water to yield the already described aryl ether (VII).

参考文献 中间体
【1】 Brennan, J.P. (Abbott GmbH & Co. KG); Chemical process for the reduction of 1-substd.-3-hydroxymethyl-4-(4-fluorophenyl)tetrahydropyridines. US 6326496; WO 9852920 .
【2】 Hansen, J.B.; Engelstoft, M.; Treppendahl, S.; Bentzen, B.; Lehmann, S. (Novo Nordisk A/S); Process for preparing 4-aryl-piperidine derivs.. CA 2220963; EP 0828735; WO 9636636 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 62567 1-fluoro-4-isopropenylbenzene C9H9F 详情 详情
(II) 62568 [1-ethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydro-3-pyridinyl]methanol C14H18FNO 详情 详情
(III) 62569 [(3S)-1-ethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydro-3-pyridinyl]methanol C14H18FNO 详情 详情
(IV) 62570 [(3R)-1-ethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydro-3-pyridinyl]methanol C14H18FNO 详情 详情
(V) 62571 [(3S,4R)-1-ethyl-4-(4-fluorophenyl)piperidinyl]methanol C14H20FNO 详情 详情
(VI) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(VII) 62573 (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-ethyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-ethyl-4-(4-fluorophenyl)piperidinyl]methyl ether C21H24FNO3 详情 详情
(VIII) 62572 [(3R,4R)-1-ethyl-4-(4-fluorophenyl)piperidinyl]methanol C14H20FNO 详情 详情

合成路线15

The condensation of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (I) with 4-fluorophenylmagnesium bromide (II) in toluene, ether/toluene or ether/dichloromethane gives 1-methyl-4-(4-fluorophenyl)piperidine-3-carboxylic acid methyl ester (III) / (IV), which are an intermediates in the synthesis of paroxetine.(Scheme 10786008a).

参考文献 中间体
【1】 Ward, N. (GlaxoSmithKline plc); Process for making paroxetine. US 6172233 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(III) 56454 (rac)-methyl (3R,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate C14H18FNO2 详情 详情
rac-(IV) 56455 (rac)-methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate C14H18FNO2 详情 详情
(I) 38648 methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate C8H13NO2 详情 详情
(II) 13643 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide 352-13-6 C6H4BrFMg 详情 详情
Extended Information