|
【结 构 式】 
|
【分子编号】10985 【品名】1,3-Benzodioxol-5-ol; Sesamol 【CA登记号】533-31-3 |
【 分 子 式 】C7H6O3 【 分 子 量 】138.12284 【元素组成】C 60.87% H 4.38% O 34.75% |
合成路线1
该中间体在本合成路线中的序号：(V)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.
| 【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
该中间体在本合成路线中的序号：(VI)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.
| 【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
该中间体在本合成路线中的序号：(II)By condensation of 4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine (I) with 3,4-methylenedioxyphenol (II) with dicyclohexylcarbodiimide (DCC) at 180 C.
| 【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 . |
合成路线4
该中间体在本合成路线中的序号：(VI)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.
| 【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
该中间体在本合成路线中的序号：(XII)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.
| 【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
该中间体在本合成路线中的序号：(XIV)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.
| 【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
该中间体在本合成路线中的序号：(IX)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.
| 【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
该中间体在本合成路线中的序号：(X)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.
| 【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
该中间体在本合成路线中的序号：(XV)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.
| 【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10
该中间体在本合成路线中的序号：(VI)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).
| 【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11
该中间体在本合成路线中的序号：(XXIV)6-(Benzyloxy)-7-methyl-1,3-benzodioxole-5-carbaldehyde (scheme 13922101a, cp. (I)). The protection of the OH group of phenol (XXIV) with Mom-Br and NaH in DMF/ethyl ether gives the methoxymethyl ether (XXV), which is methylated with MeI and BuLi in hexane yielding the 4-methyl derivative (XXVI). The formylation of (XXVI) with n-BuLi and DMF in THF affords the carbaldehyde (XXVII), which is deprotected with MsOH in dichloromethane giving 6-hydroxy-7-methyl-1,3-benzodioxole-5-carbaldehyde (XXVIII). Finally, this compound is benzylated with benzyl bromide and NaH in DMF providing the desired intermediate (I).
| 【1】 Gin, D.Y.; Corey, E.J.; Kania, R.S.; Enantioselective total synthesis of Ecteinascidin 743. J Am Chem Soc 1996, 118, 38, 9202-03. |
| 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) | 36449 | 6-(benzyloxy)-7-methyl-1,3-benzodioxole-5-carbaldehyde | C16H14O4 | 详情 | 详情 | |
| (XXIV) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XXV) | 38101 | 1,3-benzodioxol-5-yl methoxymethyl ether; 5-(methoxymethoxy)-1,3-benzodioxole | C9H10O4 | 详情 | 详情 | |
| (XXVI) | 38102 | 5-(methoxymethoxy)-4-methyl-1,3-benzodioxole; methoxymethyl 4-methyl-1,3-benzodioxol-5-yl ether | C10H12O4 | 详情 | 详情 | |
| (XXVII) | 38103 | 6-(methoxymethoxy)-7-methyl-1,3-benzodioxole-5-carbaldehyde | C11H12O5 | 详情 | 详情 | |
| (XXVIII) | 38104 | 6-hydroxy-7-methyl-1,3-benzodioxole-5-carbaldehyde | C9H8O4 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XI)A new synthesis of MKC-242 has been described: The tosylation of 2,2-dimethyl-1,3-dioxolane-4(R)-methanol (I) with tosyl chloride in pyridine gives the expected tosylate (II), which is condensed with pyrocatechol monobenzyl ether (III) by means of NaH in N-methylpyrrolidone (NMP) yielding 4(S)-(2-benzyloxyphenoxymethyl)-2,2-dimethyl-1,3-dioxolane (IV). The hydrolysis of the dioxolane ring with hot acetic acid affords the diol (V), which is tosylated with tosyl chloride, triethylamine and dimethylaminopyridine (DMAP) in dichloromethane to give the ditosylate (VI). The debenzylation of (VI) with H2 over Pd/C in methanol/ethyl acetate yields the phenol (VII), which is cyclized by means of K2CO3 in NMP affording 2(R)-(tosyloxymethyl)-1,4-benzodioxane (VIII). Finally, this compound is condensed with 3-(1,3-benzodioxol-5-yloxy)propylamine (IX) by means of ethyl diisopropylamine in NMP. The amine (IX) used as second starting compound has been obtained as follows: The condensation of N-(3-bromopropyl)phthalimide (X) with 5-hydroxy-1,3-benzodioxole (XI) by means of NaH in hot NMP gives N-[3-(1,3-benzodioxol-5-yloxy)propyl]phthalimide (XII), which is then treated with hydrazine in refluxing methanol to obtain amine (IX).
| 【1】 Sugano, M.; Saito, K.; Yamabe, H.; Chaki, H.; Abe, M.; Tabata, R.; Synthesis and 5-HT1A affinity of an optically active benzodioxane derivative MKC-242; a novel anxiolytic and antidepressant agent. 214th ACS Natl Meet (Sept. 7-11, Las Vegas) 1997, Abst MEDI 019. |
| 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) | 12698 | [(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 14347-78-5 | C6H12O3 | 详情 | 详情 |
| (II) | 15208 | (S)-(+)-2,2-Dimethyl-4-(hydroxymethyl)-1,3-dioxolane-p-toluenesulfonate; [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | 23735-43-5 | C13H18O5S | 详情 | 详情 |
| (III) | 15209 | Phenol, 2-(phenylmethoxy)-; 2-(benzyloxy)phenol | 6272-38-4 | C13H12O2 | 详情 | 详情 |
| (IV) | 15210 | benzyl 2-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]phenyl ether; (4R)-4-[[2-(benzyloxy)phenoxy]methyl]-2,2-dimethyl-1,3-dioxolane | C19H22O4 | 详情 | 详情 | |
| (V) | 15211 | (2S)-3-[2-(benzyloxy)phenoxy]-1,2-propanediol | C16H18O4 | 详情 | 详情 | |
| (VI) | 15212 | (1S)-2-[2-(benzyloxy)phenoxy]-1-[(4-methylphenoxy)methyl]ethyl 4-methylbenzenesulfonate | C30H30O6S | 详情 | 详情 | |
| (VII) | 15213 | (1S)-2-(2-hydroxyphenoxy)-1-[(4-methylphenoxy)methyl]ethyl 4-methylbenzenesulfonate | C23H24O6S | 详情 | 详情 | |
| (VIII) | 15214 | (2S)-2-[(4-methylphenoxy)methyl]-2,3-dihydro-1,4-benzodioxine; (2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylphenyl ether | C16H16O3 | 详情 | 详情 | |
| (IX) | 15206 | 3-(1,3-benzodioxol-5-yloxy)-1-propanamine; 3-(1,3-benzodioxol-5-yloxy)propylamine | C10H13NO3 | 详情 | 详情 | |
| (X) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (XI) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XII) | 15218 | 2-[3-(1,3-benzodioxol-5-yloxy)propyl]-1H-isoindole-1,3(2H)-dione | C18H15NO5 | 详情 | 详情 |