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【结 构 式】 
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【分子编号】10987 【品名】(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 【CA登记号】 |
【 分 子 式 】C20H22FNO3 【 分 子 量 】343.3980232 【元素组成】C 69.95% H 6.46% F 5.53% N 4.08% O 13.98% |
合成路线1
该中间体在本合成路线中的序号：(VII)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：(VIII)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：(VII)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4
该中间体在本合成路线中的序号：(XI)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 |