|
【结 构 式】 
|
【分子编号】43487 【品名】[(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol 【CA登记号】105812-81-5 |
【 分 子 式 】C13H18FNO 【 分 子 量 】223.2904632 【元素组成】C 69.93% H 8.13% F 8.51% N 6.27% O 7.17% |
合成路线1
该中间体在本合成路线中的序号：(IV)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2
该中间体在本合成路线中的序号：(IV)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3
该中间体在本合成路线中的序号：(IX)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).
| 【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4
该中间体在本合成路线中的序号：(V)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.
| 【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 |