【结 构 式】 |
【分子编号】56457 【品名】methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C14H18FNO2 【 分 子 量 】251.3008632 【元素组成】C 66.91% H 7.22% F 7.56% N 5.57% O 12.73% |
合成路线1
该中间体在本合成路线中的序号:(VII)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 |