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【结 构 式】 
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【分子编号】56487 【品名】ethyl (3S,4R)-4-(4-fluorophenyl)-2,6-dioxo-3-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C14H14FNO4 【 分 子 量 】279.2679032 【元素组成】C 60.21% H 5.05% F 6.8% N 5.02% O 22.92% |
合成路线1
该中间体在本合成路线中的序号：(III)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).
| 【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 |