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【结 构 式】

【分子编号】56491

【品名】benzyl (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-piperidinecarboxylate

【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%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VII)

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
Extended Information