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【结 构 式】

【药物名称】Transcainide, R-54718

【化学名称】(±)-trans-4-(Dimethylamino)-N-(2,6-dimethylphenyl)-1-(2-hydroxycyclohexyl)-4-piperidinecarboxamide

【CA登记号】88296-62-2

【 分 子 式 】C22H35N3O2

【 分 子 量 】373.54315

【开发单位】Janssen (Originator)

【药理作用】Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS

合成路线1

The hydrolysis of 1-benzyl-4-(methylamino)piperidine-4-carboxamide (I) with refluxing concentrated aqueous HCl gives the corresponding free acid (II), which is debenzylated with H2 over Pd/C in basic medium yielding 4-(methylamino)piperidine-4-carboxylic acid sodium salt (III). The protection of (III) with benzyl chloroformate (IV) in basic THF - water affords 1-(benzyloxycarbonyl)-4-(methylamino)piperidine 4 carboxylic acid (V), which by cyclization with phosgene in dioxane is converted to benzyl 1-methyl-2,4-dioxo 3-oxa-1,8-diazaspiro[4.5]decane-8 carboxylate (VI). The reaction of (VI) with 2,6-dimethylaniline (II) by heating at 160 C gives benzyl 4-(2,6-dimethylphenylaminocarbonyl)-4-(methylamino)piperidine-1-carboxylate (VIII), which is methylated with refluxing methyl iodide to the corresponding dimethylamino compound (IX). The deprotection of (IX) with H2 over Pd/C in methanol yields 4-(dimethylamino)-N-(2,6-dimethylphenyl)piperidine-4-carboxamide (X), which is finally condensed with 1,2-epoxycyclohexane (XI) in refluxing ethanol.

1 De Bruyn, M.F.L.; Van Daele, G.H.P.; Verdonck, M.G.C. (Janssen Pharmaceutica NV); N-Aryl-alpha-aminocarboxamide derivs.. EP 0121972; ES 8506615 .
2 Castaner, J.; Prous, J.; Transcainidine. Drugs Fut 1988, 13, 3, 239.
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) 22019 1-benzyl-4-(methylamino)-4-piperidinecarboxamide 1024-11-9 C14H21N3O 详情 详情
(II) 22020 1-benzyl-4-(methylamino)-4-piperidinecarboxylic acid C14H20N2O2 详情 详情
(III) 22021 sodium 4-(methylamino)-4-piperidinecarboxylate C7H13N2NaO2 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 22023 1-[(benzyloxy)carbonyl]-4-(methylamino)-4-piperidinecarboxylic acid C15H20N2O4 详情 详情
(VI) 22024 benzyl 1-methyl-2,4-dioxo-3-oxa-1,8-diazaspiro[4.5]decane-8-carboxylate C16H18N2O5 详情 详情
(VII) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(VIII) 22026 benzyl 4-[(2,6-dimethylanilino)carbonyl]-4-(methylamino)-1-piperidinecarboxylate C23H29N3O3 详情 详情
(IX) 22027 benzyl 4-(dimethylamino)-4-[(2,6-dimethylanilino)carbonyl]-1-piperidinecarboxylate C24H31N3O3 详情 详情
(X) 22028 4-(dimethylamino)-N-(2,6-dimethylphenyl)-4-piperidinecarboxamide C16H25N3O 详情 详情
(XI) 17986 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide 286-20-4 C6H10O 详情 详情
Extended Information