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【结 构 式】 
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【分子编号】22021 【品名】sodium 4-(methylamino)-4-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C7H13N2NaO2 【 分 子 量 】180.182268 【元素组成】C 46.66% H 7.27% N 15.55% Na 12.76% O 17.76% |
合成路线1
该中间体在本合成路线中的序号：(III)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 |
合成路线2
该中间体在本合成路线中的序号：(I)Bubbling dry HCl through a methanol solution of 1-oxyl-3-carboxy-2,2,5,5-tetramethylpyrrolidine (I) for a short period of time leads to the nitroxide radical methyl ester (II). Reduction of (II) to the hydroxylamine (III) is then accomplished by treatment with hydrazine in MeOH. Alternatively, upon treatment of (I) with HCl/MeOH for longer than 24 h, this undergoes both esterification and reduction to the hydroxylamine methyl ester (III). Further acetylation of hydroxylamine (III) by using Ac2O in the presence of Et3N yields the title compound.
| 【1】 Yordanov, A.T.; Yamada, K.-i.; Krishna, M.C.; Russo, A.; Yoo, J.; English, S.; Mitchell, J.B.; Brechbiel, M.W.; Acyl-protected hydroxylamines as spin label generators for EPR brain imaging. J Med Chem 2002, 45, 11, 2283. |