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【结 构 式】 
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【分子编号】41462 【品名】4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]-N,N-diethylbenzamide 【CA登记号】 |
【 分 子 式 】C24H33N3O 【 分 子 量 】379.54564 【元素组成】C 75.95% H 8.76% N 11.07% O 4.22% |
合成路线1
该中间体在本合成路线中的序号：(X)The reductocondensation of 3-methyl-4-oxopiperidine-1-carboxylic acid methyl ester (I) with aniline (II) by means of TsOH and NaBH4 in refluxing toluene gives 3-methyl-4-(phenylamino)piperidine-1-carboxylic acid methyl ester (III), which is acylated with propionyl anhydride yielding the corresponding propionamide as a mixture of cis and trans isomers, from which the racemic cis isomer (rac)-(IV) is isolated by crystallization. The optical resolution of (rac)-(IV) with d-tartaric acid followed by treatment with NaOH affords (3S.4R)-3-methyl-4-(phenylamino)piperidine (3S,4R)-(V), which is methylated with methyl iodide and K2CO3 to provide (3S,4R)-1,3-dimethyl-4-(phenylamino)piperidine (VI) (1). The condensation of (VI) with the 4-fluorobenzoate (VII) by means of BuLi in THF furnishes the corresponding tertiary amine (VIII), which is transesterified with NaOMe and hydrolyzed with ethanol/water to give the free benzoic acid (IX). The condensation of (IX) with diethylamine by means of BOP and TEA yields the corresponding diethylamide (X), which is demethylated by acylation with phenyl chloroformate and cleavage with KOH to afford the free piperidine NH compound (XI). Finally this piperidine derivative is allylated with allyl bromide (XII) and K2CO3 in ethanol.
| 【1】 Niemegeers, C.J.E.; Van Bever, W.F.M.; Janssen, P.A.J.; Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-[3-methyl-1-(2-phenylethyl)-4-piperidyl]-N-phenylpropanamide and N-[3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl]-N-phenylpropanamide. J Med Chem 1974, 17, 10, 1047-1051. |
| 【2】 Carroll, F.I.; Thomas, J.B.; Dersch, C.M.; Rothman, R.B.; Mascarella, S.W.; Burges, J.P.; Xu, H.; Herault, X.M.; Horel, R.B.; (±)-4-[(N-Allyl-cis-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding for the delta opioid receptor. Bioorg Med Chem Lett 1999, 9, 20, 3053. |
| 【3】 Carroll, F.I.; Horel, R.B.; Rothman, R.B.; Mascarella, S.W.; Dersch, C.M.; Atkinson, R.N.; Xu, H.; Herault, X.M.; Thomas, J.B.; Optically pure (-)-4-[(N-allyl-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding and full agonist activity for the delta opioid receptor. Bioorg Med Chem Lett 1999, 9, 23, 3347. |
| 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) | 41454 | methyl 3-methyl-4-oxo-1-piperidinecarboxylate | C8H13NO3 | 详情 | 详情 | |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 41455 | methyl 4-anilino-3-methyl-1-piperidinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (IV) | 41456 | methyl (3S,4R)-3-methyl-4-(propionylanilino)-1-piperidinecarboxylate | C17H24N2O3 | 详情 | 详情 | |
| (V) | 41457 | N-[(3S,4R)-3-methylpiperidinyl]-N-phenylamine; (3S,4R)-3-methyl-N-phenyl-4-piperidinamine | C12H18N2 | 详情 | 详情 | |
| (VI) | 41459 | N-[(3S,4R)-1,3-dimethylpiperidinyl]-N-phenylamine; (3S,4R)-1,3-dimethyl-N-phenyl-4-piperidinamine | C13H20N2 | 详情 | 详情 | |
| (VII) | 41458 | 2,6-di(tert-butyl)-4-methoxyphenyl 4-fluorobenzoate | C22H27FO3 | 详情 | 详情 | |
| (VIII) | 41460 | 2,6-di(tert-butyl)-4-methoxyphenyl 4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]benzoate | C35H46N2O3 | 详情 | 详情 | |
| (IX) | 41461 | 4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]benzoic acid | C20H24N2O2 | 详情 | 详情 | |
| (X) | 41462 | 4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]-N,N-diethylbenzamide | C24H33N3O | 详情 | 详情 | |
| (XI) | 41463 | N,N-diethyl-4-[[(3S,4R)-3-methylpiperidinyl]anilino]benzamide | C23H31N3O | 详情 | 详情 | |
| (XII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |