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【结 构 式】

【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%

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:(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
Extended Information