新产品编号:1743873
Chemical Name: (-)-4-[N-[1-Allyl-3(S)-methylpiperidin-4(R)-yl]-N-phenylamino]-N,N-diethylbenzamide
项目整合开发状态: Biological Testing
项目研究机构: National Institute on Drug Abuse (Originator), Research Triangle Institute (Originator)
合成路线:Condensation of 1,3-dimethyl-4-piperidone (I) with aniline in the presence of titanium tetraisopropoxide produced imine (II).This was reduced with NaBH4 to give the corresponding amine as a mixture of geometric isomers,from which the desired cis isomer (III) was isolated by column chromatography.Coupling of (III) with 4-fluorobenzoate ester (IV) in the presence of butyllithium yielded the diaryl amine (V).Removal of the 2,6-di-tert-butyl-4-methoxyphenyl ester of (V) was accomplished by transesterification with sodium methoxide,followed by saponification of the methyl ester.The resulting carboxylic acid (VI) was then converted into diethyl amide (VII) using diethylamine and BOP reagent.N-Demethylation of (VII) with phenyl chloroformate furnished the phenyl carbamate (VIII),that was further hydrolyzed and decarboxylated to give piperidine (IX).This was finally alkylated with allyl bromide in the presence of K2CO3.
合成路线: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.
📌 参考资料/链接：
参考文献标题:(?-4-[(N-Allyl-cis-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding for the delta opioid receptor
文献作者:Thomas,J.B.; Herault,X.M.; Rothman,R.B.; Burges,J.P.; Mascarella,S.W.; Xu,H.; Horel,R.B.; Dersch,C.M.; Carroll,F.I.
参考来源:Bioorg Med Chem Lett 1999,9(20),3053
📄 详细内容
合成路线: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.
参考文献标题: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
文献作者:Thomas,J.B.; Atkinson,R.N.; Herault,X.M.; Rothman,R.B.; Mascarella,S.W.; Dersch,C.M.; Xu,H.; Horel,R.B.; Carroll,F.I.
参考来源:Bioorg Med Chem Lett 1999,9(23),3347
合成路线: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.
参考文献标题: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
文献作者:Van Bever,W.F.M.; Niemegeers,C.J.E.; Janssen,P.A.J.
参考来源:J Med Chem 1974,17(10),1047-1051