1-benzyl-4-(methylamino)-4-piperidinecarboxamide -Drug Synthesis Database

【结构式】

【分子编号】22019

【品名】1-benzyl-4-(methylamino)-4-piperidinecarboxamide

【CA登记号】1024-11-9

【分子式】C₁₄H₂₁N₃O

【分子量】247.34036

【元素组成】C 67.98% H 8.56% N 16.99% O 6.47%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【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：(III)

The title compound is prepared by two related methods. N-Benzyl-4-piperidone (I) is condensed with KCN and MeNH2.HCl to produce amino nitrile (II). Partial hydrolysis of nitrile (II) with H2SO4 furnishes amide (III). Condensation of the amino amide (III) with triethyl orthoformate gives rise to the spiro imidazolinone (IV). Catalytic hydrogenation of the imidazoline double bond of (IV) and simultaneous N-benzyl group hydrogenolysis gives rise to 1-methyl-1,3,8-triazaspiro[4,5]decan-4-one (V). This is finally alkylated with 4'-fluoro-4-chlorobutyrophenone (VI) to yield the desired compound (1,2).

参考文献中间体

合成目标

【1】 Metwally, K.A.; Dukat, M.; Egan, C.T.; Smith, C.; Dupre, A.; Gauthier, C.B.; Herrick-Davis, K.; Teitler, M.; Glennon, R.A.; Spiperone: Influence of spiro ring substituents on 5-HT2A serotonin receptor binding. J Med Chem 1998, 41, 25, 5084.
【2】 Janssen, P.A.J. (Janssen Pharmaceutica NV); 2,4,8-Triaza-spiro(4,5)dec-2-enes. US 3155669 .

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)	15720	1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one	3612-20-2	C₁₂H₁₅NO	详情	详情
(II)	64576	1-benzyl-4-(methylamino)-4-piperidinecarbonitrile		C₁₄H₁₉N₃	详情	详情
(III)	22019	1-benzyl-4-(methylamino)-4-piperidinecarboxamide	1024-11-9	C₁₄H₂₁N₃O	详情	详情
(IV)	64577	8-benzyl-1-methyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one		C₁₅H₁₉N₃O	详情	详情
(V)	64578	1-methyl-1,3,8-triazaspiro[4.5]decan-4-one		C₈H₁₅N₃O	详情	详情
(VI)	35864	4-chloro-1-(4-fluorophenyl)-1-butanone	3874-54-2	C₁₀H₁₀ClFO	详情	详情

Extended Information