1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine -Drug Synthesis Database

【结构式】

【分子编号】54994

【品名】1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine

【CA登记号】

【分子式】C₁₈H₂₂N₂

【分子量】266.38616

【元素组成】C 81.16% H 8.32% N 10.52%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(IV)

N-Benzyl-4-hydroxy-4-phenylpiperidine (II) was prepared by addition of phenyllithium to N-benzyl-4-piperidone (I). Carbinol (II) was then converted to acetamide (III) by acid-catalyzed Ritter reaction with acetonitrile. Replacement of the acetamido for an N-Boc group in (III) was effected by acidic hydrolysis of amide (III) to give (IV), followed by treatment with di-tert-butyl dicarbonate. The resultant 1-benzyl-4-(Boc-amino)-4-phenylpiperidine (V) was subjected to catalytic hydrogenolysis in the presence of Pd/C, and the N-debenzylated piperidine (VI) was reprotected as the N-trityl derivative (VII) by treatment with triphenylmethyl chloride and triethylamine. Reduction of the N-Boc group of (VII) by LiAlH4, yielded the N-methyl amine (VIII). After acylation of (VIII) with acetyl chloride to acetamide (IX), its N-trityl group was cleaved by treatment with hot aqueous formic acid to produce the intermediate piperidine (X).

参考文献中间体

合成目标

【1】 Bichon, D.; Van Broeck, D.; Proietto, V.; Gueule, P.; Emonds-Alt, X. (Sanofi-Synthélabo); Novel N-(3,4-dichlorophenyl-propyl)-piperidine derivs. as selective human NK3-receptor antagonists. EP 0673928; FR 2717477; FR 2717478; FR 2719311; JP 1996048669; US 5741910; US 5942523; US 6124316 .

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)	29470	1-benzyl-4-phenyl-4-piperidinol		C₁₈H₂₁NO	详情	详情
(III)	54993	N-(1-benzyl-4-phenyl-4-piperidinyl)acetamide		C₂₀H₂₄N₂O	详情	详情
(IV)	54994	1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine		C₁₈H₂₂N₂	详情	详情
(V)	59263	tert-butyl 1-benzyl-4-phenyl-4-piperidinylcarbamate		C₂₃H₃₀N₂O₂	详情	详情
(VI)	54998	tert-butyl 4-phenyl-4-piperidinylcarbamate		C₁₆H₂₄N₂O₂	详情	详情
(VII)	59264	tert-butyl 4-phenyl-1-trityl-4-piperidinylcarbamate		C₃₅H₃₈N₂O₂	详情	详情
(VIII)	59265	N-methyl-4-phenyl-1-trityl-4-piperidinamine; N-methyl-N-(4-phenyl-1-trityl-4-piperidinyl)amine		C₃₁H₃₂N₂	详情	详情
(IX)	59266	N-methyl-N-(4-phenyl-1-trityl-4-piperidinyl)acetamide		C₃₃H₃₄N₂O	详情	详情
(X)	59267	N-methyl-N-(4-phenyl-4-piperidinyl)acetamide		C₁₄H₂₀N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

In a further method, aminopiperidine (IV) was converted to the formamide (XL) by heating in ethyl formate. Formyl group reduction in (XL) with LiAlH4 provided the N-metyl amine (XLI). The N-benzyl group of (XLI) was then removed by catalytic hydrogenation over Pd/C. Alkylation of the resultant piperidine (XLII) with mesylate (XXVII) gave adduct (XLIII). After acetylation of (XLIII) in neat Ac2O, the racemic mixture was separated by chiral HPLC.

参考文献中间体

合成目标

【1】 Giardina, G.A.M.; et al.; A reliable and efficient synthesis of SR 142801. Bioorg Med Chem Lett 1996, 6, 19, 2307.
【2】 Grugni, M.; Rigolio, R.; Erhard, K.F. (GlaxoSmithKline Inc.; GlaxoSmithKline SpA); Process for the preparation of 3,3-disubstd. piperidines. WO 9805640 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	54994	1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine	C₁₈H₂₂N₂	详情	详情
(XXVII)	59278	3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate	C₂₂H₂₅Cl₂NO₄S	详情	详情
(XL)	59286	1-benzyl-4-phenyl-4-piperidinylformamide	C₁₉H₂₂N₂O	详情	详情
(XLI)	59287	1-benzyl-N-methyl-4-phenyl-4-piperidinamine; N-(1-benzyl-4-phenyl-4-piperidinyl)-N-methylamine	C₁₉H₂₄N₂	详情	详情
(XLII)	59288	N-methyl-4-phenyl-4-piperidinamine; N-methyl-N-(4-phenyl-4-piperidinyl)amine	C₁₂H₁₈N₂	详情	详情
(XLIII)	59289	(3-(3,4-dichlorophenyl)-3-{3-[4-(methylamino)-4-phenyl-1-piperidinyl]propyl}-1-piperidinyl)(phenyl)methanone	C₃₃H₃₉Cl₂N₃O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XVII)

Acetamide (XVI) was obtained by the Ritter reaction of 1-benzyl-4-phenyl-piperidin-4-ol (XV) with acetonitrile. Acidic hydrolysis of amide (XVI) provided the aminopiperidine (XVII), which was converted into urea (XVIII) upon treatment with N,N-dimethylcarbamoyl chloride. Hydrogenolytic cleavage of the N-benzyl group of (XVIII) gave piperidine (XIX), which was finally alkylated with the mesylate (XIV) to furnish the title compound.

参考文献中间体

合成目标

【1】 Emonds-Alt, X.; Grossriether, I.; Gueule, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthélabo); Substd. heterocyclic cpds., preparation method therefor and pharmaceutical compsns. containing same. EP 1156049; FR 2729952; FR 2729953; FR 2729954; JP 1999507324; JP 2001131171; US 5641777; WO 9623787 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	54992	2-[(2R)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl methanesulfonate	C₂₀H₂₁F₂NO₅S	详情	详情
(XV)	29470	1-benzyl-4-phenyl-4-piperidinol	C₁₈H₂₁NO	详情	详情
(XVI)	54993	N-(1-benzyl-4-phenyl-4-piperidinyl)acetamide	C₂₀H₂₄N₂O	详情	详情
(XVII)	54994	1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine	C₁₈H₂₂N₂	详情	详情
(XVIII)	54995	N'-(1-benzyl-4-phenyl-4-piperidinyl)-N,N-dimethylurea	C₂₁H₂₇N₃O	详情	详情
(XIX)	54996	N,N-dimethyl-N'-(4-phenyl-4-piperidinyl)urea	C₁₄H₂₁N₃O	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XVII)

In an alternative process, the chiral morpholino alcohol (XIII) was activated as the sulfonate ester (XX) employing benzenesulfonyl chloride under phase-transfer conditions. Condensation of the alkyl sulfonate (XX) with 4-(tert-butoxycarbonylamino)-4-phenylpiperidine (XXI) afforded the N-substituted piperidine (XXII). The Boc protecting group of (XXII) was then removed by means of a methanolic solution of HCl, yielding the primary amine (XXIII). Alternatively, amine (XXIII) was synthesized by condensation of sulfonate (XX) with 4-amino-4-phenylpiperidine (XXIV) (obtained by catalytic hydrogenolysis of the N-benzyl piperidine (XVII)). Aminopiperidine (XXIII) was finally converted to the title urea by reaction with phosgene, followed by condensation with dimethylamine.

参考文献中间体

合成目标

【1】 Bonnefoy, S.; Aulombard, A.; Lucas, E.; Bernon, F.; Burgos, A.; Cabos, C. (Sanofi-Synthélabo); Method for preparing (R)-(+)-3-[1-[2-(4-benzoyl-2-(2,3-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperidin-4-yl]-1,1-dimethylurea, its salts solvates and/or hydrates. FR 2787790; US 6392039; WO 0039126 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	54991	[(2R)-2-(3,4-difluorophenyl)-2-(2-hydroxyethyl)morpholinyl](phenyl)methanone	C₁₉H₁₉F₂NO₃	详情	详情
(XVII)	54994	1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine	C₁₈H₂₂N₂	详情	详情
(XX)	54997	2-[(2R)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl benzenesulfonate	C₂₅H₂₃F₂NO₅S	详情	详情
(XXI)	54998	tert-butyl 4-phenyl-4-piperidinylcarbamate	C₁₆H₂₄N₂O₂	详情	详情
(XXII)	54999	tert-butyl 1-{2-[(2R)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl}-4-phenyl-4-piperidinylcarbamate	C₃₅H₄₁F₂N₃O₄	详情	详情
(XXIII)	55000	[(2R)-2-[2-(4-amino-4-phenyl-1-piperidinyl)ethyl]-2-(3,4-difluorophenyl)morpholinyl](phenyl)methanone	C₃₀H₃₃F₂N₃O₂	详情	详情
(XXIV)	55001	4-phenyl-4-piperidinylamine; 4-phenyl-4-piperidinamine	C₁₁H₁₆N₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(II)

Acidic hydrolysis of 4-acetylamino-1-benzyl-4-phenylpiperidine (I) gives diamine (II). Subsequent acylation of (II) with dimethylcarbamoyl chloride affords urea (III). The N-benzyl protecting group is then removed by catalytic hydrogenolysis over Pd/C to furnish piperidine (IV)

参考文献中间体

合成目标

【1】 Proietto, V.; Van Broeck, D.; Edmonds-Alt, X.; Aulombard, A. (Sanofi-Synthelabo); Ureidopiperidine derivs. as selective human NK3 receptor antagonists. EP 1119552; JP 2002527423; US 6465489; WO 0021931 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	54993	N-(1-benzyl-4-phenyl-4-piperidinyl)acetamide	C₂₀H₂₄N₂O	详情	详情
(II)	54994	1-benzyl-4-phenyl-4-piperidinylamine; 1-benzyl-4-phenyl-4-piperidinamine	C₁₈H₂₂N₂	详情	详情
(III)	54995	N'-(1-benzyl-4-phenyl-4-piperidinyl)-N,N-dimethylurea	C₂₁H₂₇N₃O	详情	详情
(IV)	54996	N,N-dimethyl-N'-(4-phenyl-4-piperidinyl)urea	C₁₄H₂₁N₃O	详情	详情

Extended Information