1-benzyl-4-phenyl-4-piperidinol -Drug Synthesis Database

【结构式】

【分子编号】29470

【品名】1-benzyl-4-phenyl-4-piperidinol

【CA登记号】

【分子式】C₁₈H₂₁NO

【分子量】267.37088

【元素组成】C 80.86% H 7.92% N 5.24% O 5.98%

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：(I)

The intermediate piperidine (III) was prepared from 1-benzyl-4-hydroxy-4-phenylpiperidine (I) via conversion to acetamide (II) by means of a Ritter reaction with acetonitrile and H2SO4, followed by hydrogenolysis of the N-benzyl protecting group

参考文献中间体

合成目标

【1】 Hale, J.J.; Finke, P.E.; MacCross, M.; A facile synthesis of the novel neurokinin A antagonist SR 48968. Bioorg Med Chem Lett 1993, 3, 2, 319.
【2】 Emonds-Alt, X.; Goulaouic, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthelabo); Arylalkylamines, process for their preparation and pharmaceutical compsns. containing them. EP 0474561; FR 2666335; FR 2678267; JP 1992261155; US 5236921; US 5350852 .
【3】 Descamps, M.; Radisson, J.; Anne-Archard, G. (Sanofi-Synthélabo); Process for the preparation of the (-)-N-methyl-N-[4-(4-phenyl-4-acetyl-aminopiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-benzamide and its pharmaceutically acceptable salts. EP 0698601 .
【4】 Finke, P.E.; Mills, S.G.; Hale, J.J.; MacCoss, M. (Merck & Co., Inc.); Process of making chiral 2-aryl-1,4-butanediamine derivs.. WO 9407839 .
【5】 Emonds-Alt, X.; Proietto, V.; Van Broeck, D.; Vilain, P.; Advenier, C.; Neliat, G.; Le Fur, G.; Breliere, J.-C.; Pharmacological profile and chemical synthesis of SR 48968, a non-peptide antagonist of the neurokinin A (NK2) receptor. Bioorg Med Chem Lett 1993, 3, 5, 925.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	29470	1-benzyl-4-phenyl-4-piperidinol	C₁₈H₂₁NO	详情	详情
(II)	54993	N-(1-benzyl-4-phenyl-4-piperidinyl)acetamide	C₂₀H₂₄N₂O	详情	详情
(III)	59283	N-(4-phenyl-4-piperidinyl)acetamide	C₁₃H₁₈N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

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3

该中间体在本合成路线中的序号：(II)

A new method has been reported. Formamide (XL) was prepared form carbinol (II) by a modified Ritter reaction with cyanotrimethylsilane. Subsequent reduction of (XL) with LiAlH4 gave the N-methyl amine (XLI), which was converted to acetamide (XLIV) by treatment with acetyl chloride. Benzyl group hydrogenolysis in (XLIV) afforded the piperidine (X). Finally, alkylation of piperidine (X) with the chiral alkyl iodide (XXXV) provided the title compound.

参考文献中间体

合成目标

【1】 Chen, H.G.; et al.; A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist. Bioorg Med Chem Lett 1997, 7, 5, 555.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(II)	29470	1-benzyl-4-phenyl-4-piperidinol	C₁₈H₂₁NO	详情	详情
(X)	59267	N-methyl-N-(4-phenyl-4-piperidinyl)acetamide	C₁₄H₂₀N₂O	详情	详情
(XXXV)	29469	[(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone	C₂₁H₂₂Cl₂INO	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
(XLIV)	59290	N-(1-benzyl-4-phenyl-4-piperidinyl)-N-methylacetamide	C₂₁H₂₆N₂O	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XV)

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5

该中间体在本合成路线中的序号：(XVIII)

The protection of 3-bromo-1-propanol (I) with dihydropyran (DHP) and p-toluenesulfonic acid gives the tetrahydropyranyl ether (II), which is condensed with 3,4-dichlorophenylacetonitrile (III) by means of NaH in THF yielding the pentanenitrile (IV). The condensation of (IV) with ethyl 3-bromopropionate (V) by means of potassium hexamethyldisylazide (KHMDS) in THF affords the heptanoate (VI), which is reductocyclized with H2 over RaNi in ethanol/aq. NH4OH affording the piperidone (VII). The reduction of (VII) by means of LiAlH4 in THF gives the piperidine (VIII), which is deprotected with HCl in ethyl ether yielding the racemic propanol (IX). The optical resolution of (IX) by means of (+)-camphorsulfonic acid in isopropanol affords the desired enantiomer (X), which is acylated with benzoyl chloride (XI) and DIEA in dichloromethane providing the benzoylpiperidine (XII). The reaction of (XII) with methanesulfonyl chloride and triethylamine gives the mesylate (XIII), which is treated with KI in refluxing acetone to yield the 3-iodopropyl derivative (XIV). Finally, (XIV) is condensed with 4-hydroxy-4-phenylpiperidine (XV) by means of KHCO3 in hot acetonitrile. The intermediate 4-hydroxy-4-phenylpiperidine (XV) has been obtained as follows: The reaction of 1-benzyl-4-piperidone (XVI) with phenyllithium in THF gives 1-benzyl-4-hydroxy-4-phenylpiperidine (XVII), which is then debenzy-lated by hydrogenation with H2.

参考文献中间体

合成目标

【1】 Kuo, B.-S.; Lee, H.T.; Roth, B.D.; Chung, F.-Z.; Atherton, J.; Chen, M.H.; Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists. Acta Pharm Sin 1999, 20, 3, 283.
【2】 Chen, M.H.G.; Lee, H.T.; Chung, F.-Z. (Pfizer Inc.); 3-Alkyl-3-phenyl-piperidines. WO 9811090 .

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)	12573	3-Bromo-1-propanol; 3-Bromopropanol	627-18-9	C₃H₇BrO	详情	详情
(II)	29460	2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether		C₉H₁₇BrO₂	详情	详情
(III)	26935	2-(3,4-dichlorophenyl)acetonitrile	3218-49-3	C₈H₅Cl₂N	详情	详情
(IV)	29461	2-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile		C₁₇H₂₁Cl₂NO₂	详情	详情
(V)	29132	ethyl 3-bromopropanoate	539-74-2	C₅H₉BrO₂	详情	详情
(VI)	29462	ethyl 4-cyano-4-(3,4-dichlorophenyl)-8-(tetrahydro-2H-pyran-2-yloxy)octanoate		C₂₂H₂₉Cl₂NO₄	详情	详情
(VII)	29463	5-(3,4-dichlorophenyl)-5-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-2-piperidinone		C₂₀H₂₇Cl₂NO₃	详情	详情
(VIII)	29464	3-(3,4-dichlorophenyl)-3-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]piperidine; 4-[3-(3,4-dichlorophenyl)-3-piperidinyl]butyl tetrahydro-2H-pyran-2-yl ether		C₂₀H₂₉Cl₂NO₂	详情	详情
(IX)	29465	3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol		C₁₄H₁₉Cl₂NO	详情	详情
(X)	29466	3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol		C₁₄H₁₉Cl₂NO	详情	详情
(XI)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(XII)	29467	[(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone		C₂₁H₂₃Cl₂NO₂	详情	详情
(XIII)	29468	3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate		C₂₂H₂₅Cl₂NO₄S	详情	详情
(XIV)	29469	[(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone		C₂₁H₂₂Cl₂INO	详情	详情
(XV)	28021	4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine	40807-61-2	C₁₁H₁₅NO	详情	详情
(XVI)	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
(XVII)	24014	Phenyllithium	591-51-5	C₆H₅Li	详情	详情
(XVIII)	29470	1-benzyl-4-phenyl-4-piperidinol		C₁₈H₂₁NO	详情	详情

Extended Information