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【结 构 式】

【分子编号】29467

【品名】[(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone

【CA登记号】

【 分 子 式 】C21H23Cl2NO2

【 分 子 量 】392.32456

【元素组成】C 64.29% H 5.91% Cl 18.07% N 3.57% O 8.16%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XXXIII)

In a further procedure, nitrile (XXIII) was alkylated with ethyl 3-bromopropionate (XXVIII) to give cyano ester (XXIX). Catalytic hydrogenation of the cyano group of (XXIX) gave rise to the piperidinone (XXX), which was further reduced to piperidine (XXXI) with LiAlH4 in THF. Acid deprotection of the tetrahydropyranyl group of (XXXI), followed by resolution with (+)-camphorsulfonic acid, furnished the desired (S)-piperidinoalcohol camphorsulfonate salt (XXXII). Treatment of piperidine (XXXII) with benzoyl chloride in the presence of DIEA yielded benzamide (XXXIII). Conversion of the primary alcohol of (XXXIII) into the desired alkyl iodide (XXXV) was achieved via formation of the mesylate ester (XXXIV), followed by displacement of the mesylate group with KI in refluxing acetone.

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 CAS号 分子式 供应商 用于合成
(XXIII) 59274 2-(3,4-dichlorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)pentanenitrile C16H19Cl2NO2 详情 详情
(XXVIII) 29132 ethyl 3-bromopropanoate 539-74-2 C5H9BrO2 详情 详情
(XXIX) 59279 ethyl 4-cyano-4-(3,4-dichlorophenyl)-7-(tetrahydro-2H-pyran-2-yloxy)heptanoate C21H27Cl2NO4 详情 详情
(XXX) 59280 5-(3,4-dichlorophenyl)-5-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-piperidinone C19H25Cl2NO3 详情 详情
(XXXI) 59281 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]propyl tetrahydro-2H-pyran-2-yl ether; 3-(3,4-dichlorophenyl)-3-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]piperidine C19H27Cl2NO2 详情 详情
(XXXII) 59282   C24H35Cl2NO5S 详情 详情
(XXXIII) 29467 [(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone C21H23Cl2NO2 详情 详情
(XXXIV) 29468 3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate C22H25Cl2NO4S 详情 详情
(XXXV) 29469 [(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone C21H22Cl2INO 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XII)

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.

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

合成路线3

该中间体在本合成路线中的序号:(V)

The previously reported (hydroxypropyl)piperidine derivative (V) is subjected to Swern oxidation to produce aldehyde (VI). Then, reductive amination of (VI) with piperidine (IV) in the presence of NaBH3CN affords the target compound

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 CAS号 分子式 供应商 用于合成
(IV) 54996 N,N-dimethyl-N'-(4-phenyl-4-piperidinyl)urea C14H21N3O 详情 详情
(V) 29467 [(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone C21H23Cl2NO2 详情 详情
(VI) 60037 3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propanal C21H21Cl2NO2 详情 详情
Extended Information