[(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone -Drug Synthesis Database

【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 合成路线2 合成路线3

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.

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	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.

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

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

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
(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