4-(4-fluorobenzyl)piperidine -Drug Synthesis Database

【结构式】

【分子编号】16794

【品名】4-(4-fluorobenzyl)piperidine

【CA登记号】92822-02-1

【分子式】C₁₂H₁₆FN

【分子量】193.2641832

【元素组成】C 74.58% H 8.34% F 9.83% N 7.25%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(II)

A new synthesis of eliprodil and the asymmetric synthesis of its two enantiomers have been reported: 1) Racemic eliprodil is obtained by condensation of 4-chlorophenacyl bromide (I) with 4-(4-fluorobenzyl)piperidine (II) by means of K2CO3 in refluxing ethanol to give 1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidin-1-yl]ethanone (III), which is then reduced with KBH4 in methanol.

参考文献中间体

合成目标

【1】 Di Fabio, R.; Thomas, R.J.; Pietra, C.; Ziviani, L.; The asymmetric synthesis of both enantiomers of eliprodil. Bioorg Med Chem Lett 1995, 5, 6, 551.

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)	16720	2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone	536-38-9	C₈H₆BrClO	详情	详情
(II)	16794	4-(4-fluorobenzyl)piperidine	92822-02-1	C₁₂H₁₆FN	详情	详情
(III)	16795	1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidino]-1-ethanone		C₂₀H₂₁ClFNO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

2) The (R)- and (S)-enantiomers eliprodil are obtained as follows: The asymmetric dihydroxylation of 4-chlorostyrene (IV) by the Sharpless asymmetric dihydroxylation (AD) procedure (J Org Chem 1992, 57: 2768) methods alpha and beta (AD-alpha and AD-beta) gives both the (S)- and (R)-enantiomers of 1-(4-chlorophenyl)ethane-1,2-diol (Valpha) and (Vbeta), respectively. These compounds, by treatment first with methanesulfonyl chloride and then with K2CO3, yield the corresponding epoxides (VIalpha) and (VIbeta), respectively. Finally, both compounds are condensed with 4-(4-fluorobenzyl)piperidine (II) in refluxing isopropanol.

参考文献中间体

合成目标

【1】 Di Fabio, R.; Thomas, R.J.; Pietra, C.; Ziviani, L.; The asymmetric synthesis of both enantiomers of eliprodil. Bioorg Med Chem Lett 1995, 5, 6, 551.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Va)	16797	(1S)-1-(4-chlorophenyl)-1,2-ethanediol		C₈H₉ClO₂	详情	详情
(Vb)	16798	(1R)-1-(4-chlorophenyl)-1,2-ethanediol		C₈H₉ClO₂	详情	详情
(VIa)	16799	(2S)-2-(4-chlorophenyl)oxirane		C₈H₇ClO	详情	详情
(VIb)	16800	(2R)-2-(4-chlorophenyl)oxirane		C₈H₇ClO	详情	详情
(S)-isomer	16801	(1S)-1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidino]-1-ethanol		C₂₀H₂₃ClFNO	详情	详情
(R)-isomer	16802	(1R)-1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidino]-1-ethanol		C₂₀H₂₃ClFNO	详情	详情
(II)	16794	4-(4-fluorobenzyl)piperidine	92822-02-1	C₁₂H₁₆FN	详情	详情
(IV)	16796	p-chlorostyrene; 1-chloro-4-vinylbenzene	1073-67-2	C₈H₇Cl	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

The enzymatic hydrolysis of (rac)-2-(4-chlorophenyl)oxirane (I) with Solanum tuberosum hydrolase enzyme (St-EH) gives a mixture of unreacted (R)-epoxide (R)-(II) and (R)-diol (R)-(III); this enzyme attacks with marked preference the (S)-epoxide at the more substituted position, with inversion of the configuration. The resulting mixture, without isolation, is treated with Aspergillus niger hydrolase enzyme (At-EH), affording enantiomerically pure (R)-diol (R)-(III); this enzyme attacks with marked preference the (R)-epoxide (R)-(II) at the less-substituted position, consequently with retention of the configuration. The resulting (R)-diol (R)-(III) is converted into (R)-(-)-212381 by known methods.

参考文献中间体

合成目标

【1】 Manoj, K.M.; Baratti, J.; Archelas, A.; Furstoss, R.; Microbiological transformations. Part 45: A green chemistry preparative scale synthesis of enantiopure building blocks of eliprodil: Elaboration of a high substrate concentration epoxide hydrolase-catalyzed hydrolytic kinetic resolution process. Tetrahedron 2001, 57, 4, 695.
【2】 Di Fabio, R.; Thomas, R.J.; Pietra, C.; Ziviani, L.; The asymmetric synthesis of both enantiomers of eliprodil. Bioorg Med Chem Lett 1995, 5, 6, 551.

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)	15243	2-(4-chlorophenyl)oxirane		C₈H₇ClO	详情	详情
(II)	16800	(2R)-2-(4-chlorophenyl)oxirane		C₈H₇ClO	详情	详情
(III)	16798	(1R)-1-(4-chlorophenyl)-1,2-ethanediol		C₈H₉ClO₂	详情	详情
(IV)	16794	4-(4-fluorobenzyl)piperidine	92822-02-1	C₁₂H₁₆FN	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

Condensation of 2-(bromomethyl)-N-methyl-3-nitrobenzamide (I) with 4-(4-fluorobenzyl)piperidine (II) affords the piperidinylmethyl benzamide (III). The nitro group of (III) is then reduced by catalytic hydrogenation over Pd/C to provide aniline (IV). Subsequent coupling of aniline (IV) with 3-acetylphenyl isocyanate (V) leads to the target N,N'-diaryl urea.

参考文献中间体

合成目标

【1】 Ko, S.S.; Santella, J.B. III; Wacker, D.A.; Kim, U.T.; Duncia, J.V.K. (Bristol-Myers Squibb Co.); N-Ureidoalkyl-piperidines as modulators of chemokine receptor activity. EP 1140087; US 6492400; WO 0035454 .

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)	61267	2-(bromomethyl)-N-methyl-3-nitrobenzamide		C₉H₉BrN₂O₃	详情	详情
(II)	16794	4-(4-fluorobenzyl)piperidine	92822-02-1	C₁₂H₁₆FN	详情	详情
(III)	61268	2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-N-methyl-3-nitrobenzamide		C₂₁H₂₄FN₃O₃	详情	详情
(IV)	61269	3-amino-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-N-methylbenzamide		C₂₁H₂₆FN₃O	详情	详情
(V)	61270	3-Acetylphenyl isocyanate 3(and 4)-(Vinylbenzyl)-2-chloroethyl sulfone	23188-64-9	C₉H₇NO₂	详情	详情

Extended Information