2-(4-chlorophenyl)acetonitrile -Drug Synthesis Database

【结构式】

【分子编号】22871

【品名】2-(4-chlorophenyl)acetonitrile

【CA登记号】140-53-4

【分子式】C₈H₆ClN

【分子量】151.59508

【元素组成】C 63.38% H 3.99% Cl 23.39% N 9.24%

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：(II)

Condensation of 3,4,5-trichloro nitrobenzene (I) with 4-chlorobenzeneacetonitrile (II) by means of NaOH and N,N,N-triethylbenzylammonium chloride in THF yields substituted nitrobenzeneacetonitrile (III), which is subjected to hydrogenation over Pt/C in MeOH in the presence of thiophene to provide aniline (IV). Treatment of (IV) with HCl, HOAc and NaNO2, followed by reaction with ethyl N-(2-cyanoacetyl) carbamate (V) in AcOEt, furnishes ethyl carbamate derivative (VI), which is then subjected to cyclization by means of KOAc in refluxing HOAc to yield perhydro-3,5-dioxo-1,2,4-triazine derivative (VII). Hydrolysis of the nitrile moiety of (VII) by treatment with HCl in refluxing HOAc gives carboxylic acid (VIII), which is finally decarboxylated by heating in 2-mercaptoacetic acid to provide the desired product.

参考文献中间体

合成目标

【1】 Boeckx, G.M.; Sipido, V.; Raeymaekers, A.H.M. (Janssen Pharmaceutica NV); alpha-Aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitriles. AU 8545664; EP 0170316; ES 8609284; ES 8705403; JP 1986043176; JP 1993017454; US 4631278 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	13297	Thiophene	110-02-1	C₄H₄S	详情	详情
(A)	48246	N-benzyl-N,N-dipropyl-1-propanaminium chloride		C₁₆H₂₈ClN	详情	详情
(I)	48245	1,2,3-trichloro-5-nitrobenzene	20098-48-0	C₆H₂Cl₃NO₂	详情	详情
(II)	22871	2-(4-chlorophenyl)acetonitrile	140-53-4	C₈H₆ClN	详情	详情
(III)	48247	2-(4-chlorophenyl)-2-(2,6-dichloro-4-nitrophenyl)acetonitrile		C₁₄H₇Cl₃N₂O₂	详情	详情
(IV)	48248	2-(4-amino-2,6-dichlorophenyl)-2-(4-chlorophenyl)acetonitrile		C₁₄H₉Cl₃N₂	详情	详情
(V)	48249	ethyl 2-cyanoacetylcarbamate		C₆H₈N₂O₃	详情	详情
(VI)	48250	ethyl 2-cyano-2-((Z)-2-[3,5-dichloro-4-[(4-chlorophenyl)(cyano)methyl]phenyl]hydrazono)acetylcarbamate		C₂₀H₁₄Cl₃N₅O₃	详情	详情
(VII)	48251	2-[3,5-dichloro-4-[(4-chlorophenyl)(cyano)methyl]phenyl]-3,5-dioxo-1,2,4-triazinane-6-carbonitrile		C₁₈H₁₀Cl₃N₅O₂	详情	详情
(VIII)	48252	2-[3,5-dichloro-4-[(4-chlorophenyl)(cyano)methyl]phenyl]-3,5-dioxo-1,2,4-triazinane-6-carboxylic acid		C₁₈H₁₁Cl₃N₄O₄	详情	详情
(C)	12893	Ethanethioic S-acid		C₂H₄OS	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

4-Chlorobenzyl cyanide (I) is cycloalkylated with 1,3-dibromopropane to yield 1-(4-chlorophenyl)cyclobutyl cyanide (II). The cyclobutyl cyanide (II) is treated with 2-methylpropyl magnesium bromide te give the imine salt (III), which may be either hydrolyzed to the ketone (IV), which is then formylaminated with formamide and formic acid and subsequently hydrolyzed, or reduced with sodium borohydride in ethanol to give 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (V). Eschweiler-Clarke methylation and hydrochloride formation yield N-[1-[1-(4-chlorophenyl)cyclo butyl]-3-methylbutyl]-N,N-dimethylamine hydrochloride monohydrate

参考文献中间体

合成目标

【1】 Jeffery, J.E.; Kozlik, A.; Wilmshurst, E.C. (The Boots Company plc); Substd. cyclobutanes, process for their preparatio. DE 3212682; GB 2098602; US 4806570 .
【2】 Jeffery, J.E. (The Boots Company plc); N,N-Dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-me. GB 2184122; US 4929629 .
【3】 Buckett, W.R.; Harris, P.J.; SIBUTRAMINE HYDROCHLORIDE < Rec INN; BAN >. Drugs Fut 1988, 13, 8, 736.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	22876	bromo(isobutyl)magnesium	926-62-5	C₄H₉BrMg	详情	详情
(I)	22871	2-(4-chlorophenyl)acetonitrile	140-53-4	C₈H₆ClN	详情	详情
(II)	22872	1-(4-chlorophenyl)cyclobutanecarbonitrile		C₁₁H₁₀ClN	详情	详情
(III)	22873	1-[1-(4-Chlorophenyl)cyclobutyl]-3-methylbutylideneamine bromomagnesium salt		C₁₅H₁₉BrClMgN	详情	详情
(IV)	22874	1-[1-(4-chlorophenyl)cyclobutyl]-3-methyl-1-butanone		C₁₅H₁₉ClO	详情	详情
(V)	22875	1-[1-(4-chlorophenyl)cyclobutyl]-3-methyl-1-butanamine; 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine	84467-54-9	C₁₅H₂₂ClN	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

(4-Chlorophenyl)acetonitrile (I) is reduced with DIBAL to the aldehyde (II), which is subsequently converted to enamine (III) by treatment with dimethylamine in the presence of CaCl2 as the dehydrating agent. Condensation of enamine (III) with 2-cyclohexenone (IV) produces a mixture of the trans endo/exo substituted bicycloalkanones (V) and (VI), separable by column chromatography. Reduction of the endo isomer (V) with NaBH4 yields the bicyclic amino alcohol as a diastereomeric mixture. After chromatographic isolation, the desired isomer is esterified with benzoyl chloride to furnish the corresponding amino ester, which is finally converted to the title hydrochloride salt.

参考文献中间体

合成目标

【1】 Coons, S.; et al.; Synthesis and pharmacology of potential site-specific cocaine abuse treatment agents: The role of the phenyl group in 2-substituted-6-aminobicyclo[2.2.2]octanes. Med Chem Res 2002, 11, 1, 24.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIa)	57732	(1S,2R,4S,5R,6R)-5-(4-chlorophenyl)-6-(dimethylamino)bicyclo[2.2.2]octan-2-ol		C₁₆H₂₂ClNO	详情	详情
(VIIb)	57733	(1S,2S,4S,5R,6R)-5-(4-chlorophenyl)-6-(dimethylamino)bicyclo[2.2.2]octan-2-ol		C₁₆H₂₂ClNO	详情	详情
(I)	22871	2-(4-chlorophenyl)acetonitrile	140-53-4	C₈H₆ClN	详情	详情
(II)	57728	2-(4-chlorophenyl)acetaldehyde		C₈H₇ClO	详情	详情
(III)	57729	(E)-2-(4-chlorophenyl)-N,N-dimethyl-1-ethenamine; N-[(E)-2-(4-chlorophenyl)ethenyl]-N,N-dimethylamine		C₁₀H₁₂ClN	详情	详情
(IV)	26253	2-cyclohexen-1-one；Cyclohex-2-enone；2-cyclohexenone	930-68-7	C₆H₈O	详情	详情
(V)	57730	(1S,4S,5R,6R)-5-(4-chlorophenyl)-6-(dimethylamino)bicyclo[2.2.2]octan-2-one		C₁₆H₂₀ClNO	详情	详情
(VI)	57731	(1S,4S,5S,6S)-5-(4-chlorophenyl)-6-(dimethylamino)bicyclo[2.2.2]octan-2-one		C₁₆H₂₀ClNO	详情	详情

Extended Information