3,4-dichloroaniline -Drug Synthesis Database

【结构式】

【分子编号】23629

【品名】3,4-dichloroaniline

【CA登记号】95-76-1

【分子式】C₆H₅Cl₂N

【分子量】162.01784

【元素组成】C 44.48% H 3.11% Cl 43.76% N 8.65%

与该中间体有关的原料药合成路线共 6 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6

合成路线1

该中间体在本合成路线中的序号：(V)

The reaction of cyclopentene oxide (I) with dimethylamine (II) gives 2-(dimethylamino)cyclopentanol (III), which is treated with methanesulfonyl chloride and NaH in THF to afford the corresponding methasulfonyl ester (IV). The condensation of (IV) with 3,4-dichloroaniline (V) in THF yields N,N-dimethyl-N'-(3,4-dichlorophenyl)cyclopentane-1,2-diamine (VI), which is acylated with propionic anhydride (A) and treated finally with maleic acid (B).

参考文献中间体

合成目标

【1】 Szmuszkovicz, J.; N-(2-Aminocyclopentyl)acylanilides and treating depression. BE 0861351; BE 0861355; US 4156015 .
【2】 Szmuszkovicz, J.; Composes alcanoylanilides et leur preparation. BE 0875461 .
【3】 Szmuszkovicz, J.; N-(2-aminocyclopentyl)amides. BE 0867554; DE 2817112; FR 2416882; GB 1581914; JP 54106451; NL 7803442 .
【4】 Szmuszkovicz, J.; Anilide derivatives as antidepressants. US 4128663; US 4148913 .
【5】 Szmuszkovicz, J.; N-(2-Aminocyclopentyl)acylanilides and treating depression. US 4156733; US 4157398 .
【6】 Szmuszkovicz, J.; Kane, M.P.; von Voigtlander, P.F.; A new non-tricyclic antidepressant agent. Synthesis and activity of N-[trans-2-(dimethyamino)cyclopentyl]-N-(3,4-dichlorophenyl)propanamide and related compounds. J Med Chem 1981, 24, 10, 1230-36.
【7】 Owen, R.T.; Serradell, M.N.; Castaner, J.; U-48753 E. Drugs Fut 1984, 9, 11, 846.

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)	20095	propionic anhydride	123-62-6	C₆H₁₀O₃	详情	详情
(B)	23808	Fumaric acid; (E)-2-butenedioic acid	110-17-8	C₄H₄O₄	详情	详情
(I)	34274	(1R,5S)-6-oxabicyclo[3.1.0]hexane		C₅H₈O	详情	详情
(II)	19443	N-methylmethanamine; N,N-dimethylamine	124-40-3	C₂H₇N	详情	详情
(III)	34275	(1S,2S)-2-(dimethylamino)cyclopentanol		C₇H₁₅NO	详情	详情
(IV)	34276	N,N-dimethyl-N-((1S,2S)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclopentyl)amine; (1S,2S)-N,N-dimethyl-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclopentanamine		C₁₀H₂₁NOS	详情	详情
(V)	23629	3,4-dichloroaniline	95-76-1	C₆H₅Cl₂N	详情	详情
(VI)	34277	N-[(1S,2S)-2-(3,4-dichloroanilino)cyclopentyl]-N,N-dimethylamine; (1S,2S)-N(1)-(3,4-dichlorophenyl)-N(2),N(2)-dimethyl-1,2-cyclopentanediamine		C₁₃H₁₈Cl₂N₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (II), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords the title product as a mixture of two diastereomeric racemates that are separated by column chromatography.

参考文献中间体

合成目标

【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 .
【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707.

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)	53530	1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione	606-23-5	C₉H₆O₂	详情	详情
(II)	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(III)	53531	2-Benzylidene-1,3-indandione	n/a	C₁₆H₁₀O₂	详情	详情
(IV)	53532		n/a	C₁₆H₁₀O₃	详情	详情
(V)	23629	3,4-dichloroaniline	95-76-1	C₆H₅Cl₂N	详情	详情
(VI)	11182	2,5-Furandione; Maleic anhydride	108-31-6	C₄H₂O₃	详情	详情
(VII)	53533	1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione	19844-27-0	C₁₀H₅Cl₂NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

参考文献中间体

合成目标

【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 .
【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707.

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)	53530	1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione	606-23-5	C₉H₆O₂	详情	详情
(II)	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(III)	53531	2-Benzylidene-1,3-indandione	n/a	C₁₆H₁₀O₂	详情	详情
(IV)	53532		n/a	C₁₆H₁₀O₃	详情	详情
(V)	53533	1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione	19844-27-0	C₁₀H₅Cl₂NO₂	详情	详情
(VI)	23629	3,4-dichloroaniline	95-76-1	C₆H₅Cl₂N	详情	详情
(VII)	11182	2,5-Furandione; Maleic anhydride	108-31-6	C₄H₂O₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

The condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (II), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords a mixture of two diastereomeric racemates from which the desired isomer (VIII) is separated by column chromatography (1-3). Finally, (VIII) is reduced with NaBH4 in methanol to provide a diastereomeric mixture from which the title product is separated by chromatography.

参考文献中间体

合成目标

【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707.
【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Tetracyclic heterocycles as antimicrobial agents. US 6153645; WO 0017206 .
【3】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 .

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)	53530	1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione	606-23-5	C₉H₆O₂	详情	详情
(II)	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(III)	53531	2-Benzylidene-1,3-indandione	n/a	C₁₆H₁₀O₂	详情	详情
(IV)	53532		n/a	C₁₆H₁₀O₃	详情	详情
(V)	53533	1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione	19844-27-0	C₁₀H₅Cl₂NO₂	详情	详情
(VI)	23629	3,4-dichloroaniline	95-76-1	C₆H₅Cl₂N	详情	详情
(VII)	11182	2,5-Furandione; Maleic anhydride	108-31-6	C₄H₂O₃	详情	详情
(VIII)	53598		n/a	C₂₆H₁₅Cl₂NO₅	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VI)

The condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (III), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords a mixture of two diastereomeric racemates from which the desired isomer (VIII) is separated by column chromatography (1-3). Finally, (VIII) is reduced with NaBH4 in methanol to provide a diastereomeric mixture from which the title product is separated by chromatography.

参考文献中间体

合成目标

【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707.
【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 .
【3】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Tetracyclic heterocycles as antimicrobial agents. US 6153645; WO 0017206 .

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)	53530	1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione	606-23-5	C₉H₆O₂	详情	详情
(II)	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(III)	53531	2-Benzylidene-1,3-indandione	n/a	C₁₆H₁₀O₂	详情	详情
(IV)	53532		n/a	C₁₆H₁₀O₃	详情	详情
(V)	53533	1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione	19844-27-0	C₁₀H₅Cl₂NO₂	详情	详情
(VI)	23629	3,4-dichloroaniline	95-76-1	C₆H₅Cl₂N	详情	详情
(VII)	11182	2,5-Furandione; Maleic anhydride	108-31-6	C₄H₂O₃	详情	详情
(VIII)	53598		n/a	C₂₆H₁₅Cl₂NO₅	详情	详情

合成路线6

该中间体在本合成路线中的序号：(II)

The reductocondensation of N-Boc-piperidin-4-one (I) with 3,4-dichloroaniline (II) by means of NaHB(OAc)3 in dichloroethane gives the secondary amine (III), which is acylated with chloroacetyl chloride (IV) by means of K2CO3 in dichloromethane to yield the chloroacetamide (V). The reaction of (V) with 3,5-dimethylphenol (VI) by means of Cs2CO3 in acetonitrile affords the aryl ether (VII), which is finally Boc deprotected with TFA in dichloromethane to provide the title trisubstituted acetamide.

参考文献中间体

合成目标

【1】 Pirlot, N.; Balançon, L.; Berton, O.; Genicot, C.; Lamberty, Y.; Quéré, L.; Pasau, P.; Lallemand, B.; Talaga, P.; Ryckmans, T.; First dual NK1 antagonists-serotonin reuptake inhibitors: Synthesis and SAR of a new class of potential antidepressants. Bioorg Med Chem Lett 2002, 12, 2, 261.

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)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(II)	23629	3,4-dichloroaniline	95-76-1	C₆H₅Cl₂N	详情	详情
(III)	54455	tert-butyl 4-(3,4-dichloroanilino)-1-piperidinecarboxylate		C₁₆H₂₂Cl₂N₂O₂	详情	详情
(IV)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(V)	54456	tert-butyl 4-[3,4-dichloro(2-chloroacetyl)anilino]-1-piperidinecarboxylate		C₁₈H₂₃Cl₃N₂O₃	详情	详情
(VI)	46786	3,5-dimethylphenol	108-68-9	C₈H₁₀O	详情	详情
(VII)	54457	tert-butyl 4-{3,4-dichloro[2-(3,5-dimethylphenoxy)acetyl]anilino}-1-piperidinecarboxylate		C₂₆H₃₂Cl₂N₂O₄	详情	详情

Extended Information