2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile -Drug Synthesis Database

【结构式】

【分子编号】18202

【品名】2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile

【CA登记号】3215-64-3

【分子式】C₈H₅Cl₂N

【分子量】186.03984

【元素组成】C 51.65% H 2.71% Cl 38.11% N 7.53%

与该中间体有关的原料药合成路线共 5 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1

该中间体在本合成路线中的序号：(I)

1) By methanolysis of 2,6-dichlorophenylacetonitrile (I) by means of H2SO4 to methyl 2,6-dichlorophenylacetate (II), which is then condensed with guanidine (A) in isopropanol. 2) By condensation of S-methylisothiourea (V) with 2,6-dichlorophenylacetyl chloride (VI) in acetone to afford S-methyl-N-(2,6-dichlorophenylacetyl)isothiourea (VII); this product is then treated with ammonia in isopropanol. 3) By condensation of 2,6-dichlorophenylacetic acid (VIII) with guanidine (A) in toluene.

参考文献中间体

合成目标

【1】 Arrigoni-Martelli, E.; Castaner, J.; BS 100-141. Drugs Fut 1976, 1, 4, 167.
【2】 Bream, J.B.; et al.; Substituted phenylacetylguanidines: A new class of antihypertensive agents. Arzneim-Forsch Drug Res 1975, 25, 10, 1477.
【3】 Bream, J.B.; et al. (Novartis AG); Substituted phenylacethyl derivatives of guanidine, O-alkylisoureas, S-alkylisothioureas and p-benzylalkylisothioureas. DE 179348; FR 1584670; GB 1235723; US 3632645 .

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)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(I)	18202	2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile	3215-64-3	C₈H₅Cl₂N	详情	详情
(II)	40327	methyl 2-(2,6-dichlorophenyl)acetate	54551-83-6	C₉H₈Cl₂O₂	详情	详情
(V)	10272	[[Amino(imino)methyl]sulfanyl]methane	2986-19-8	C₂H₆N₂S	详情	详情
(VI)	40329	2-(2,6-dichlorophenyl)acetyl chloride		C₈H₅Cl₃O	详情	详情
(VII)	40330	1,3-dichloro-2-(2-[[imino(methylsulfanyl)methyl]amino]-2-oxoethyl)benzene		C₁₀H₁₀Cl₂N₂OS	详情	详情
(VIII)	40328	2-(2,6-dichlorophenyl)acetic acid	6575-24-2	C₈H₆Cl₂O₂	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) By reaction of the nitrile (I) with ethyl formate (B) by means of NaOEt in ethanol to give alpha-formyl-2,6-dichlorophenylacetonitrile (III), which is condensed with guanidine hydrochloride (A) by means of NaOEt in ethanol to yield alpha-(guanidinomethylene)-2,6-dichlorophenylacetonitrile (IV); this product is finally hydrolyzed and rearranged by means of HCl.

参考文献中间体

合成目标

【1】 Arrigoni-Martelli, E.; Castaner, J.; BS 100-141. Drugs Fut 1976, 1, 4, 167.
【2】 Bream, J.B.; et al.; Verfahren zur Herstellung von Acylguanidinen. CH 511816 .
【3】 Bream, J.B.; et al.; Verfahren zur Herstellung von Acylguanidinen. CH 518910 .

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)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(B)	16602	ethyl formate	109-94-4	C₃H₆O₂	详情	详情
(I)	18202	2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile	3215-64-3	C₈H₅Cl₂N	详情	详情
(III)	40331	2-(2,6-dichlorophenyl)-2-hydroxyacetonitrile		C₈H₅Cl₂NO	详情	详情
(IV)	40332	N''-[(Z)-2-cyano-2-(2,6-dichlorophenyl)ethenyl]guanidine		C₁₀H₈Cl₂N₄	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 reaction of chloropyrimidine (I) with methylamine in the presence of triethylamine in THF yielded aminopyrimidine (II). The reduction of the ester group of (II) with LiAlH4 gave benzylic alcohol (III), which was oxidized to aldehyde (IV) with MnO2. This was condensed with 2,6-dichlorophenylacetonitrile (V) in DMF at 105 C in the presence of K2CO3 to provide pyridopyrimidine (VI). The imino group of (VI) was then acetylated with Ac2O, and the resulting N-acetylimine (VII) was hydrolyzed in boiling 6 N HCl to provide pyridopyrimidinone (VIII). Oxidation with two equivalents of m-chloroperbenzoic acid gave sulfone (IX), which was displaced with aniline (X) in refluxing AcOH to furnish (XI). Finally, (XI) was dissolved in boiling isopropanol and converted to the dihydrochloride by addition of an isopropanolic solution of HCl.

参考文献中间体

合成目标

【1】 2-Substituted aminopyrido[2,3-d]pyrimidin-7(8H)-ones. Structure-activity relationships against selected tyrosine kinases and in vitro and in vivo anticancer activity. J Med Chem 1998, 41, 17, 3276.

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)	18198	ethyl 4-chloro-2-(methylsulfanyl)-5-pyrimidinecarboxylate; ETHYL 4-CHLORO-2-METHYLTHIO-5-PYRIMIDINECARBOXYLATE	5909-24-0	C₈H₉ClN₂O₂S	详情	详情
(II)	18199	ethyl 4-(methylamino)-2-(methylsulfanyl)-5-pyrimidinecarboxylate		C₉H₁₃N₃O₂S	详情	详情
(III)	18200	[4-(methylamino)-2-(methylsulfanyl)-5-pyrimidinyl]methanol		C₇H₁₁N₃OS	详情	详情
(IV)	18201	4-(methylamino)-2-(methylsulfanyl)-5-pyrimidinecarbaldehyde		C₇H₉N₃OS	详情	详情
(V)	18202	2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile	3215-64-3	C₈H₅Cl₂N	详情	详情
(VI)	18203	6-(2,6-dichlorophenyl)-8-methyl-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-imine		C₁₅H₁₂Cl₂N₄S	详情	详情
(VII)	18204	N-[6-(2,6-dichlorophenyl)-8-methyl-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-ylidene]acetamide		C₁₇H₁₄Cl₂N₄OS	详情	详情
(VIII)	18205	6-(2,6-dichlorophenyl)-8-methyl-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one		C₁₅H₁₁Cl₂N₃OS	详情	详情
(IX)	18206	6-(2,6-dichlorophenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one		C₁₅H₁₁Cl₂N₃O₃S	详情	详情
(X)	18207	4-[2-(diethylamino)ethoxy]aniline; N-[2-(4-aminophenoxy)ethyl]-N,N-diethylamine		C₁₂H₂₀N₂O	详情	详情
(XI)	18208	6-(2,6-dichlorophenyl)-2-[4-[2-(diethylamino)ethoxy]anilino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one		C₂₆H₂₇Cl₂N₅O₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

The condensation of 2-(2,6-dichlorophenyl)acetonitrile (I) with ethyl acetate (II) by means of sodium ethoxide in refluxing ethanol gives 2-(2,6-dichlorophenyl)-3-oxobutyronitrile (III), which is methylated with diazomethane in ether yielding the enol ether (IV). Finally, this compound is cyclized with guanidine (V) by means of sodium ethoxide in refluxing ethanol.

参考文献中间体

合成目标

【1】 Miller, A.A.; Nobbs, M.S.; Hyde, R.M.; Leach, M.J. (Glaxo Wellcome plc); Pharmacologically active CNS cpds.. AU 8945964; EP 0372934; EP 0713703; EP 0715851; EP 0727212; EP 0727213; EP 0727214; JP 1990202876; US 5587380; US 5597828; US 5635507; US 5684005 .

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)	18202	2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile	3215-64-3	C₈H₅Cl₂N	详情	详情
(II)	17491	ethyl acetate	141-78-6	C₄H₈O₂	详情	详情
(III)	28609	2-(2,6-dichlorophenyl)-3-oxobutanenitrile		C₁₀H₇Cl₂NO	详情	详情
(IV)	28610	(Z)-2-(2,6-dichlorophenyl)-3-methoxy-2-butenenitrile		C₁₁H₉Cl₂NO	详情	详情
(V)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

The condensation of 2-(2,6-dichlorophenyl)acetonitrile (I) with 3,6-dichloropyridazin-3-yl)acetonitrile (III), wich is condensed with 2,4-difluorothiophenol (IV) by means of NaH in THF to yield the thioether (V). The partial hydrolysis of the cyano group of (V) with conc. H2SO4 at 100 CC affords the acetamide (VI), wich is finally cyclized with N,N-dimethylformamidedimethylacetal (VII) in refluxing toluene te provide the target pyrimido-pyridazine derivative.

参考文献中间体

合成目标

【1】 Salituro, F.G.; Duffy, J.P.; Murcko, M.A.; Bemis, G.W.; Su, M.; Wilson, K.P.; Cochran, J.E.; Harrington, E.M.; Galullo, V.P. (Vertex Pharmaceuticals Inc.); Substd. nitrogen containing heterocycles as inhibitors of p38 protein kinase. EP 0951467; JP 2001506266; WO 9827098 .

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)	18202	2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile	3215-64-3	C₈H₅Cl₂N	详情	详情
(II)	11292	3,6-Dichloropyridazine	141-30-0	C₄H₂Cl₂N₂	详情	详情
(III)	60561	2-(2,6-dichlorophenyl)-2-(6-methyl-3-pyridazinyl)acetonitrile		C₁₃H₉Cl₂N₃	详情	详情
(IV)	60562	2,4-difluorobenzenethiol; 2,4-difluorophenylhydrosulfide		C₆H₄F₂S	详情	详情
(V)	60563	2-(2,6-dichlorophenyl)-2-{6-[(2,4-difluorophenyl)sulfanyl]-3-pyridazinyl}acetonitrile		C₁₈H₉Cl₂F₂N₃S	详情	详情
(VI)	60564	2-(2,6-dichlorophenyl)-2-{6-[(2,4-difluorophenyl)sulfanyl]-3-pyridazinyl}acetamide		C₁₈H₁₁Cl₂F₂N₃OS	详情	详情
(VII)	11984	N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal	4637-24-5	C₅H₁₃NO₂	详情	详情

Extended Information