6-chloro-2-(methylamino)-3-nitrobenzonitrile -Drug Synthesis Database

【结构式】

【分子编号】52341

【品名】6-chloro-2-(methylamino)-3-nitrobenzonitrile

【CA登记号】

【分子式】C₈H₆ClN₃O₂

【分子量】211.60736

【元素组成】C 45.41% H 2.86% Cl 16.75% N 19.86% O 15.12%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

Nucleophilic substitution of 2,6-dichloro-3-nitrobenzonitrile (I) with methylamine provided the 2-(methylamino) regioisomer (II). The remaining chloride was subsequently displaced with the potassium enolate of ethyl 2-methylacetoacetate (III), yielding adduct (IV). After catalytic hydrogenation of the nitro group of (IV), the resulting amine (V) was condensed with 2,6-dichlorophenyl isothiocyanate (VI) to produce thiourea (VII), which was further cyclized to the benzimidazole (VIII) upon desulfuration with mercuric oxide. Decarbethoxylation and simultaneous cyclization between keto and cyano groups of (VIII) under acidic conditions gave rise to the fused pyridone system (IX). Regioselective oxidation of one methyl group of (IX) using selenium dioxide in hot dioxan furnished aldehyde (X). To this was added the vinyl Grignard reagent (XI), producing the allyl alcohol (XII), which was further esterified to acetate (XIII) with acetic anhydride and triethylamine. Finally, palladium-catalyzed displacement of the acetate group of (XIII) with diethylamine, with concomitant double bond rearrangement, produced the title allylic amine.

参考文献中间体

合成目标

【1】 Goldberg, D.; Cardozo, M.G.; Tschantz, M.A.; Moss, N.; Morwick, T.; Prokopowicz, A.S. III; Snow, R.J.; Patel, U.R.; Wang, X.-J.; Hammach, A.; Takahashi, H. (Boehringer Ingelheim Pharmaceuticals Inc.); Heterocyclic cpds. useful as inhibitors of tyrosine kinases. WO 0125238 .

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)	52340	2,6-Dichloro-3-nitrobenzonitrile	5866-98-8	C₇H₂Cl₂N₂O₂	详情	详情
(II)	52341	6-chloro-2-(methylamino)-3-nitrobenzonitrile		C₈H₆ClN₃O₂	详情	详情
(III)	10362	ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate	609-14-3	C₇H₁₂O₃	详情	详情
(IV)	52342	ethyl 2-[2-cyano-3-(methylamino)-4-nitrophenyl]-2-methyl-3-oxobutanoate		C₁₅H₁₇N₃O₅	详情	详情
(V)	52343	ethyl 2-[4-amino-2-cyano-3-(methylamino)phenyl]-2-methyl-3-oxobutanoate		C₁₅H₁₉N₃O₃	详情	详情
(VI)	52344	2,6-Dichlorophenyl isothiocyanate	6590-95-0	C₇H₃Cl₂NS	详情	详情
(VII)	52345	ethyl 2-[2-cyano-4-({[(2,6-dichlorophenyl)amino]carbothioyl}amino)-3-(methylamino)phenyl]-2-methyl-3-oxobutanoate		C₂₂H₂₂Cl₂N₄O₃S	详情	详情
(VIII)	52346	ethyl 2-{7-cyano-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}-2-methyl-3-oxobutanoate		C₂₂H₂₀Cl₂N₄O₃	详情	详情
(IX)	52347	2-[(2,6-dichlorophenyl)amino]-1,6,7-trimethyl-1,8-dihydro-9H-imidazo[4,5-h]isoquinolin-9-one		C₁₉H₁₆Cl₂N₄O	详情	详情
(X)	52348	2-[(2,6-dichlorophenyl)amino]-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde		C₁₉H₁₄Cl₂N₄O₂	详情	详情
(XI)	16524	bromo(vinyl)magnesium	1826-67-1	C₂H₃BrMg	详情	详情
(XII)	52349	2-[(2,6-dichlorophenyl)amino]-7-(1-hydroxy-2-propenyl)-1,6-dimethyl-1,8-dihydro-9H-imidazo[4,5-h]isoquinolin-9-one		C₂₁H₁₈Cl₂N₄O₂	详情	详情
(XIII)	52350	1-{2-[(2,6-dichlorophenyl)amino]-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl}-2-propenyl acetate		C₂₃H₂₀Cl₂N₄O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Nucleophilic substitution of 2,6-dichloro-3-nitrobenzonitrile (I) with methylamine provided the 2-(methylamino) regioisomer (II). The remaining chloride was subsequently displaced with the potassium enolate of ethyl 2-methylacetoacetate (III), yielding adduct (IV). After catalytic hydrogenation of the nitro group of (IV), the resulting amine (V) was condensed with 2,6-dichlorophenyl isothiocyanate (VI) to produce thiourea (VII), which was further cyclized to the benzimidazole (VIII) upon desulfuration with mercuric oxide. Decarbethoxylation and simultaneous cyclization between keto and cyano groups of (VIII) under acidic conditions gave rise to the fused pyridone system (IX). Regioselective oxidation of one methyl group of (IX) using selenium dioxide in hot dioxan furnished aldehyde (X). To this was added the vinyl Grignard reagent (XI), producing the allyl alcohol (XII), which was further esterified to acetate (XIII) with acetic anhydride and triethylamine. Finally, palladium-catalyzed displacement of the acetate group of (XIII) with dimethylamine, with concomitant double bond rearrangement, produced the title allylic amine.

参考文献中间体

合成目标

【1】 Goldberg, D.; Cardozo, M.G.; Tschantz, M.A.; Moss, N.; Morwick, T.; Prokopowicz, A.S. III; Snow, R.J.; Patel, U.R.; Wang, X.-J.; Hammach, A.; Takahashi, H. (Boehringer Ingelheim Pharmaceuticals Inc.); Heterocyclic cpds. useful as inhibitors of tyrosine kinases. WO 0125238 .

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)	52340	2,6-Dichloro-3-nitrobenzonitrile	5866-98-8	C₇H₂Cl₂N₂O₂	详情	详情
(II)	52341	6-chloro-2-(methylamino)-3-nitrobenzonitrile		C₈H₆ClN₃O₂	详情	详情
(III)	10362	ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate	609-14-3	C₇H₁₂O₃	详情	详情
(IV)	52342	ethyl 2-[2-cyano-3-(methylamino)-4-nitrophenyl]-2-methyl-3-oxobutanoate		C₁₅H₁₇N₃O₅	详情	详情
(V)	52343	ethyl 2-[4-amino-2-cyano-3-(methylamino)phenyl]-2-methyl-3-oxobutanoate		C₁₅H₁₉N₃O₃	详情	详情
(VI)	52344	2,6-Dichlorophenyl isothiocyanate	6590-95-0	C₇H₃Cl₂NS	详情	详情
(VII)	52345	ethyl 2-[2-cyano-4-({[(2,6-dichlorophenyl)amino]carbothioyl}amino)-3-(methylamino)phenyl]-2-methyl-3-oxobutanoate		C₂₂H₂₂Cl₂N₄O₃S	详情	详情
(VIII)	52346	ethyl 2-{7-cyano-2-[(2,6-dichlorophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}-2-methyl-3-oxobutanoate		C₂₂H₂₀Cl₂N₄O₃	详情	详情
(IX)	52347	2-[(2,6-dichlorophenyl)amino]-1,6,7-trimethyl-1,8-dihydro-9H-imidazo[4,5-h]isoquinolin-9-one		C₁₉H₁₆Cl₂N₄O	详情	详情
(X)	52348	2-[(2,6-dichlorophenyl)amino]-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde		C₁₉H₁₄Cl₂N₄O₂	详情	详情
(XI)	16524	bromo(vinyl)magnesium	1826-67-1	C₂H₃BrMg	详情	详情
(XII)	52349	2-[(2,6-dichlorophenyl)amino]-7-(1-hydroxy-2-propenyl)-1,6-dimethyl-1,8-dihydro-9H-imidazo[4,5-h]isoquinolin-9-one		C₂₁H₁₈Cl₂N₄O₂	详情	详情
(XIII)	52350	1-{2-[(2,6-dichlorophenyl)amino]-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl}-2-propenyl acetate		C₂₃H₂₀Cl₂N₄O₃	详情	详情

Extended Information