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【结 构 式】

【分子编号】52342

【品名】ethyl 2-[2-cyano-3-(methylamino)-4-nitrophenyl]-2-methyl-3-oxobutanoate

【CA登记号】

【 分 子 式 】C15H17N3O5

【 分 子 量 】319.3172

【元素组成】C 56.42% H 5.37% N 13.16% O 25.05%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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.

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:(IV)

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.

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