【结 构 式】 |
【药物名称】 【化学名称】2-(2,6-Dichlorophenylamino)-7-[3-(diethylamino)-1-propenyl]-1,6-dimethyl-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-9-one 【CA登记号】333456-14-7 【 分 子 式 】C25H27Cl2N5O 【 分 子 量 】484.43284 |
【开发单位】Boehringer Ingelheim (Originator) 【药理作用】Antiarthritic Drugs, IMMUNOMODULATING AGENTS, Immunosuppressants, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Src Kinase Inhibitors |
合成路线1
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 |