新产品编号:2036543
Chemical Name: N-[5-[N-[5-[N-[5-[N-(2-Amidinoethyl)carbamoyl]-1-methyl-1H-pyrrol-3-yl]carbamoyl]-1-methyl-1H-pyrrol-3-yl]carbamoyl]-1-methyl-1H-pyrrol-3-yl]-3-[8-(chloromethyl)-4-hydroxy-1-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indazol-6-ylcarbonyl]-1-methyl-1H-pyrazole
项目整合开发状态: Biological Testing
项目研究机构: Rega Institute for Medical Research (Originator), Tokyo Medical and Dental University (Originator), Universit?di Ferrara (Originator)
合成路线:The methylation of 6-chloro-1H-indole-2-carboxylic acid ethyl ester (I) with NaH and Me-I in DMF gives the 1-methylindole derivative (II),which is condensed with 2-chloro-2-oxoacetic acid ethyl ester (III) by means of TiCl4 in dichloroethane to yield 6-chloro-2-[2-(ethoxycarbonyl)-1-methyl-1H-indol-3-yl]-2-oxoacetic acid ethyl ester (IV).The cyclization of (IV) with phenylhydrazine (V) in refluxing acetic acid affords the 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylic acid ethyl ester (VI).The reduction of the ester group of (VI) by means of NaBH4 in refluxing THF/methanol affords the hydroxymethyl derivative (VII),which is oxidized with MnO2 in refluxing dichloromethane to provide the corresponding carbaldehyde (VIII).The reaction of (VIII) with p-Toluenesulfonylmethyl isocyanide (TosMIC) and potassium tert-butoxide in dimethoxyethane gives the acetonitrile derivative (IX),which is hydrolyzed with HCl in refluxing methanol to yield the acetate ester derivative (X).Finally,this compound is treated with dimethylamine and trimethylaluminum in toluene to afford the target dimethylacetamide derivative.
📌 参考资料/链接：
参考文献标题:4-Oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-acetamide derivs.,their preparation and their application in therapy
文献作者:Bartsch,R.; Sevrin,M.; Froissant,J.; Evanno,Y.; Dubois,L.; Marguet,F.; Gille,C.(Sanofi-Synthabo)
参考来源:EP 1000063; FR 2766823; JP 2001512122; US 6262045; WO 9906406
📄 详细内容
合成路线:The pyrazoledicarboxylic acid mono-methyl ester (I) was converted to the methyl benzyl diester (II) by treatment with benzyl bromide in the presence of DBU.Selective hydrolysis of the methyl ester function with KOH then provided the carboxylic acid (III).Coupling of acid (III) with deformyl distamycin A (IV) using EDC and HOBt gave amide (V).The protecting benzyl ester group of (V) was cleaved by catalytic hydrogenation over Pd/C to yield acid (VI).Amine (VIII) was obtained by acid cleavage of the Boc group from the protected precursor (VII).Subsequent coupling of amine (VIII) with carboxylic acid (VI) furnished the title compound.
参考文献标题:Design,synthesis,DNA binding,and biological evaluation of water-soluble hybrid molecules containing two pyrazole analogues of the alkylating cyclopropylpyrroloindole (CPI) subunit of the antitumor agent CC-1065 and polypyrrole minor groove binders
文献作者:Baraldi,P.G.; Balboni,G.; Pavani,M.G.; Spalluto,G.; Tabrizi,M.A.; Clercq,E.D.; Balzarini,J.; Bando,T.; Sugiyama,H.; Romagnoli,R.
参考来源:J Med Chem 2001,44(16),2536