Uses
N-[4-[[(Z)-(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)phenylmethyl]amino]phenyl]-N,4-dimethyl-1-piperazineacetamide was used in the study to discover a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth. N-[4-[[(Z)-(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)phenylmethyl]amino]phenyl]-N,4-dimethyl-1-piperazineacetamide is an impurity of Intedanib (I666650), which is an antitumor agent.
Synthesis
1)(Z)-3-{1-[4-(N-(4-benzylpiperazinylmethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylene}-2-dihydroindolone
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylene)-2-dihydroindolone and 4-[N-(4-benzylpiperazinylmethyl-carbonyl)-N-methyl-amino]-aniline in DMF, followed by treatment with methanolic solution of sodium hydroxide.
2) (Z)-3-{1-[4-(N-piperazinylmethylcarbonyl-N-methyl-amino)-phenyl-amino]-1-phenyl-methylene}-2-dihydroindolone-dihydrochloride (nidanib impurity E)
390 mg (0.7 mmol) of (Z)-3-{1-[4-(N-(N-benzylpiperazinylmethylcarbonyl)-N-methyl-amino)-phenylamino]-1-phenyl-methylene}-2-dihydroindolone was dissolved in 20 ml of dichloromethane, heated for 30 min at room temperature after the addition of 0.2 g (1.4 mmol) of chloroethyl 1-chloroformate and refluxed for 60 min. The solvent was concentrated by evaporation and the residue was mixed with 10 ml of methanol and refluxed for 90 minutes. After stirring for 18 hours at room temperature, the product was filtered by suction, washed with methanol and dried. Nidanib impurity E Yield: 200 mg (51% of theoretical value)
