1168152-07-5

Basic information

• Product Name: (E)-Methyl 1-acetyl-3-(Methoxy(phenyl)Methylene)-2-oxoindoline-6-carboxylate
• Synonyms: (E)-Methyl 1-acetyl-3-(Methoxy(phenyl)Methylene)-2-oxoindoline-6-carboxylate;1-Acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester;methyl (3E)-1-acetyl-3-[methoxy(phenyl)methylidene]-2-oxoindole-6-carboxylate;(E)-1-acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester;(Z)-methyl 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxoindoline-6-carboxylate;Methyl (3E)-1-acetyl-3-[methoxy(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate
• CAS NO: 1168152-07-5
• Molecular Formula: C₂₀H₁₇NO₅
• Molecular Weight: 351.35268
• Product Categories: Intermediate of BIBF-1120 and PKI587
• Mol File: 1168152-07-5.mol

Chemical Properties

• Boiling Point: 547.7±50.0 °C(Predicted)
• Appearance: /
• Density: 1.304±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: -2.33±0.20(Predicted)
• CAS DataBase Reference: (E)-Methyl 1-acetyl-3-(Methoxy(phenyl)Methylene)-2-oxoindoline-6-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: (E)-Methyl 1-acetyl-3-(Methoxy(phenyl)Methylene)-2-oxoindoline-6-carboxylate(1168152-07-5)
• EPA Substance Registry System: (E)-Methyl 1-acetyl-3-(Methoxy(phenyl)Methylene)-2-oxoindoline-6-carboxylate(1168152-07-5)

Safety Data

• Hazardous Substances Data: 1168152-07-5(Hazardous Substances Data)

Upstream product

• 14192-26-8 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 676326-36-6 1-acetyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 707-07-3 orthobenzoic acid trimethyl ester 

Downstream Products

• 334950-66-2 (Z)-3-[(1-methylpiperidin-4-ylamino)-phenyl-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 656247-17-5 nintedanib 
• 334949-29-0 (Z)-3-{[4-(N-acetyl-dimethylcarbamoylmethyl-amino)-phenylamino]-phenyl-methylene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 334950-47-9 (Z)-3-({4-[N-acetyl-(3-dimethylaminopropyl)-amino]-phenylamino}-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 334949-37-0 (Z)-3-({4-[N-acetyl-(2-dimethylaminoethyl)-amino]-phenylamino}-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 334949-33-6 (Z)-3-({4-[(2-dimethylaminoethyl)-methanesulfonyl-amino]-phenylamino}-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 466694-50-8 (Z)-3-({4-[(3-dimethylaminopropyl)-methyl-carbamoyl]-phenylamino}-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 894783-61-0 (Z)-3-({4-[2-(4-methylpiperazin-1-yl)acetylamino]-phenylamino}-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 334950-51-5 (Z)-2-oxo-3-{[4-(2-oxo-pyrrolidin-1-ylmethyl)-phenylamino]-phenylmethylene}-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 334949-28-9 (Z)-3-[(4-dimethylaminomethyl-phenylamino)-phenyl-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 1987887-92-2 methyl (Z)-3-(((4-(methylamino)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate 
• 894783-71-2 BIBF 1202 

Relevant articles and documents

Harnessing affinity-based protein profiling to reveal a novel target of nintedanib

Nintedanib (BIBF1120), a triple angiokinase inhibitor, was first approved for idiopathic pulmonary fibrosis (IPF) therapy and is also efficacious for lung carcinoma, and interstitial lung diseases, far beyond its inhibition of VEGFR/PDGFR/FGFR. We identified tripeptidyl-peptidase 1 (TPP1) as one of the direct targets of nintedanib employing the affinity-based protein profiling (AfBPP) technique. This may be a new mechanism for nintedanib's role different from tyrosine kinase inhibition.

Method for preparing nintedanib ethanesulfonate

The invention discloses a method for preparing nintedanib ethanesulfonate. The method comprises the following steps: carrying out acylation reaction on 2-oxoindole-6-methyl formate and acetic anhydride to obtain 1-acetyl-2-oxoindoline -6-methyl formate; condensing with trimethyl orthobenzoate to generate 1-acetyl-3-(methoxyphenyl methylene)-2-oxoindoline-6-methyl formate, and finally reacting withN-(4-aminophenyl)-N, 4-dimethyl-1-piperazinecarboxamide; under the condition of not separating a main product, adding an alkali for deprotection to generate nintedanib, and finally salifying with ethanesulfonic acid to generate the nintedanib ethanesulfonate. The method has the advantages of mild reaction conditions, simple process operation and high yield, can obtain the nintedanib ethanesulfonate with the purity of 100% without refining, and is suitable for industrial production.

SYNTHESIS OF A 2-INDOLINONE DERIVATIVE KNOWN AS INTERMEDIATE FOR PREPARING NINTEDANIB

The invention discloses the preparation method of methyl (E)-1-acetyl-3-(methoxy(phenyl)methylene)-2-oxoindoline-6-carboxylatefrom methyl 2-oxoindoline-6-carboxylate using high reaction temperatures and a reaction solvent enabling azeotropic removal of acetic acid during the reaction.

A METHOD FOR PREPARING METHYL (Z)-3-[[4-[METHYL[2-(4-METHYL-1-PIPERAZINYL)ACETYL] AMINO]PHENYL]AMINO]PHENYLMETHYLENE)-OXINDOLE-6-CARBOXYLATE (INTEDANIB, NINTEDANIB)

The invention relates to a method of synthesizing methyl (Z)-3-[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl] amino]phenyl] amino]phenylmethylene)-oxindole-6-carboxylate of formula (1), known under the generic name of intedanib or nintedanib. The present method comprises a) a reaction of methyl oxindole-6-carboxylate with acetic anhydride at a temperature of 130 - 140°C, providing methyl 1-acetyl-oxindole-6-carboxylate; b) a reaction of methyl 1-acetyl-oxindole-6-carboxylate of with trimethyl orthobenzoate and acetic anhydride in the presence of toluene, providing methyl (E)-1-acetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate; c) a reaction (E)-1-acetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide and subsequently with an alkali hydroxide or alkali alkoxide in methanol or ethanol without isolation of the intermediate, providing methyl (Z)-3-[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl] amino]phenylmethylene)-oxindole-6-carboxylate, wherein the reaction is conducted at a temperature of 50 to 100°C. (1)

Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120)

Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a newtreatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.