656247-17-5

Basic information

• Product Name: Nintedanib
• Synonyms: Nintedanib;Nintedanib (BIBF 1120);Nintedanib/Intedanib/Vargatef;Intedanib Vargatef;methyl (3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]-phenylmethylidene]-2-oxo-1H-indole-6-carboxylate Nintedanib (BIBF 1120);Vargatef (nintedanib);3-[(4-{Methyl-[2-(4-methyl-piperazin-1-yl)-acetyl]-amino}-phenylamino)-phenyl-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester;3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
• CAS NO: 656247-17-5
• Molecular Formula: C₃₁H₃₃N₅O₄
• Molecular Weight: 539.62482
• EINECS: 1592732-453-0
• Product Categories: Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitors;Amines;Nintedanib
• Mol File: 656247-17-5.mol

Chemical Properties

• Boiling Point: 742.199°C at 760 mmHg
• Flash Point: 402.667°C
• Appearance: /
• Density: 1.284g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.658
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 11.06±0.20(Predicted)
• CAS DataBase Reference: Nintedanib(CAS DataBase Reference)
• NIST Chemistry Reference: Nintedanib(656247-17-5)
• EPA Substance Registry System: Nintedanib(656247-17-5)

Safety Data

• Hazardous Substances Data: 656247-17-5(Hazardous Substances Data)

Usage

Mechanism of action

Nintedanib is a small molecule that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fms-like tyrosine kinase-3 (FLT3). Among them, FGFR, PDGFR, and VEGFR have been implicated in IPF pathogenesis. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signaling which is crucial for the proliferation, migration, and transformation of fibroblasts representing essential mechanisms of the IPF pathology. In addition, nintedanib inhibits the following nRTKs: Lck, Lyn and Src kinases. The contribution of FLT3 and nRTK inhibition to IPF efficacy is unknown.

indications

Nintedanib ( Vargatef ) is an oral triple angiokinase inhibitor which simultaneously inhibits vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR) signalling pathways. Growing scientific evidence shows that these three different angiokinase receptors play an important role not only in angiogenesis but also in tumour growth and metastasis. Nintedanib is currently being investigated in patients with various solid tumours including Phase III studies in advanced NSCLC, colorectal cancer (refractory to standard treatment) and ovarian cancer, and also in Phase II studies in mesothelioma, kidney cancer (renal cell carcinoma) and liver cancer (hepatic cell carcinoma). In the EU, nintedanib in the treatment of idiopathic pulmonary fibrosis (IPF) has recently received a positive CHMP opinion. The U.S. Food and Drug Administration (FDA) has approved nintedanib capsules under the brand name OFEV for oral use for the treatment of IPF.

Drugbank Description

Nintedanib is a drug indicated for the treatment of idiopathic pulmonary fibrosis (IPF) that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fms-like tyrosine kinase-3 (FLT3). Among them, FGFR, PDGFR, and VEGFR have been implicated in IPF pathogenesis. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signaling which is crucial for the proliferation, migration, and transformation of fibroblasts representing essential mechanisms of the IPF pathology. In addition, nintedanib inhibits the following nRTKs: Lck, Lyn and Src kinases. The contribution of FLT3 and nRTK inhibition to IPF efficacy is unknown. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease characterized by a progressive loss of lung function with worsening dyspnoea and cough. Development is thought to be instigated by repetitive lung injury (such as by cigarette smoke, industrial dusts, gastrooesophageal reflux and viral infection) leading to destruction of epithelial alveolar cells. Subsequent dysregulation of the repair process results in the proliferation/migration of fibroblasts and their differentiation into myofibroblasts, abnormal extracellular matrix deposition and excessive collagen accumulation in the lung interstitium and alveolar space, leading to progressive fibrosis and stiffening of the lungs. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) mediate various processes, including fibrogenesis and angiogenesis, and are implicated in the pathogenesis of IPF. By blocking substrate binding and downstream signalling cascades, nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of extracellular matrix. References https://www.drugbank.ca/drugs/DB09079

Uses

Different sources of media describe the Uses of 656247-17-5 differently. You can refer to the following data:
1. It is an indolinone derivative potently blocking VEGF-, PDGF-, and FGF-receptor kinases; an indolinone as triple angiokinase inhibitors.
2. BIBF1120 (Vargatef) is a potent inhibitor of VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50 of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM, respectively.
3. It is an indolinone derivative potently blocking VEGF-, PDGF-, and FGF-receptor kinases; an indolinone as triple angiokinase inhibitors. An antitumor agent.

Definition

ChEBI: A member of the class of oxindoles that is a kinase inhibitor used (in the form of its ethylsulfonate salt) for the treatment of idiopathic pulmonary fibrosis and cancer.

Biological Activity

nintedanib (bibf 1120) is an indolinone-derived oral active, triple angiokinase inhibitor of vascular endothelial growth factor receptor (vegfr)1-3, fibroblast growth factor receptor (fgfr)1-3 and platelet-derived growth factor receptor (pdgfr)α/β1. it has shown potent antiangiogenic activity at nanomolar (ic50, 20-100 nmol/l) by blocking these receptor-mediated signaling pathways1,2. nintedanib (bibf 1120) is in clinical development for the treatment of idiopathic pulmonary fibrosis as these receptors have been shown to be potentially involved in the pathogenesis of pulmonary fibrosis3,4. as a novel angiogenesis inhibitor, it is also being widely evaluated in different cancer models and has displayed significant anti-tumor activities by inhibiting tumor blood vessel formation5-7.to further evaluate its antitumor effects on multiple tumors, nintedanib is currently entering several

Clinical Use

Tyrosine kinase inhibitor: Treatment of locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology in combination with docetaxel Treatment of Idiopathic Pulmonary Fibrosis (IPF)

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration reduced by rifampicin - avoid. Antifungals: concentration increased by ketoconazole. Antipsychotics: increased risk of agranulocytosis with clozapine - avoid.

Metabolism

Nintedanib is metabolised in the liver, initially by hydrolytic cleavage by esterases and then by glucuronidation by uridine diphosphate glucuronosyltransferase enzymes. Only a minor portion is metabolised by cytochrome P450 isoenzymes, mainly CYP3A4. More than 90% of a dose is eliminated by faecal/biliary excretion.

references

[1]hilberg, f. et al. bibf 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. cancer research 68, 4774-4782, doi:10.1158/0008-5472.can-07-6307 (2008).

InChI:InChI=1/C31H33N5O4/c1-34-15-17-36(18-16-34)20-27(37)35(2)24-12-10-23(11-13-24)32-29(21-7-5-4-6-8-21)28-25-14-9-22(31(39)40-3)19-26(25)33-30(28)38/h4-14,19,32H,15-18,20H2,1-3H3,(H,33,38)/b29-28-

Synthetic route

methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate ethanesulfonate salt (656247-18-6) → nintedanib (656247-17-5)

Conditions	Yield
With sodium hydrogencarbonate In water; ethyl acetate at 40℃; for 1h;	98.7%
With sodium carbonate In water pH=9; Solvent; pH-value;	20 g

N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine (262368-30-9) + (E)-1-acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (1168152-07-5) → nintedanib (656247-17-5)

Conditions	Yield
Stage #1: N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine; (E)-1-acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester With methanol In N,N-dimethyl-formamide at 75℃; for 4h; Large scale; Stage #2: With methanol; potassium hydroxide In N,N-dimethyl-formamide Temperature; Large scale;	94.6%
Stage #1: N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine; (E)-1-acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester In methanol for 5h; Reflux; Stage #2: With potassium hydroxide In methanol at 20 - 70℃; for 0.5h; Concentration; Reagent/catalyst; Temperature; Solvent;	90%
Stage #1: N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine; (E)-1-acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester In methanol; N,N-dimethyl-formamide Reflux; Stage #2: With piperidine In methanol; N,N-dimethyl-formamide Reflux;	88%
Stage #1: N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine; (E)-1-acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester In methanol for 5h; Reflux; Stage #2: With potassium hydroxide In methanol	84%
Stage #1: N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine; (E)-1-acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester In N,N-dimethyl-formamide at 80℃; for 1h; Stage #2: With piperidine In N,N-dimethyl-formamide at 20℃; for 2h;	77%

1-methyl-piperazine (109-01-3) + methyl 1-acetyl-3-(((4-(2-chloro-N-methylacetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate → nintedanib (656247-17-5)

Conditions	Yield
In N,N-dimethyl-formamide at 45 - 50℃;	93.74%

1-methyl-piperazine (109-01-3) + methyl-1-acetyl-3-((4-(2-chloro-N-ethylacetamido)phenyl)amino(phenyl)methylene)-2-oxoindoline-6-carboxylate → nintedanib (656247-17-5)

Conditions	Yield
In N,N-dimethyl-formamide at 45 - 50℃;	93.74%

1-methyl-piperazine (109-01-3) + C26H22ClN3O4 → nintedanib (656247-17-5)

Conditions	Yield
In toluene at 65℃; for 4h; Solvent; Temperature;	93%

N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine (262368-30-9) + methyl 3-[bromo(phenyl)methylidene]-2-oxoindoline-6-formate → nintedanib (656247-17-5)

Conditions	Yield
With sodium hydrogencarbonate In ethanol for 2h; Reflux;	92.7%

N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine (262368-30-9) + methyl 1-acetyl-3-[methoxy(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate → nintedanib (656247-17-5)

Conditions	Yield
With pyrrolidine In methanol at 25 - 50℃; for 6h;	91.37%

1-acetyl-3-(Z)-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-methylaminophenyl)amino)-1-phenylmethylene]-6-methoxycarbonyl-2-indolinone → nintedanib (656247-17-5)

Conditions	Yield
With methanol; potassium hydroxide at 20℃; Reagent/catalyst; Large scale;	91.3%
With methanol; potassium hydroxide at 50 - 55℃; for 2h; Temperature;

N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine (262368-30-9) + (E)-methyl 3-(methoxy(phenyl)methylene)-2-indolone-6-carboxylic acid methyl ester (1168150-46-6) → nintedanib (656247-17-5)

Conditions	Yield
In methanol for 8h; Reflux;	90.8%

benzoic acid methyl ester (93-58-3) + N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine (262368-30-9) + 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (14192-26-8) → nintedanib (656247-17-5)

Conditions	Yield
Stage #1: benzoic acid methyl ester; 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; Stage #2: N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine In N,N-dimethyl-formamide at 20℃; for 4h;	89.7%

N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine (262368-30-9) + 3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylic acid methyl ester (1160293-22-0) → nintedanib (656247-17-5)

Conditions	Yield
In methanol at 10℃; for 9.5h; Product distribution / selectivity; Heating / reflux;	89%
In methanol for 7.5h; Product distribution / selectivity; Heating / reflux;	89%
In methanol; N,N-dimethyl-formamide at 0℃; for 9h; Product distribution / selectivity; Heating / reflux;	88.1%

N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine (262368-30-9) + methyl 1-acetyl-3-[ethoxy(phenyl)methylidene]-2-oxo-2,3-dihydro-7H-indole-6-carboxylate (1175365-43-1) → nintedanib (656247-17-5)

Conditions	Yield
Stage #1: N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine; methyl 1-acetyl-3-[ethoxy(phenyl)methylidene]-2-oxo-2,3-dihydro-7H-indole-6-carboxylate In DMF (N,N-dimethyl-formamide) at 80℃; for 1h; Stage #2: With piperidine In DMF (N,N-dimethyl-formamide) at 20℃; for 2h;	77%

N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine (262368-30-9) + (Z)-1-acetyl-3-(ethoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (1027407-75-5) → nintedanib (656247-17-5)

Conditions	Yield
With piperidine In DMF (N,N-dimethyl-formamide) at 20 - 80℃; for 3h;	77%
Stage #1: N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine; (Z)-1-acetyl-3-(ethoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester In N,N-dimethyl-formamide at 80℃; for 1h; Stage #2: With piperidine at 20℃; for 2h;	72%
Stage #1: N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine; (Z)-1-acetyl-3-(ethoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester In N,N-dimethyl-formamide at 180℃; for 8h; Stage #2: With piperidine In N,N-dimethyl-formamide at 20℃; for 2h;	72%
Stage #1: N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine; (Z)-1-acetyl-3-(ethoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester In N,N-dimethyl-formamide at 80℃; for 1h; Stage #2: With piperidine In N,N-dimethyl-formamide at 20℃; for 2h;	1.3 g

N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine (262368-30-9) + methyl (Z)-3-(methoxy(phenyl)methylene)-2-oxoindole-6-carboxylate → nintedanib (656247-17-5)

Conditions	Yield
With methanol In N,N-dimethyl-formamide for 5h; Reflux;	73.2%

N-methyl(p-nitroaniline) (100-15-2) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dmap / dichloromethane / 5 - 20 °C 2.1: toluene / 2.5 h / 40 - 55 °C 2.2: 20 °C / 750.08 Torr 3.1: methanol / 8 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: lithium carbonate / 1,4-dioxane; water / 3 h / 33 °C 2.1: potassium carbonate / acetone / 12 h / 20 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C / 2585.81 Torr 4.1: N,N-dimethyl-formamide / 1 h / 80 °C 4.2: 2 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: triethylamine / isopropyl alcohol / 0.25 h / 25 °C 1.2: 3 h / 25 °C 2.1: hydrogen; palladium on activated charcoal / isopropyl alcohol / 12 h / 30 °C 3.1: acetic acid / N,N-dimethyl-formamide / 0.25 h / 20 °C 3.2: 5 h / 90 °C 4.1: hydrogenchloride / methanol; dichloromethane / 3 h / 20 °C 5.1: ethyl acetate / 1 h / 40 °C / Inert atmosphere 6.1: toluene / 4 h / 65 °C View Scheme
Multi-step reaction with 4 steps 1.1: ethyl acetate / 1 h / 70 °C 2.1: toluene / 2 h / 55 °C 3.1: palladium on activated charcoal; hydrogen / isopropyl alcohol / 12 h / 20 °C 4.1: N,N-dimethyl-formamide / 1 h / 80 °C 4.2: 2 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: ethyl acetate / 1 h / 70 °C 2.1: toluene / 2 h / 55 °C 3.1: palladium on activated charcoal; hydrogen / isopropyl alcohol / 12 h / 20 °C 4.1: N,N-dimethyl-formamide / 8 h / 180 °C 4.2: 2 h / 20 °C View Scheme

2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (14192-26-8) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene / 4 h / Reflux 2.1: acetic anhydride / toluene / Reflux 2.2: 120 h / 20 - 104 °C 3.1: potassium hydroxide; methanol / 0.67 h / Reflux 4.1: methanol / 8 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: toluene / 110 °C 2.1: N,N-dimethyl-formamide / 1 h / 80 °C 2.2: 2 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: toluene; cyclohexane / 6 h / 80 - 90 °C / Inert atmosphere 2: acetic anhydride / toluene / 4 h / Reflux 3: methanol; potassium hydroxide / 3 h / Reflux 4: methanol / N,N-dimethyl-formamide / 5 h / Reflux View Scheme

methyl 1-(2-chloroacetyl)-2-oxoindoline-6-carboxylate (1160293-25-3) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: acetic anhydride / toluene / Reflux 1.2: 120 h / 20 - 104 °C 2.1: potassium hydroxide; methanol / 0.67 h / Reflux 3.1: methanol / 8 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: acetic anhydride / toluene / 4 h / Reflux 2: methanol; potassium hydroxide / 3 h / Reflux 3: methanol / N,N-dimethyl-formamide / 5 h / Reflux View Scheme
Multi-step reaction with 6 steps 1.1: acetic anhydride / 6 h / 124 °C 2.1: sodium carbonate / methanol / 0.5 h / 63 °C 3.1: acetic acid / N,N-dimethyl-formamide / 0.25 h / 20 °C 3.2: 5 h / 90 °C 4.1: hydrogenchloride / methanol; dichloromethane / 3 h / 20 °C 5.1: ethyl acetate / 1 h / 40 °C / Inert atmosphere 6.1: toluene / 4 h / 65 °C View Scheme

(E)-1-cholroacetyl-3-(methoxy(phenyl)methylene)-2-indolone-6-methylformate (1174335-83-1) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium hydroxide; methanol / 0.67 h / Reflux 2: methanol / 8 h / Reflux View Scheme

2-chloro-N-methyl-N-(4-nitrophenyl)acetamide (2653-16-9) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetone / 12 h / 20 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C / 2585.81 Torr 3.1: N,N-dimethyl-formamide / 1 h / 80 °C 3.2: 2 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: toluene / 2 h / 55 °C 2.1: palladium on activated charcoal; hydrogen / isopropyl alcohol / 12 h / 20 °C 3.1: N,N-dimethyl-formamide / 1 h / 80 °C 3.2: 2 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: acetic acid; iron / water / 1.5 h / 20 - 45 °C 2: methanol; N,N-dimethyl-formamide / 12 h / 60 - 65 °C 3: N,N-dimethyl-formamide / 45 - 50 °C View Scheme
Multi-step reaction with 3 steps 1.1: toluene / 2 h / 55 °C 2.1: palladium on activated charcoal; hydrogen / isopropyl alcohol / 12 h / 20 °C 3.1: N,N-dimethyl-formamide / 8 h / 180 °C 3.2: 2 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: ethyl acetate / 2 h / 40 - 50 °C 2: palladium 10% on activated carbon; hydrogen / isopropyl alcohol / 20 °C 3: methanol; N,N-dimethyl-formamide / 7 h / Reflux View Scheme

N-methyl-2-(4-methylpiperazin-1-yl)-N-(4-nitrophenyl)-acetamide (1139453-98-7) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C / 2585.81 Torr 2.1: N,N-dimethyl-formamide / 1 h / 80 °C 2.2: 2 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: palladium on activated charcoal; hydrogen / isopropyl alcohol / 12 h / 20 °C 2.1: N,N-dimethyl-formamide / 1 h / 80 °C 2.2: 2 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: palladium on activated charcoal; hydrogen / isopropyl alcohol / 12 h / 20 °C 2.1: N,N-dimethyl-formamide / 8 h / 180 °C 2.2: 2 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / isopropyl alcohol / 20 °C 2: methanol; N,N-dimethyl-formamide / 7 h / Reflux View Scheme

4-methoxycarbonylmethyl-3-nitrobenzoic acid methyl ester (334952-07-7) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: acetic acid; palladium 10% on activated carbon; hydrogen / 2.5 h / 20 °C / 2585.81 Torr 2.1: toluene / 110 °C 3.1: N,N-dimethyl-formamide / 1 h / 80 °C 3.2: 2 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: acetic anhydride / Reflux 2: N,N-dimethyl-formamide / 2 h / 80 - 85 °C 3: palladium 10% on activated carbon; isopropyl alcohol / 4 h / 20 °C / 3750.38 - 6000.6 Torr 4: toluene / 5 h / 115 - 120 °C View Scheme

methyl 3-nitrobenzoate (618-95-1) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium tert-butylate / N,N-dimethyl-formamide / 0.17 h / -10 °C 2.1: acetic acid; palladium 10% on activated carbon; hydrogen / 2.5 h / 20 °C / 2585.81 Torr 3.1: toluene / 110 °C 4.1: N,N-dimethyl-formamide / 1 h / 80 °C 4.2: 2 h / 20 °C View Scheme

para-nitrophenyl bromide (586-78-7) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 16 h / 20 °C / Heating; Sealed tube 2.1: lithium carbonate / 1,4-dioxane; water / 3 h / 33 °C 3.1: potassium carbonate / acetone / 12 h / 20 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C / 2585.81 Torr 5.1: N,N-dimethyl-formamide / 1 h / 80 °C 5.2: 2 h / 20 °C View Scheme

3-nitrobenzoic acid (121-92-6) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: thionyl chloride / 2 h / 0 - 50 °C 2.1: potassium tert-butylate / N,N-dimethyl-formamide / 0.17 h / -10 °C 3.1: acetic acid; palladium 10% on activated carbon; hydrogen / 2.5 h / 20 °C / 2585.81 Torr 4.1: toluene / 110 °C 5.1: N,N-dimethyl-formamide / 1 h / 80 °C 5.2: 2 h / 20 °C View Scheme

methyl-1-(chloroacetyl)-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol; potassium hydroxide / 3 h / Reflux 2: methanol / N,N-dimethyl-formamide / 5 h / Reflux View Scheme

N-chloroacetyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylic acid methyl ester (1160293-24-2) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium carbonate / methanol / 0.5 h / 63 °C 2.1: acetic acid / N,N-dimethyl-formamide / 0.25 h / 20 °C 2.2: 5 h / 90 °C 3.1: hydrogenchloride / methanol; dichloromethane / 3 h / 20 °C 4.1: ethyl acetate / 1 h / 40 °C / Inert atmosphere 5.1: toluene / 4 h / 65 °C View Scheme

3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylic acid methyl ester (1160293-22-0) → nintedanib (656247-17-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: acetic acid / N,N-dimethyl-formamide / 0.25 h / 20 °C 1.2: 5 h / 90 °C 2.1: hydrogenchloride / methanol; dichloromethane / 3 h / 20 °C 3.1: ethyl acetate / 1 h / 40 °C / Inert atmosphere 4.1: toluene / 4 h / 65 °C View Scheme

methyl 3-nitro-4-chlorobenzoate (14719-83-6) → nintedanib (656247-17-5)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: sodium tert-pentoxide / 1-methyl-pyrrolidin-2-one / 1.5 h / 75 °C 2.1: palladium 10% on activated carbon; hydrogen / acetic acid / 45 °C 3.1: acetic acid / 2 h / 115 °C 4.1: toluene / 3 h / 120 °C 5.1: acetic anhydride / 6 h / 124 °C 6.1: sodium carbonate / methanol / 0.5 h / 63 °C 7.1: acetic acid / N,N-dimethyl-formamide / 0.25 h / 20 °C 7.2: 5 h / 90 °C 8.1: hydrogenchloride / methanol; dichloromethane / 3 h / 20 °C 9.1: ethyl acetate / 1 h / 40 °C / Inert atmosphere 10.1: toluene / 4 h / 65 °C View Scheme

[4-(methoxycarbonyl)-2-nitrophenyl]malonic acid dimethyl ester (1160293-27-5) → nintedanib (656247-17-5)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: palladium 10% on activated carbon; hydrogen / acetic acid / 45 °C 2.1: acetic acid / 2 h / 115 °C 3.1: toluene / 3 h / 120 °C 4.1: acetic anhydride / 6 h / 124 °C 5.1: sodium carbonate / methanol / 0.5 h / 63 °C 6.1: acetic acid / N,N-dimethyl-formamide / 0.25 h / 20 °C 6.2: 5 h / 90 °C 7.1: hydrogenchloride / methanol; dichloromethane / 3 h / 20 °C 8.1: ethyl acetate / 1 h / 40 °C / Inert atmosphere 9.1: toluene / 4 h / 65 °C View Scheme

nintedanib (656247-17-5) + ethanesulfonic acid (594-45-6) → methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate ethanesulfonate salt (656247-18-6)

Conditions	Yield
In methanol for 4h; Reflux;	100%
In methanol; water at 60℃;	97.3%
In methanol; water; isopropyl alcohol at 0 - 65℃; for 1h;	95%

nintedanib (656247-17-5) + L-Tartaric acid (87-69-4) → methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate L-tartrate

Conditions	Yield
In water; butanone at 50℃; for 1.01667h;	98%

nintedanib (656247-17-5) + maleic acid (110-16-7) → methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate maleic acid salt (959761-95-6)

Conditions	Yield
In water; ethyl acetate at 50℃; for 1.01667h;	96%

nintedanib (656247-17-5) + methanesulfonic acid (75-75-2) → methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate dimethanesulfonic acid salt

Conditions	Yield
In methanol at 50℃; for 1.01667h;	93%

nintedanib (656247-17-5) + methanesulfonic acid (75-75-2) → methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate methanesulfonic acid salt (790241-30-4)

Conditions	Yield
In methanol; water at 60℃; for 1h;	92%

nintedanib (656247-17-5) + sodium dodecyl-sulfate (151-21-3) → nintedanib dilauryl sulfate

Conditions	Yield
With hydrogenchloride In methanol; water at 25 - 55℃; for 1.5h; Solvent;	89.3%

nintedanib (656247-17-5) + toluene-4-sulfonic acid (104-15-4) → methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate p-toluenesulfonic acid salt (959761-81-0)

Conditions	Yield
In water; butanone at 50℃; for 1.01667h; Solvent;	86%

nintedanib (656247-17-5) + sodium dodecyl-sulfate (151-21-3) → nintedanib monolauryl sulfate

Conditions	Yield
With hydrogenchloride; sodium hydrogencarbonate In ethanol; water at 60℃; for 1h; Solvent;	81.5%

nintedanib (656247-17-5) → methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate phosphoric acid salt (959761-75-2)

Conditions	Yield
With phosphoric acid In ethyl acetate at 50℃; for 0.0166667h;	70%

nintedanib (656247-17-5) + acetic acid (64-19-7) → methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate acetic acid salt

Conditions	Yield
In butanone at 50℃;	64%

nintedanib (656247-17-5) → nintedanib hydrochloride (959761-73-0)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; 2,2,2-trifluoroethanol; water at 20 - 50℃; under 7.50075 Torr; for 48.5h;
With hydrogenchloride In water; acetone at 20 - 40℃; for 72h;

nintedanib (656247-17-5) + ethanesulfonic acid (594-45-6) → Intedanib bisethanesulfonate

Conditions	Yield
In methanol; water Reflux;

Upstream product

• 262368-30-9 N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine 
• 1175365-43-1 methyl 1-acetyl-3-[ethoxy(phenyl)methylidene]-2-oxo-2,3-dihydro-7H-indole-6-carboxylate 
• 1027407-75-5 (Z)-1-acetyl-3-(ethoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 1160293-22-0 3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylic acid methyl ester 
• 1168152-07-5 (E)-1-acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 100-15-2 N-methyl(p-nitroaniline) 
• 1168150-46-6 (E)-methyl 3-(methoxy(phenyl)methylene)-2-indolone-6-carboxylic acid methyl ester 
• 14192-26-8 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester 
• 1160293-25-3 methyl 1-(2-chloroacetyl)-2-oxoindoline-6-carboxylate 
• 1174335-83-1 (E)-1-cholroacetyl-3-(methoxy(phenyl)methylene)-2-indolone-6-methylformate 
• 618-95-1 methyl 3-nitrobenzoate 
• 586-78-7 para-nitrophenyl bromide 
• 121-92-6 3-nitrobenzoic acid 
• 1160293-24-2 N-chloroacetyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylic acid methyl ester 

Downstream Products

• 656247-18-6 methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate ethanesulfonate salt 
• 894783-71-2 BIBF 1202 
• 959761-81-0 methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate p-toluenesulfonic acid salt 
• 959761-95-6 methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate maleic acid salt 
• 959761-75-2 methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate phosphoric acid salt 
• 790241-30-4 methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate methanesulfonic acid salt 
• 959761-74-1 nintedanib hydrobromide 

Relevant articles and documents

AN IMPROVED HIGHLY EFFICIENT PROCESS FOR THE PREPRATION OF NINTEDANIB AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

The present invention relates to an improved highly efficient and economic process for large-scale production of Nintedanib and pharmaceutically acceptable salt thereof. The present invention also relates to a single step process that form highly pure Nintedanib through novel intermediates. In this process, Nintedanib base [I] is prepared in a single step, in-situ process wherein the process is performed by formation of two novel intermediates namely, methyl-1-(bromoacetyl)-2-oxo-2,3-dihydro-1H-indole-6-carboxylate and methyl-(3Z)-1-(bromoacetyl)-3-[methoxy(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate. This process avoids use of expensive and hazardous reagent and solvent such as methyl cyclohexane. Further, there is no isolation and analysis of any intermediate after every step completion that made the process easy to perform without much hurdles. Along with the ease of performance, present invention process also gives high-purity final product with high yield. This makes the process highly cost-effective and time-efficient.

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.

Refining method of amino intermediate

The invention relates to a tefining method of an amino intermediate represented by formula (I). Through the refining method, the concentrations of a genotoxic impurity 1 (N-(4-nitrophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide) and an impurity 2 (N-(4-(hydroxyamino) phenyl)-N-methyl-2- (4-methylpiperazin-1-yl) acetamide) can be controlled to 4 ppm or less. According to the present invention, the contents of the genotoxic impurity 1 and the genotoxic impurity 2 in the formula (I) are significantly reduced, such that the process guarantee is provided for the industrial preparation of high-quality nintedanib ethanesulfonate, and the medication safety is ensured.

Preparation method of nintedanib key intermediate

The invention provides a preparation method of a nintedanib key intermediate, and belongs to the technical field of synthesis of medical intermediates. The first preparation method comprises the following steps: carrying out a nitro reduction reaction on a compound IV by taking an alcohol reagent or tetrahydrofuran as a solvent, taking hydrazine hydrate as a reducing agent and taking palladium carbon (Pd/C) as a catalyst until the nitro reduction reaction is complete, performing filtering to remove the catalyst under the protection of nitrogen, performing desolventizing to remove the solvent, performing dissolving by using dichloromethane, performing filtering to remove impurities, and performing desolventizing to obtain a compound I; the second method comprises the following steps: carrying out a nitro reduction reaction on a compound IV by taking hydrazine hydrate as a reducing agent and anhydrous ferric trichloride and activated carbon as catalysts until the nitro reduction reaction is complete, performing performing filtering to remove the catalyst, performing desolventizing to remove the solvent, dissolving dichloromethane, drying anhydrous sodium sulfate, performing filtering, and performing desolventizing to obtain a compound I. The preparation method provided by the invention is high in yield, strong in operability and high in safety, belongs to an environment-friendly process, and is suitable for industrial large-scale production.

Cycloisomerization of Carbamoyl Chlorides in Hexafluoroisopropanol: Stereoselective Synthesis of Chlorinated Methylene Oxindoles and Quinolinones

Hexafluoroisopropanol (HFIP) was employed as an additive for the generation of 3-(chloromethylene)oxindoles via the chloroacylation of alkyne-tethered carbamoyl chlorides. This reaction avoids the use of a metal catalyst and accesses products in high yields and stereoselectivities. Additionally, this reaction is scalable and proved amenable to a series of product derivatizations, including the synthesis of nintedanib. The reactivity of alkene-tethered carbamoyl chlorides with hexafluoroisopropanol (HFIP) was harnessed towards the synthesis of 2-quinolinones.

Preparation method of dihydroindolone derivative and intermediate thereof

The invention provides a dihydroindolone derivative represented by a formula I, and a preparation method of an intermediate of the dihydroindolone derivative. The preparation method of the dihydroindole derivative intermediate comprises the following steps: enabling 2-oxoindole-6-methyl formate and acetic anhydride to react in methylbenzene under the heating condition of 100 DEG C to 110 DEG C toobtain 1-acetyl-2-oxodihydroindolone-6-methyl formate. The preparation method of the indolinone derivative comprises the following steps: (1) carrying out a condensation reaction on 1-acetyl-2-oxodihydroindolone-6-methyl formate and trimethyl orthobenzoate or triethyl orthobenzoate to obtain a compound represented by a formula IV; (2) enabling the compound represented by the formula IV to react with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazine-1-yl) acetamide to obtain a compound represented by a formula V; and (3) deprotecting the compound represented by the formula V to obtain the compound represented by the formula I.

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.

Preparation method of high-purity nintedanib ethanesulfonate

The invention discloses a preparation method of high-purity nintedanib ethanesulfonate, which comprises the following steps: 1, carrying out one-pot reaction on toluene, SM01, triethyl orthobenzoate,acetic anhydride and DMAP, and carrying out suction filtration to obtain a high-purity intermediate INT02; 2, reacting INT02 and SM02 in a specific solvent system and then separating to obtain an intermediate INT03; 3, enabling INT03, methanol and KOH to react to obtain INT04; 4, reacting INT04, methyl alcohol and ethanesulfonic acid, adding methyl tert-butyl ether and isopropyl ether to obtain nintedanib ethanesulfonate.

3-(dimethylamino(phenyl)methylene)-2-oxindole-6-carboxylic acid methyl ester as well as preparation method and application thereof

The invention discloses 3-(dimethylamino(phenyl)methylene)-2-oxoindole-6-carboxylic acid methyl ester as well as a preparation method and application thereof. The compound provided by the invention can be used as a reference substance for detection of Nintedanib related substances, and is used for purity control of Nintedanib raw materials or preparations.

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.