Nintedanib

Base Information

• Chemical Name: Nintedanib
• CAS No.: 656247-17-5
• Molecular Formula: C31H33N5O4
• Molecular Weight: 539.634
• Mol file: 656247-17-5.mol

Synonyms:Vargatef;

Chemical Property of Nintedanib

Chemical Property:

• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.658
• Boiling Point: 742.199°C at 760 mmHg
• PKA: 11.06±0.20(Predicted)
• Flash Point: 402.667°C
• PSA: 94.22000
• Density: 1.284g/cm³
• LogP: 3.70270
• Storage Temp.: Refrigerator
• Solubility.: DMSO (Slightly), Methanol (Slightly)

Purity/Quality:

99%MIN ^*data from raw suppliers

Intedanib ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Description: Nintedanib is an oral administrated triple tyrosine kinase inhibitors developed by Boehringer Ingelheim, Germany. Its targets include platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and basic fiber (BFGF), being able to also inhibit the activation of MAPK and Akt. At present, it is mainly used for cancer treatment, such as colorectal cancer, ovarian cancer and multiple myeloma. The study regarding to the respiratory diseases mainly focuses on the clinical treatment of advanced non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF). In June 2014, Boehringer Ingelheim has announced that the marketing authorization application of Nintedanib for the treatment of Idiopathic Pulmonary Fibrosis (IPF) had been confirmed by the European Medicines Agency (EMA) and been included in the accelerated approval list by the EMA.
• 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.
• Uses: It is an indolinone derivative potently blocking VEGF-, PDGF-, and FGF-receptor kinases; an indolinone as triple angiokinase inhibitors. 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. It is an indolinone derivative potently blocking VEGF-, PDGF-, and FGF-receptor kinases; an indolinone as triple angiokinase inhibitors. An antitumor agent.
• 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.

Technology Process of Nintedanib

There total 63 articles about Nintedanib which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 98.7%

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 (656247-17-5,928326-83-4)

Guidance literature:

With sodium hydrogencarbonate; In water; ethyl acetate; at 40 ℃; for 1h;

Reference yield: 96.0%

N-[(4-methyl-piperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylendiamine (262368-30-9) + methyl (E)-3-(chloro(phenyl)methylene)-2-oxoindoline-6-carboxylate → nintedanib (656247-17-5,928326-83-4)

Guidance literature:

In N,N-dimethyl-formamide; at 80 ℃; Inert atmosphere;

DOI:10.1002/anie.202103323

Reference yield: 94.6%

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 (656247-17-5,928326-83-4)

Guidance literature:

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;

With methanol; potassium hydroxide; In N,N-dimethyl-formamide; Temperature; Large scale;

upstream raw materials:

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

(Z)-1-acetyl-3-(ethoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester

3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylic acid methyl ester

Downstream raw materials:

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

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

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

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

Refernces

• 1、 -. "Refining method of amino intermediate". Paragraph 0059; 0060. . Retrieved 2021/03/03.
• 2、 Bajohr, Jonathan,Lautens, Mark,Mirabi, Bijan,Rodríguez, José F.,Whyte, Andrew,Zhang, Anji. "Cycloisomerization of Carbamoyl Chlorides in Hexafluoroisopropanol: Stereoselective Synthesis of Chlorinated Methylene Oxindoles and Quinolinones". . p. 18478 - 18483. Retrieved 2021/07/19.