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656247-18-6

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656247-18-6 Usage

Description

Nintedanib esylate is a potent, oral triple angiokinase inhibitor developed by Boehringer Ingelheim that targets proangiogenic and pro-fibrotic pathways mediated by the vascular endothelial growth factor receptor, fibroblast growth factor receptor and plateletderived growth factor receptor families, as well as Src and Flt-3 kinases. It was approved for the treatment of idiopathic pulmonary fibrosis (IPF), a condition in which the lungs become progressively scarred over time, by the US FDA in October 2014 and by the EMA in January 2015. The FDA granted nintedanib esylate fast-track, priority review, orphan product, and breakthrough designations. The drug was also approved by the EMA in November 2014 for treatment of non-small cell lung cancer in combination with docetaxel after first-line chemotherapy.

Uses

Nintedanib Esylate is the salt form of Nintedanib, which is angiokinase inhibitor and is used in the treatment of idiopathic pulmonary fibrosis. Also inhibits the process blood vessel formation which may be used to assist in cancer therapy.

Definition

ChEBI: An organosulfonate salt obtained by combining nintedanib with one molar equivalent of ethanesulfonic acid. A kinase inhibitor used for the treatment of idiopathic pulmonary fibrosis and cancer.

Synthesis

The synthesis of indolinone 197 commenced with commercial 4-chloro-3-nitro-benzoic acid (194)—esterification of which preceded displacement of the chloride by dimethyl malonate (195) in the presence of base to generate nitrobenzene 196. Hydrogenation of 196 under acidic conditions furnished 6-methyoxycarbonyl- substituted oxindole 197 by decarboxylative cyclization in 87% yield. Acylation of indolinone 197 with chloroacetic anhydride in refluxing toluene and subsequent condensation with trimethyl orthobenzoate resulted in indolone 198, which was isolated in 86% yield over the two-step sequence. While these two steps could reportedly be combined into a one-pot protocol using acetic anhydride as the solvent, the stepwise procedure was found to be more amenable for large-scale synthesis due to fewer complications with undesired side products. Subjection of 198 to methanolic potassium hydroxide followed by condensation with aniline fragment 199 in refluxing methanol and then exposure to aqueous ethanesulfonic acid in methanol provided nintedanib esylate (XXIII) in 82% over the three-step sequence. Aniline fragment 199 was prepared in three steps and 82% overall yield via initial acylation of N-methyl-4-nitroaniline 200 with chloro acetylchloride followed by displacement of the a-amidochloride with N-methylpiperazine and hydrogenative reduction of the nitro group gave the desired aniline.183,184

Check Digit Verification of cas no

The CAS Registry Mumber 656247-18-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 6,5,6,2,4 and 7 respectively; the second part has 2 digits, 1 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 656247-18:
(8*6)+(7*5)+(6*6)+(5*2)+(4*4)+(3*7)+(2*1)+(1*8)=176
176 % 10 = 6
So 656247-18-6 is a valid CAS Registry Number.

656247-18-6SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 13, 2017

Revision Date: Aug 13, 2017

1.Identification

1.1 GHS Product identifier

Product name Nintedanib esylate

1.2 Other means of identification

Product number -
Other names (3S,5S)-3,5-Bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-hydroxy-cyclohexanecarboxylic Acid Methyl Ester

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:656247-18-6 SDS

656247-18-6Downstream Products

656247-18-6Relevant articles and documents

Refining method of amino intermediate

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Paragraph 0061; 0062, (2021/03/03)

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.

Method for preparing nintedanib ethanesulfonate

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Paragraph 0028; 0040; 0047-0048; 0049; 0056-0057; 0058-0066, (2020/11/12)

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.

Method for preparing Nintedanib ethylsulfonate

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Paragraph 0049; 0051-0076, (2019/08/12)

The invention relates to a method for preparing Nintedanib ethylsulfonate. The method comprises the following steps: (1) adding 1-acetyl-3-[methoxy(phenyl)methylene]-2-oxo-indolinyl-6-methyl formate (compound A) into a reaction solvent to react with N-(4-amino phenyl)-N,4-dimethyl-1-piperazinyl acetamide (compound B), adding pyrrolidine for continuous reaction after the reaction ends up, carryingout crystallization, carrying out stirring washing with a mixed solvent, and carrying out drying, so as to produce (3Z)-3-{[(4-{methyl-[(4-methyl piperazin-1-yl)acetyl]amino}phenyl)amino]-(phenyl)methylene} -2-oxo-2,3-indolinyl-6-methyl formate (compound C); and (2) subjecting the compound C to a reaction with ethyl sulfonic acid, carrying out crystallization, carrying out filtering, and carryingout drying, thereby producing the Nintedanib ethylsulfonate. According to the method, the Nintedanib ethylsulfonate with high purity, good yield and low impurity level is obtained through reactions oftwo steps.

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