656247-18-6 Usage
Description
Nintedanib Ethanesulfonate Salt, also known as Nintedanib Esylate, is a potent, oral triple angiokinase inhibitor developed by Boehringer Ingelheim. It targets proangiogenic and pro-fibrotic pathways mediated by the vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor families, as well as Src and Flt-3 kinases. It is an organosulfonate salt obtained by combining nintedanib with one molar equivalent of ethanesulfonic acid.
Uses
Used in Pulmonary Fibrosis Treatment:
Nintedanib Ethanesulfonate Salt is used as an antifibrotic agent for the treatment of idiopathic pulmonary fibrosis (IPF), a condition in which the lungs become progressively scarred over time. It was approved by the US FDA in October 2014 and by the EMA in January 2015.
Used in Cancer Therapy:
Nintedanib Ethanesulfonate Salt is used as an angiokinase inhibitor for cancer therapy. It inhibits the process of blood vessel formation, which is essential for tumor growth and metastasis. The drug was also approved by the EMA in November 2014 for the treatment of non-small cell lung cancer in combination with docetaxel after first-line chemotherapy.
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.
656247-18-6Relevant 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.