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.
656247-18-6Relevant articles and documents
Refining method of amino intermediate
-
, (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.
Preparation method of high-purity nintedanib ethanesulfonate
-
, (2020/11/12)
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.
SYNTHESIS OF A 2-INDOLINONE DERIVATIVE KNOWN AS INTERMEDIATE FOR PREPARING NINTEDANIB
-
, (2019/06/13)
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.
