- Synthesis method of pyrrotinib maleate intermediate
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The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of a pyrrotinib maleate intermediate. The synthesis method comprises the following steps: by taking a formula II as an initial raw material, reacting the formula II with cyanoacetamide under the action of a sulfonic acid compound to obtain a compound shown in a formula III; carrying out heating reflux reaction on the compound as shown in the formula III, 4-nitro-3-ethoxyaniline and triethyl orthoformate, and obtaining a solid intermediate product after the reaction is finished; subjecting the obtained solid intermediate product and Lewis acid to a heating ring closing reaction to obtain a compound shown in a formula IV; and carrying out reduction reaction on the compound as shown in the formula IV, hydrazine hydrate and activated carbon under the action of a catalyst to prepare the compound as shown in the formula I, namely the pyrrotinib maleate intermediate disclosed by the invention. The method is short in reaction route, high in yield, simple and convenient to operate, free of extreme reaction conditions and expensive raw materials, lower in production cost and beneficial to industrial production.
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- Neratinib intermediate crystal as well as preparation method and application thereof
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The invention relates to a neratinib intermediate crystal as well as a preparation method and application thereof. The invention especially relates to a crystal form II of an intermediate A compound 6-amino-4-(3-chloro-4-(pyridine-2-substituted methoxy) aniline)-7-ethoxyquinoline carbonitrile. The crystal form II comprises diffraction peaks with diffraction angles 2 theta of 6.3 degrees, 7.8 degrees, 14.0 degrees, 15.1 degrees, 17.1 degrees, 18.8 degrees, 21.5 degrees, 22.2 degrees, 23.4 degrees and 27.5 degrees in an XRPD spectrum. When the intermediate crystal form II is used for preparing the neratinib, the dosage of a solvent can be remarkably reduced, the reaction time is shortened, the yield is increased, and meanwhile, the residual quantity of the intermediate A in a final product is remarkably reduced.
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Paragraph 0064-0068; 0069-0070; 0074-0078
(2021/04/21)
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- Preparation Method for Tyrosine Kinase Inhibitor and Intermediate Thereof
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Provided is a preparation method for a tyrosine kinase inhibitor and an intermediate thereof. Specifically, a preparation method for a cyanoquinoline compound is provided. The method has a high yield, good product purity, and mild reaction conditions.
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Paragraph 0090
(2020/08/19)
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- Preparation method of 3-cyano-4-anilino-6-aminoquinoline derivative
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The invention discloses a preparation method of a 3-cyano-4-anilino-6-aminoquinoline derivative. According to the preparation method, zinc nitrate is carefully selected as a specific catalyst and is combined with a specific solvent and a specific reaction temperature, so that few byproducts are produced in the preparation process, products of -CN hydrolysis and side chain amide hydrolysis in quinoline rings do not exist in the products basically, and the yield of a target product is high. The method has the advantages of mild reaction process, high safety and no use of specific equipment, andis suitable for industrial production. The preparation method has the advantages of simplicity, cheap and easily available raw materials, mild reaction conditions, no need of large equipment, high final product yield and high purity, and is suitable for industrial popularization.
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Paragraph 0030-0032; 0036-0043
(2020/11/12)
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- Design, synthesis and biological study of potent and covalent HER-2 tyrosine kinase inhibitors with low cytotoxicity in vitro
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The discovery and development of a novel HER-2 tyrosine kinase inhibitor for the treatment of HER2-positive breast cancer are presented in this article. EGFR family has been recognized as a crucial meditator in the cancer progression; HER-2 tyrosine kinase was one of the members among them. In the effort to explore potent HER-2 inhibitors, a novel series of 4-anilino-3-cyanoquinoline derivatives have been designed, synthesized and evaluated. Most compounds possessed modest proliferation inhibition on SK-BR-3 cell line and HER-2 kinase. Compound 16 appeared to be the most potent compound (HER-2 kinase IC50: 19.4?nM, SK-BR-3 IC50: 94?nM). In the experiment of cellular cytotoxicity assay, compound 16 shows a much lower cytotoxicity than neratinib on Beas-2b cell line (Human bronchial epithelial cells). In conclusion, compound 16 would be a promising lead compound for further anti-breast cancer drug discovery.
- Jin, Shuyu,Sun, Xiuyun,Liu, Dan,Xie, Hua,Rao, Yu
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p. 1333 - 1345
(2019/05/06)
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- Preparation method of antineoplastic drug maleic acid neratinib
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The invention provides a preparation method of antineoplastic drug maleic acid neratinib. The defects in the prior art are overcome. The preparation method comprises the steps that the formula II and the formula III are coupled to form the formula IV under the effect of a catalyst; a nitro-compound IV is reduced under the effect of a reduction system to form a formula V; an amino compound V and a formula VI are condensed to obtain neratinib VII, and then the neratinib VII and maleic acid form a salt to obtain the maleic acid neratinib I. By the adoption of the technical route, the preparation method has the advantages that the synthetic route is short, reaction conditions are mild, the yield is high, raw materials are wide in source, and environmental protection is achieved.
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- Quinoline and quinazoline derivatives, preparation method, intermediate, composition and use thereof (by machine translation)
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The invention discloses a quinoline and quinazoline derivative I, a preparation method, an intermediate C, composition and an application. The preparation method comprises two methods, wherein the first method comprises steps as follows: 1, a compound A and a compound B react in a solvent under the action of alkali 1 to obtain a compound C; and 2, the product C obtained in the step 1 reacts with a compound D under the action of alkali 2; and the second comprises step as follows: the compound A and a compound E react in the solvent under the action of the alkali 1. The invention further provides the application of the compound represented in formula I or medicine composition in preparation of an EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor, an A431 or H1975 cell proliferation inhibitor or medicine for preventing or treating tumor diseases. The provided compound has better antitumor activity.
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Paragraph 0463; 0473; 0477-0479
(2016/11/07)
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- The Wittig-Horner reaction for the synthesis of neratinib
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The Wittig-Horner reaction is a classic method to get alkenes by reaction phosphonates with carbonyl compounds. In this study, it was used for the synthesis of the anticancer drug neratinib. In this method, ethyl diethoxyphosphinylacetate and dimethylaminoacetaldehyde diethylacetal, replacing (E)-4-(dimethylamino)but-2-enoyl acid hydrochloride and oxalyl chloride, were used to synthesize the 6-position side chain of neratinib.
- Gu, Ning,Yang, Jiabin,Wang, Peng,Li, Lushen,Chen, Yang,Ji, Min
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p. 3105 - 3110
(2013/09/23)
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- Irreversible inhibition of epidermal growth factor receptor activity by 3-aminopropanamides
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Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3- carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6- yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.
- Carmi, Caterina,Galvani, Elena,Vacondio, Federica,Rivara, Silvia,Lodola, Alessio,Russo, Simonetta,Aiello, Stefania,Bordi, Fabrizio,Costantino, Gabriele,Cavazzoni, Andrea,Alfieri, Roberta R.,Ardizzoni, Andrea,Petronini, Pier Giorgio,Mor, Marco
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p. 2251 - 2264
(2012/05/20)
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- SUBSTITUTED HETEROCYCLIC COMPOUNDS AS KINASES INHIBITORS AND METHOD OF USE THEREOF
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The present invention is directed to novel quinolines and quniazolines, their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof which are useful for the treatment of protein kinases mediated diseases and conditions. The compounds of this invention have a general Formula (I) wherein R1 to R11 and X are defined herein.
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Page/Page column 33
(2011/01/12)
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- Method of preparing 3-cyano-quinolines and intermediates made thereby
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The present invention relates to methods for preparing substituted 3-cyanoquinolines and intermediates obtained by the methods of the present invention. The methods of the invention comprise reacting an N-aryl-2-propanimide with phosphoryl chloride to produce the substituted 3-cyanoquinolines. The methods further comprise reacting arylamines, orthoformates and active methylenes to produce the N-aryl-2-propenamide.
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Page/Page column 19
(2010/11/24)
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- Methods of synthesizing substituted 3-cyanoquinolines and intermediates thereof
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The invention is directed to methods of making substituted 3-cyanoquinolines, including compounds according to the following formula: The methods are amenable to large scale manufacture, avoid the use of chromatographic separations, and provide stable, high purity product more efficiently than in the prior art.
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Page/Page column 19
(2008/06/13)
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- Protein tyrosine kinase enzyme inhibitors
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This invention provides compounds of formula 1, having the structure wherein R1, R2, R3, R4, and R5 are described within the specification.
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