- AN IMPROVED HIGHLY EFFICIENT PROCESS FOR THE PREPRATION OF NINTEDANIB AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
-
The present invention relates to an improved highly efficient and economic process for large-scale production of Nintedanib and pharmaceutically acceptable salt thereof. The present invention also relates to a single step process that form highly pure Nintedanib through novel intermediates. In this process, Nintedanib base [I] is prepared in a single step, in-situ process wherein the process is performed by formation of two novel intermediates namely, methyl-1-(bromoacetyl)-2-oxo-2,3-dihydro-1H-indole-6-carboxylate and methyl-(3Z)-1-(bromoacetyl)-3-[methoxy(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate. This process avoids use of expensive and hazardous reagent and solvent such as methyl cyclohexane. Further, there is no isolation and analysis of any intermediate after every step completion that made the process easy to perform without much hurdles. Along with the ease of performance, present invention process also gives high-purity final product with high yield. This makes the process highly cost-effective and time-efficient.
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Page/Page column 10; 17-18
(2022/02/15)
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- Refining method of amino intermediate
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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.
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- Synthesis of the Kinase Inhibitors Nintedanib, Hesperadin, and Their Analogues Using the Eschenmoser Coupling Reaction
-
A novel synthetic approach involving an Eschenmoser coupling reaction of substituted 3-bromooxindoles (H, 6-Cl, 6-COOMe, 5-NO2) with two substituted thiobenzanilides in dimethylformamide or acetonitrile was used for the synthesis of eight kinase inhibitor
- Marek, Luká?,Váňa, Ji?í,Svoboda, Jan,Hanusek, Ji?í
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p. 10621 - 10629
(2021/07/31)
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- DRY POWDER FORMULATION FOR INHALATION COMPRISING FINE PARTICLE OF NINTEDANIB OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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The present invention relates to a dry powder formulation for inhalation comprising fine particles of nintedanib or a pharmaceutically acceptable salt thereof. Specifically, fine particles of nintedanib or a pharmaceutically acceptable salt thereof according to the present invention have an inhalable size and particle shape, are thermodynamically stable, and exhibit high emitted dose (ED) and fine particle fraction (FPF) values, thereby being able to be easily used as the dry powder formulation for inhalation.
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Paragraph 0065-0081
(2021/02/02)
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- Preparation method of nintedanib key intermediate
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The invention provides a preparation method of a nintedanib key intermediate, and belongs to the technical field of synthesis of medical intermediates. The first preparation method comprises the following steps: carrying out a nitro reduction reaction on a compound IV by taking an alcohol reagent or tetrahydrofuran as a solvent, taking hydrazine hydrate as a reducing agent and taking palladium carbon (Pd/C) as a catalyst until the nitro reduction reaction is complete, performing filtering to remove the catalyst under the protection of nitrogen, performing desolventizing to remove the solvent, performing dissolving by using dichloromethane, performing filtering to remove impurities, and performing desolventizing to obtain a compound I; the second method comprises the following steps: carrying out a nitro reduction reaction on a compound IV by taking hydrazine hydrate as a reducing agent and anhydrous ferric trichloride and activated carbon as catalysts until the nitro reduction reaction is complete, performing performing filtering to remove the catalyst, performing desolventizing to remove the solvent, dissolving dichloromethane, drying anhydrous sodium sulfate, performing filtering, and performing desolventizing to obtain a compound I. The preparation method provided by the invention is high in yield, strong in operability and high in safety, belongs to an environment-friendly process, and is suitable for industrial large-scale production.
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Paragraph 0040-0045
(2021/09/08)
-
- Cycloisomerization of Carbamoyl Chlorides in Hexafluoroisopropanol: Stereoselective Synthesis of Chlorinated Methylene Oxindoles and Quinolinones
-
Hexafluoroisopropanol (HFIP) was employed as an additive for the generation of 3-(chloromethylene)oxindoles via the chloroacylation of alkyne-tethered carbamoyl chlorides. This reaction avoids the use of a metal catalyst and accesses products in high yields and stereoselectivities. Additionally, this reaction is scalable and proved amenable to a series of product derivatizations, including the synthesis of nintedanib. The reactivity of alkene-tethered carbamoyl chlorides with hexafluoroisopropanol (HFIP) was harnessed towards the synthesis of 2-quinolinones.
- Bajohr, Jonathan,Lautens, Mark,Mirabi, Bijan,Rodríguez, José F.,Whyte, Andrew,Zhang, Anji
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p. 18478 - 18483
(2021/07/19)
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- Harnessing affinity-based protein profiling to reveal a novel target of nintedanib
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Nintedanib (BIBF1120), a triple angiokinase inhibitor, was first approved for idiopathic pulmonary fibrosis (IPF) therapy and is also efficacious for lung carcinoma, and interstitial lung diseases, far beyond its inhibition of VEGFR/PDGFR/FGFR. We identified tripeptidyl-peptidase 1 (TPP1) as one of the direct targets of nintedanib employing the affinity-based protein profiling (AfBPP) technique. This may be a new mechanism for nintedanib's role different from tyrosine kinase inhibition.
- Chen, Xiong,Li, Manru,Li, Menglin,Wang, Dongmei,Zhang, Jinlan
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p. 3139 - 3142
(2021/04/02)
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- 3-(dimethylamino(phenyl)methylene)-2-oxindole-6-carboxylic acid methyl ester as well as preparation method and application thereof
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The invention discloses 3-(dimethylamino(phenyl)methylene)-2-oxoindole-6-carboxylic acid methyl ester as well as a preparation method and application thereof. The compound provided by the invention can be used as a reference substance for detection of Nintedanib related substances, and is used for purity control of Nintedanib raw materials or preparations.
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Paragraph 0059-0069
(2020/07/24)
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- Preparation method of high-purity nintedanib ethanesulfonate
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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.
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Paragraph 0219; 0222
(2020/11/12)
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- METHODS FOR PREPARING NINTEDANIB AND INTERMEDIATES THEREOF
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The present application provides a method for preparing nintedanib. The method of the present application is carried out by using 4-halo-3-nitro-benzoic acid methyl ester (compound II) and 3-oxo-3-phenylpropionate (compound III) as raw materials, and prep
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- Preparation method of amino intermediate (by machine translation)
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Compared with an existing preparation method, the method for preparing. the amine-based (I) intermediate disclosed by the invention comprises the following, steps: carrying (III) out condensation, reduction and the like of the compound of. the formula I to obtain, the target compound (I), and 1 remarkably reducing the, content of the impurities in the obtained compound according to the, invention as compared with the existing preparation. method. (by machine translation)
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- Preparation method of nintedanib key intermediate
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The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a nintedanib key intermediate compound II. A compound IV is reduced by adopting a common reaction reagent under the conditions of normal temperature and normal pressure, so that a high-purity compound II can be conveniently obtained. The adopted reaction conditions are mild, high-pressure equipment is avoided, the technical operation is simple, the conditions are mild, the process is safer and more environmentally friendly, and the feasibility of large-scale productionof nintedanib is greatly improved.
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Paragraph 0069-0074
(2020/10/27)
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- Preparation method of dihydroindolone derivative and intermediate thereof
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The invention provides a dihydroindolone derivative represented by a formula I, and a preparation method of an intermediate of the dihydroindolone derivative. The preparation method of the dihydroindole derivative intermediate comprises the following steps: enabling 2-oxoindole-6-methyl formate and acetic anhydride to react in methylbenzene under the heating condition of 100 DEG C to 110 DEG C toobtain 1-acetyl-2-oxodihydroindolone-6-methyl formate. The preparation method of the indolinone derivative comprises the following steps: (1) carrying out a condensation reaction on 1-acetyl-2-oxodihydroindolone-6-methyl formate and trimethyl orthobenzoate or triethyl orthobenzoate to obtain a compound represented by a formula IV; (2) enabling the compound represented by the formula IV to react with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazine-1-yl) acetamide to obtain a compound represented by a formula V; and (3) deprotecting the compound represented by the formula V to obtain the compound represented by the formula I.
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Paragraph 0114-0132
(2020/09/23)
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- Method for preparing nintedanib ethanesulfonate
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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.
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- Method for preparing Nintedanib ethylsulfonate
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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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Paragraph 0049-0050; 0054; 0056
(2019/08/12)
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- KINASE INHIBITOR SALTS AND COMPOSITIONS THEREOF
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The present invention relates to kinase inhibitor C8-C16 aliphatic sulfate salts and compositions thereof.
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Page/Page column 74-75
(2020/01/08)
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- PROCESS FOR THE PREPARATION OF NINTEDANIB
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The present invention relates to a process for the preparation of nintedanib or salt thereof. The process comprising reacting compound of formula VI with acetic anhydride and triethyl ortho benzoate to obtain a compound of formula V; further reacting the compound of formula V with the compound of formula IV to obtain nintedanib the compound of formula I. The present invention also relates to a process to obtain crystalline compound of formula V.
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- SYNTHESIS OF A 2-INDOLINONE DERIVATIVE KNOWN AS INTERMEDIATE FOR PREPARING NINTEDANIB
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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.
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- CRYSTALLINE FORM OF 3-Z-[1-(4-(N-((4-METHYL-PIPERAZIN-1-YL)-METHYLCARBONYL)-N-METHYL-AMINO)-ANILINO)-1-PHENYL-METHYLENE]-6-METHOXYCARBONYL-2-INDOLINONE
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THE PRESENT INVENTION PROVIDES 3 - Z - [1 - (4 - (N - ((4 - METHYL - HETEROAROMATIC GUAZINE -1 - BASE) - A CARBONYL) - N - METHYL - AMINO) - ANILINO) - METHYLENE -1 - PHENYL] -6 - METHOXYCARBONYL -2 - INDOLE TRIAZOLINONE NEW FREE CRYSTAL FORM AND ITS PREPARATION METHOD, ALSO PROVIDES A PHARMACEUTICAL PREPARATION CONTAINING SAID FORM AND ITS USED FOR TREATING DISEASE IN PARTICULAR FOR THE TREATMENT OF ANGIOGENIC DISEASES OF THE EYE USE.
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Paragraph 0060; 0061; 0075; 0076
(2019/02/14)
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- INDOLINONE DERIVATIVES AS INHIBITORS OF MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
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The present disclosure relates to indolinone compounds, compositions, and methods for the inhibition of maternal embryonic leucine zipper kinase (MELK). The present disclosure further relates to indolinone compounds, compositions, and methods for the treatment or prevention of a cancer (for example, triple negative breast cancer).
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- Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth
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Despite recent advances in molecularly directed therapy, triple negative breast cancer (TNBC) remains one of the most aggressive forms of breast cancer, still without a suitable target for specific inhibitors. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC, where level of overexpression correlates with poor prognosis and an aggressive disease course. Herein, we describe the discovery through targeted kinase inhibitor library screening, and structure-guided design of a series of ATP-competitive indolinone derivatives with subnanomolar inhibition constants towards MELK. The most potent compound, 17, inhibits the expression of the anti-apoptotic protein Mcl-1 and proliferation of TNBC cells exhibiting selectivity for cells expressing high levels of MELK. These studies suggest that further elaboration of 17 will furnish MELK-selective inhibitors with potential for development in preclinical models of TNBC and other cancers.
- Edupuganti, Ramakrishna,Taliaferro, Juliana M.,Wang, Qiantao,Xie, Xuemei,Cho, Eun Jeong,Vidhu, Fnu,Ren, Pengyu,Anslyn, Eric V.,Bartholomeusz, Chandra,Dalby, Kevin N.
-
p. 2609 - 2616
(2017/04/06)
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- An improved process for the synthesis of nintedanib esylate
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Nintedanib esylate is synthesized via novel intermediates of (Z)-methyl 3-(acetoxy-phenyl)methylene)-1-acetyl-2-oxoindoline-6-carboxylate and N-(4-aminophenyl)-2-chloro-N-methylacetamide in good yields.
- Arava, Veerareddy,Gogireddy, Surendrareddy
-
p. 975 - 981
(2017/05/04)
-
- Potential impurity compound of Nintedanib, as well as preparation method, application and detection method of potential impurity compound
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The invention relates to a potential impurity compound of Nintedanib, and a preparation method, application and detection method of the potential impurity compound. The structure of the potential impurity compound is shown in the formula (as shown in the specification). The invention aims to improve the quality standard of Nintedanib through study on impurities to guarantee the safe medication of Nintedanib. According to the preparation method disclosed by the invention, the pure potential impurity compound of Nintedanib is obtained, so that a reference substance for qualitative and quantitative analysis is provided for the detection of a finished Nintedanib product.
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- Preparation method of nintedanib ethyl sulfonate
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The invention discloses a preparation method of nintedanib ethyl sulfonate. The method comprises the steps of reacting by taking 2-oxoindole-6-carboxylic acid methyl ester, triethyl orthobenzoate and acetic anhydride as starting materials to obtain a compound; and carrying out condensation on (Z)-1-acetyl-3-(ethoxy (phenyl) methylene)-2-oxo indoline-6-carboxylic acid methyl ester and the starting material N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-yl) acetamide to obtain nintedanib free alkali and carrying out salt-forming reaction of ethanesulfonic acid to prepare the nintedanib ethyl sulfonate. The method is short in step and easy to treat, and a high-quality nintedanib ethyl sulfonate crystal product is obtained without purification.
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Paragraph 0015; 0029
(2017/09/01)
-
- One-pot synthesis method of preparing nepal reaches Neeb
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The invention discloses a method for preparing Nintedanib through a one-pot process. The method comprises the following steps: taking 2-oxyindole-6-methyl carbonate, methyl benzoate and N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-yl) acetamide as initial raw materials, carrying out an alpha-hydrogen substitution reaction between 2-oxyindole-6-methyl carbonate and methyl benzoate in the presence of an inorganic base, and docking with N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-yl) acetamide. The preparation method is simple, feasible, high in yield, high in quality and convenient for industrial production.
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Paragraph 0074; 0075
(2017/08/25)
-
- A METHOD FOR PREPARING METHYL (Z)-3-[[4-[METHYL[2-(4-METHYL-1-PIPERAZINYL)ACETYL] AMINO]PHENYL]AMINO]PHENYLMETHYLENE)-OXINDOLE-6-CARBOXYLATE (INTEDANIB, NINTEDANIB)
-
The invention relates to a method of synthesizing methyl (Z)-3-[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl] amino]phenyl] amino]phenylmethylene)-oxindole-6-carboxylate of formula (1), known under the generic name of intedanib or nintedanib. The present method comprises a) a reaction of methyl oxindole-6-carboxylate with acetic anhydride at a temperature of 130 - 140°C, providing methyl 1-acetyl-oxindole-6-carboxylate; b) a reaction of methyl 1-acetyl-oxindole-6-carboxylate of with trimethyl orthobenzoate and acetic anhydride in the presence of toluene, providing methyl (E)-1-acetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate; c) a reaction (E)-1-acetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide and subsequently with an alkali hydroxide or alkali alkoxide in methanol or ethanol without isolation of the intermediate, providing methyl (Z)-3-[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl] amino]phenylmethylene)-oxindole-6-carboxylate, wherein the reaction is conducted at a temperature of 50 to 100°C. (1)
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- Preparation method of nintedanib
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The invention relates to a preparation method of nintedanib (I). The preparation method comprises the steps that 2-oxoindole-6-methyl formate (III) and benzaldehyde (II) are used as raw materials to generate a condensation reaction, so as to obtain a compound IV; then halogen or halogenating reagents are added to generate a substitution reaction, so as to obtain a compound V; the compound V and the compound IV are condensed under the action of alkali, so as to obtain the nintedanib (a compound I). The method has the advantages of short reaction time, low cost, high yield and environmental friendliness of used reagents and is suitable for industrial production. The structural formulas are shown in the description.
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Paragraph 0018
(2017/02/28)
-
- Method for preparing nepali Taida Nepal
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Disclosed is a preparation method of nintedanib (I), comprising the following steps: carrying out a condensation reaction on 4-(R acetate-2-yl)-3-nitrobenzoate (II) and trimethyl orthobenzoate to obtain (E)-4-[(2-methoxybenzylidene) R acetate-2-yl]-3-nitrobenzoate (III); carrying out a substitution reaction on the compound (EI) and N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-yl) acetamide (IV) under the action of an acid-binding agent to generate (Z)-4-{[2-(N-methyl-2-(4-methyl piperazine-1-yl) acetamido-aniline) benzylidene] R acetate-2-yl}-3-nitrobenzoate (V); and sequentially carrying out reduction reactions and cyc-lization reactions on the compound (V) to prepare the nintedanib (I). The preparation method has an easily obtained raw material and a simple process, is economical and environmentally friendly, and is suitable for industrial production.
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- POLYMORPH OF NINTEDANIB ETHANESULPHONATE, PROCESSES AND INTERMEDIATES THEREOF
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The present invention provides novel crystalline Form of Nintedanib and process for its preparation. The present invention also provides to a novel process for the preparation of Nintedanib. The present invention further provides to novel intermediates used in the preparation of Nintedanib and process for their preparation.
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- nepal reaches Neeb process and intermediates for the synthesis of (by machine translation)
-
The invention discloses a method for synthesizing nepal reaches Neeb and intermediates thereof, the synthesis method comprises: under acidic conditions, the compound of formula (II) reaction of a compound of the formula (I) compound of formula (III); compound (III) of the detached with acid uncle Ding Zhiji carbonate, adding alkali reaction of the compound of formula (V); the compound of formula (V) reaction with chloroacetic acid derivatives of formula (VI) the activation of the compound, then the reaction-methyl piperazine N, obtain nepal reaches Neeb. The present invention provides a mild reaction conditions of a new method for synthesizing nepal reaches Neeb, the invention also provides synthetic intermediates nepal reaches Neeb. (by machine translation)
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Paragraph 0031; 0105; 0106
(2016/11/02)
-
- Preparation method of crystalline nintedanib esylate
-
The invention discloses a preparation method of crystalline nintedanib esylate (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-dihydroindolone monoethyl sulfonate). The method comprises steps as follows: (1) a compound represented in the formula (B) and acylating chlorination reagent chloroacetic anhydride react, and acyl chloride (C) is obtained; (2) the compound represented in the formula (C) and trimethyl orthobenzoate have a condensation reaction, and a compound represented in the formula (D) is obtained; (3) the compound represented in the formula (D) is deprotected, and a compound represented in the formula (E) is obtained; (4) the compound represented in the formula (E) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide have a condensation reaction, and a compound represented in the formula (F) is obtained; (5) the compound represented in the formula (F) and ethanesulfonic acid have a salification reaction, and a nintedanib esylate compound represented in the formula (A) is obtained. The stable crystalline nintedanib esylate can be obtained with the method, technological conditions are mild, aftertreatment is simple, the purity is high, the reaction cost is low, and industrial production is easy to realize.
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- OXINDOLE INHIBITORS OF TYROSINE KINASE
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The present invention relates to new oxindole inhibitors of tyrosine kinase, pharmaceutical compositions thereof, and methods of use thereof.
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- INTEDANIB SALTS AND SOLID STATE FORMS THEREOF
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The present invention provides salts of Intedanib, crystalline forms of the salts of Intedanib, processes for their manufacture and their use in pharmaceutical compositions.
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- INDOLINONE DERIVATIVES AND PROCESS FOR THEIR MANUFACTURE
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The present invention relates to specific indolinone derivatives, namely the compounds of formula, in which R1 represents an hydrogen atom or a group, and R2 and R3 each represent an hydrogen atom or R2 and R3 taken together represent a group, with the proviso that when R1 represents an hydrogen atom R2 and R3 taken together represent a group, and to a process for their manufacture.
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Page/Page column 22-23; 13
(2009/07/17)
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- PROCESS FOR THE MANUFACTURE OF AN INDOLINONE DERIVATIVE
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The present invention relates to a process for the manufacture of a specific indolinone derivative and a pharmaceutically acceptable salt thereof, namely 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and its monoethanesulfonate, to new manufacturing steps and to new intermediates of this process.
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Page/Page column 4; 25
(2009/07/17)
-
- Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120)
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Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a newtreatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.
- Roth, Gerald J.,Heckel, Armin,Colbatzky, Florian,Handschuh, Sandra,Kley, J?rg,Lehmann-Lintz, Thorsten,Lotz, Ralf,Tontsch-Grunt, Ulrike,Walter, Rainer,Hilberg, Frank
-
experimental part
p. 4466 - 4480
(2010/03/02)
-
- Medicaments for the Treatment or Prevention of Fibrotic Diseases
-
The present invention relates to the use of indolinones of general formula substituted in the 6 position, wherein R1 to R5 and X are defined as in claim 1, the isomers and the salts thereof, particularly the physiologically acceptable salts thereof, as a medicament for the prevention or treatment of specific fibrotic diseases.
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Page/Page column 16
(2008/06/13)
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- Pharmaceutical combination for the treatment of diseases involving cell proliferation, migration or apotosis of myeloma cells, or angiogenesis
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The present invention relates to a pharmaceutical combination for the treatment of diseases which involves cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis. The combination comprises the co-administration of a protein tyrosine kinase receptor antagonist and of a steroid.
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- 3-Z-[1-(4-(N-((4-METHYL-PIPERAZIN-1-YL)-METHYLCARBONYL)-N-METHYL-AMINO)-ANILINO)-1-PHENYL-METHYLENE]-6-METHOXYCARBONYL-2-INDOLINONE-MONOETHANESULPHONATE AND THE USE THEREOF AS A PHARMACEUTICAL COMPOSITION
-
The present invention relates to the compound 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate of formula (I) and the use thereof as a pharmaceutical composition.
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