- Arab league law for nepal preparation method of the compound
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The invention provides a novel preparation method of an afatinib compound. Raw materials and reagents used in the preparation method have the advantages of low cost, stable chemical property and convenience in long-term storage and the content of an impurity cis-isomer in the prepared afatinib compound is very low.
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Paragraph 0052-0057; 0061
(2019/04/10)
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- PROCESS FOR THE PREPARATION OF N-[4-[(3-CHLORO-4-FLUORO PHENYL) AMINO]-7-[[(3s-TETRAHYDRO-3-FURANYL]OXY]-6-QUINAZOLINYL]-4-(DIMETHYL AMINO)-(2E)-2-BUTENAMIDE (2Z)-2-BUTENEDIOATE (1 :2) AND ITS POLYMORPHS THEREOF
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The present invention relates to an improved process for the preparation of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyl amino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) represented by the following structural formula:
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- An alternative synthesis of the non-small cell lung carcinoma drug afatinib
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Afatinib (BIBW2992) is the anticancer drug developed by Boehringer Ingelheim. This work is reporting the synthesis of the afatinib using a new route by Ullmann-Goldberg reaction from corresponding 4-anilinoquinazoline iodide as the last step in the synthesis. This route was not described previously and it could be used for synthesis of afatinib analogues.
- Kovacevic, Tatjana,Mesic, Milan,Avdagic, Amir,Zegarac, Miroslav
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p. 4180 - 4182
(2018/10/24)
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- Preparation method of afatinib and maleate thereof
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The invention belongs to the technical field of synthesis of compounds, and relates to a preparation method of afatinib and maleate thereof. The preparation method comprises the following steps: in the presence of a first organic solvent, adopting N-4-[(3-chloro-4-fluorophenyl)]-7-{[(3S)-tetrahydrofuran-3-group]oxo}-4,6-quinazoline diamine as a raw material to have the acylation reaction with (E)-4-dimethyl amino crotonate hydrochloride to obtain an acylation reaction solution under the effect of thionyl chloride, water and alkaline water are added into the acylation reaction solution, the water phase is extracted by virtue of butyl acetate, an organic phase is collected, after the organic phase is washed, the organic phase is directly stirred and precipitated to obtain an afatinib crude product, then the afatinib crude product is refined to obtain a competitive product, and the competitive product reacts with maleic acid to obtain maleic acid afatinib. The method has the characteristics of being high in product yield, high in purity, low in impurity content, mild in reaction conditions, simple in operation, suitable for industrialized production and the like.
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Paragraph 0020-0023; 0025-0044
(2018/09/08)
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- A arab league law for nepal and its preparation method and application
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The present invention provides afatinib, a preparation method therefor and an application thereof. The method comprises: by taking carbon tetrabromide and an organophosphorus compound as a condensation reagent, taking a dimethyl amino crotonic acid and/or dimethyl amino crotonic acid salt and N4-(3-chlorine-4-fluorine-phenyl)-7-(( S )-tetrahydrofuran-3-yloxy) quinazoline-4, 6-diamine as raw materials, performing a condensation reaction to generate the afatinib. According to the preparation method provided by the present invention, the carbon tetrabromide and the organophosphorus compound are taken as the condensation reagent, and the afatinib can be obtained by virtue of one-step condensation reaction. The process is simple, and during the process of preparing the afatinib, a selection range of the condensation reagent is expanded; and the reaction yield can be higher than 90%, and the product purity is higher than 95%.
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Paragraph 0051; 0053; 0054; 0055; 0059; 0062; 0065; 0069
(2018/11/03)
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- Medicine solvent compound for treating cancers and preparation method thereof
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The invention belongs to the technical field of medicines, and discloses a medicine solvent compound for treating cancers and a preparation method thereof. An afatinib ethanol solvent compound is characterized in that an X-ray powder diffraction pattern represented by a diffraction angle of 2theta+/-0.2 degree has feature diffraction peaks at 5.54 degrees, 10.47 degrees, 15.54 degrees, 16.37 degrees, 17.95 degrees, 19.71 degrees, 20.40 degrees, 24.13 degrees, 24.28 degrees, 26.05 degrees and 27.22 degrees. The preparation method is different from the prior art. The invention also discloses a preparation method of the afatinib ethanol solvent compound. The preparation method has the advantages that the preparation method is simple, the operation is easy, the yield and purity are high, the reaction conditions are moderate, and the preparation method is suitable for large-scale production.
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Paragraph 0042-0043
(2018/12/14)
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- Preparation method for afatinib
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The invention discloses a novel method for preparing afatinib. The method comprises the following steps: reducing N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine into N-(3-chloro-4-fluorophenyl)-7-fluoro-6-amino-4-quinazolinamine IV; then subjecting N-(3-chloro-4-fluorophenyl)-7-fluoro-6-amino-4-quinazolinamine IV and diethylphosphonoacetic acid to a condensation reaction so as to obtain a compound III; then subjecting the compound III and (dimethylamino)acetaldehyde diethyl acetal to a Wittig-Horner-Emmons reaction of so as to obtain a key intermediate II; and subjecting the key intermediate II and (S)-3-hydroxytetrahydrofuran to a substitution reaction so as to obtain a compound I. The method of the invention has high yield and high purity.
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- Compound, and preparation method and application thereof
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The invention relates to a compound, and a preparation method and application thereof. Specifically, the compound is as shown in a formula 1 which is described in the specification. The invention also provides the preparation method for the compound as shown in the formula 1. The preparation method comprises a step of contacting N-[4-[(3-chloro-4-fluorophenyl)amino]-7[[(3S)-tetrahydro-3-furyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butyleneamide with an alkaline aqueous solution in an organic solvent so as to obtain the compound as shown in the formula 1. The preparation method is simple to operate; a white powder product can be obtained through direct filtering after post-treatment; and the prepared compound has high purity, as high as 99% or above, and can be directly used as an impurity control substance for research on the quality of an afatinib bulk drug.
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- High-purity afatinib preparation method
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The invention discloses a high-purity afatinib preparation method, which comprises: (1) adding a trans-4-dimethylaminocrotonic acid hydrochloride to the mixed solvent of N-methylpyrrolidone and ethyl acetate, cooling, adding thionyl chloride to the system in a dropwise manner, and stirring until the reaction is completely performed; (2) dissolving N4-(3-chloro-4-fluoro-phenyl)-7-(S)-tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine by using N-methylpyrrolidone, adding the obtained solution to the reaction system obtained in the step (1), and stirring until the reaction is completely performed; and (3) adding purified water to the reaction system obtained in the step (2), quenching the reaction, adjusting the pH value with a sodium hydroxide solution, extracting with ethyl acetate, carrying out pressure reducing concentration, carrying out cooling crystallization, carrying out suction filtration, and drying to obtain the high-purity afatinib product. According to the present invention, the post-treatment of the preparation method is simple and convenient, the high purity product can be obtained without the additional refining, and the preparation method is suitable for industrial large-scale production.
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Paragraph 0057; 0068; 0059; 0060; 0061; 0062; 0063-0076
(2018/01/03)
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- PHARMACEUTICAL COMPOSITIONS COMPRISING AFATINIB
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The present invention relates to a tablet comprising Afatinib or a pharmaceutically acceptable salt thereof, wherein the tablet is obtained by direct compression. The present invention further relates to a process for manufacturing a tablet of the invention as well as the use of the tablet of the invention.
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Page/Page column 26
(2017/03/14)
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- High-selectivity method for preparing afatinib dimaleate
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The invention relates to a high-selectivity method for preparing afatinib dimaleate. The method comprises the following steps: (1) subjecting N4-(3-chloro-4-fluorophenyl)-7-[[(3S)- tetrahydro-3-furanyl] oxy] -4,6-quinazolinediamine as a starting raw material and diisopropylphosphoric acid to a condensation reaction; (2) subjecting the product of step 1 and 2--dimethylamino-1-sodium hydroxysulphonate to a Horner-Wadsworth-Emmons reaction; (3) subjecting the product of step 2 and maleic acid to a salt formation reaction to obtain afatinib dimaleate. The product provided by the invention has very few cis-isomer, and individual impurities are all controlled below 0.1%, the quality is good, and method is suitable for preparing finished products in large quantity and meeting the requirements of medicinal active pharmaceutical ingredients specified by ICH.
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Paragraph 0025; 0026; 0046-0048; 0058-0060; 0070-0072; 0082
(2017/07/01)
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- Synthesis method of anti-tumor medicine afatinib
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The invention discloses a synthesis method of an anti-tumor medicine afatinib and belongs to the technical field of pharmaceutical chemistry. The method takes 2-nitryl-5-bromophenol as a raw material and obtains the afatinib through a five-step chemical reaction. The raw material of a synthesis route is easy to obtain, a process route is shortened, the operation is simple and the yield of products is high; and industrial production is easy to realize.
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- POLYMORPHIC FORMS OF AFATINIB FREE BASE AND AFATINIB DIMALEATE
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The present invention relates to crystalline forms of Afatinib and its dimaleate salt. The present invention also relates to processes for the preparation of crystalline forms of Afatinib and its dimaleate salt. The present invention further relates to pharmaceutical compositions of such crystalline forms of Afatinib dimaleate and use thereof in the treatment of a patient in need thereof.
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Page/Page column 33; 36; 37
(2016/12/26)
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- Preparing method of Afatinib
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The invention relates to a preparing method of Afatinib. The preparing method includes the steps that 6-nitro-7-fluoro-3,4-dihydro quinazoline-4-ketone is used as a raw material and is subjected to etherification reaction with S-3-hydroxy-tetrahydrofuran; obtained 6-nitro-7-[S-(tetrahydrofuran-3-yl)oxyl]-3,4-dihydro quinazoline-4-ketone is subjected to chlorination reaction; obtained 4-chloro-6-nitro-7-[S-(tetrahydrofuran-3-yl)oxyl] quinazoline is subjected to condensation reaction; obtained 4-[(3-chloro-4-fluoro-phenyl)amino]-6-nitro-7-[S-(tetrahydrofuran-3-yl)oxyl] quinazoline is subjected to reduction reaction; E-4-dimethyl amido crotonic acid is subjected to chloroformylation reaction, and E-4-dimethyl amido crotonyl chloride and 4-[(3-chloro-4-fluoro-phenyl)amino]-6-amino-7-[S-(tetrahydrofuran-3-yl)oxyl] quinazoline are subjected to amidation reaction to obtain the finished product.
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- Preparation method for afatinib
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The invention provides a preparation method for afatinib. The preparation method comprises the following steps: subjecting trans-4-dimethylaminocrotonic acid hydrochloride (III) to chlorination so as to obtain trans-4-dimethylaminocrotonyl chloride hydrochloride (IV); and reacting the compound (IV) with N4-(3-chloro-4-fluoro-phenyl)-7-((S)-tetrahydrofuran-3-yl-oxy)quinazoline-4,6-diamine (V) so as to prepare afatinib (VI). Reaction equations are described in the specification.
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Paragraph 0035; 0038
(2016/10/08)
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- POLYMORPHS AND PROCESS FOR THE PREPARATION OF QUINAZOLINYL DERIVATIVES
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The present invention relates to Quinazolinyl derivatives polymorph, process and composition thereof. (I)
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Page/Page column 16
(2016/10/31)
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- PROCESS FOR THE MANUFACTURE OF (E)-4-N,N-DIALKYLAMINO CROTONIC ACID IN HX SALT FORM AND USE THEREOF FOR SYNTHESIS OF EGFR TYROSINE KINASE INHIBITORS
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The present invention is directed to an efficient process for the manufacture of (E)-4-N,N- dialkylamino crotonic acid in HX salt form of formula I, wherein R1 and R2 independently denote C1-3-alkyl groups and Xˉ denotes an acid anion, such as the chloride, bromide, tosylate, mesylate or trifluoroacetate anion, with high quality, and a process for synthesis of EGFR tyrosine kinase inhibitors with heterocyclic quinazoline, quinoline or pyrimidopyrimidine core structure, using the acid addition salt I and activated derivatives thereof as intermediates.
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Page/Page column 18; 19
(2015/07/16)
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- PROCESS FOR THE MANUFACTURE OF (E)-4-N,N-DIALKYLAMINO CROTONIC ACID IN HX SALT FORM AND USE THEREOF FOR SYNTHESIS OF EGFR TYROSINE KINASE INHIBITORS
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The present invention is directed to an efficient process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form of formula I wherein R1 and R2 independently denote C1-3-alkyl groups and X? denotes an acid anion, such as the chloride, bromide, tosylate, mesylate or trifluoroacetate anion, with high quality, and a process for synthesis of EGFR tyrosine kinase inhibitors with heterocyclic quinazoline, quinoline or pyrimidopyrimidine core structure, using the acid addition salt I and activated derivatives thereof as intermediates.
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Paragraph 0045
(2015/07/15)
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- CRYSTALLINE FORMS OF AFATINIB DI-MALEATE
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Crystalline forms of Afatinib di-maleate are described in the present application and processes for their preparation. The present invention also includes pharmaceutical compositions of such crystalline forms of Afatinib di-maleate, methods of their preparation and the use thereof hi the treatment of a patient in need thereof. The present invention also describes preparing Afatinib free base and salts of Afatinib, other than Afatibin di-maleate, and solid forms thereof.
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Page/Page column 13
(2013/04/24)
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- NOVEL SALTS AND POLYMORPHIC FORMS OF AFATINIB
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Afatinib salts and crystalline forms thereof are described in the present application and processes for their preparation. Crystalline forms of Afatinib are also described in the present application and processes for their preparation. The present invention also includes pharmaceutical compositions of such Afatinib salts and crystalline forms thereof or crystalline forms of Afatinib, methods of their preparation and the use thereof in the treatment of a patient in need thereof.
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Page/Page column 49-50
(2012/09/22)
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- PROCESS FOR PREPARING AMINOCROTONYLAMINO-SUBSTITUTED QUINAZOLINE DERIVATIVES
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The invention relates to an improved process for preparing aminocrotonylamino-substituted quinazoline derivatives of general formula (I) wherein the groups Ra, Rb, Rc and Rd have the meanings given in the claims, as well as sulphonyl derivatives of formula (XIII) and the use thereof as synthesis components for preparing quinazolines of formula (I). The quinazoline derivatives of formula (I) are inhibitors of signal transduction mediated by tyrosinekinases and by the Epidermal Growth Factor-Receptor (EGF-R) and are therefore particularly suitable for the treatment of tumoral diseases.
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Page/Page column 23
(2008/06/13)
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- Pharmaceutical compositions based on anticholinergics and additional active ingredients
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A pharmaceutical composition comprising an anticholinergic and at least one additional active ingredient selected from among corticosteroids, dopamine agonistes, PDE-IV inhibitors, NK1-antagonists, endothelin antagonists, antihistamines, and EGFR-kinase inhibitors, processes for preparing them and their use in the treatment of respiratory diseases.
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- Process for preparing amino crotonyl compounds
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The invention relates to an improved process for preparing 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylam ino)-1 -oxo-2-buten-1 -yl]am ino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline and related aminocrotonyl compounds and the preparation of a suitable salt of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 -yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline for use as a pharmaceutically active substance.
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Page/Page column 6
(2010/02/11)
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- Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
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A method of treating inflammatory diseases of the airways or intestines which comprises administering substances selected from the group consisting of: (a) quinazolines of general formula wherein A, B, C, D, X, Ra, Rb, Rc and n are as defined herein, (b) the compounds (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-dimethylamino-cyclohexyl)amino]-pyrimido[5,4-d]pyrimidine, (2) 4-[(R)-(1-phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, and (3) 4-{[3-chloro-4-(3-fluoro-4-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline or (d) the antibodies Cetuximab C225, Trastuzumab, ABX-EGF and Mab ICR-62, and (f) EGFR-antisense.
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- Use of inhibitors of the EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH)/prostatic hypertrophy
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The present invention relates to the use of specific EGF-receptor antagonists for preparing a pharmaceutical composition for the prevention and/or treatment of benign prostatic hyperplasia and/or prostatic hypertrophy, a method for the treatment or prevention of benign prostatic hyperplasia/prostatic hypertrophy comprising administering an EGF-receptor antagonist of groups (A), (B) or (C), described herein optionally in combination with known compounds for the treatment of benign prostatic hyperplasia/prostatic hypertrophy, as well as associated pharmaceutical compositions.
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- Quinazoline derivatives and phamaceutical compositions containing them
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A compound of general formula I wherein: Ra is a benzyl, 1-phenylethyl, or 3-chloro-4-fluorophenyl group; Rb is a dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino, bis(2-methoxyethyl)amino, morpholino, N-methyl-N-(tetrahydrofuran-3-yl)amino, N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino, N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino, N-methyl-N-(tetrahydropyran-4-yl)amino, or N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group; and Rc is a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy, or tetrahydropyran-4-ylmethoxy group, or a tautomer, stereoisomer, or salt thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases, their use in the treatment of diseases, especially tumoral diseases and diseases of the lungs and airways, and the preparation thereof.
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